Efficacy of pramipexole, a novel dopamine agonist, as monotherapy in mild to moderate Parkinson's disease

Parkinson's disease (PD) is the second most common adult-onset neurodegenerative disease. Most motoric symptoms of PD result from progressive loss of pigmented dopaminergic neurons in the substantia nigra pars compacta and attendant dopamine deficiency in its major projection sites, the caudate nucleus and putamen (striatum). The mainstay of therapy of early PD has been oral L-dihydroxyphenylalanine (levodopa) administered with dopa-decarboxylase inhibitors. The rationale for early use of monotherapy with direct-acting dopamine agonists in PD is based predominantly in the experimental laboratory. Relief of symptoms of experimental parkinsonism in primates can be accomplished by activation of a specific subfamily of dopamine receptors, the D2 subfamily, which comprises three structurally similar receptor types, D₂, D₃, and D₄.^1,2 Within the D2 subfamily, both D₂ and D₃ receptors appear to be suitable targets.^2,3 Although PD patients have been successfully maintained of monotherapy with the ergot-derived dopamine agonists bromocriptine or pergolide for up to 3 years,^4,5 clinical experience with dopamine agonist monotherapy has overall been discouraging. It is generally accepted that the clinical efficacy of dopamine agonists pales in comparison with levodopa, that supplemental levodopa is often needed within the first several months of therapy, and that adverse events related to the ergot structure of available agonists interfere with achievement of maximal benefit.^4-7 Indeed, no currently available direct-acting dopamine agonist has been systematically studied or is approved for use as monotherapy in PD.

Pramipexole is a synthetic benzothiazole derivative that binds with high affinity to both native and expressed dopamine D2 family receptors, particularly the dopamine D₃ receptor.^3,8 In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated primates, pramipexole reverses parkinsonian signs in a dose-dependent fashion.³ Pramipexole possesses full agonist efficacy compared with bromocriptine and pergolide, which are partial agonists.^9,10 It has no significant interactions with other peripheral or central adrenergic or serotonergic receptor families(Piercey, unpublished data, 1995). It is orally active and approximately 90% bioavailable. An earlier double-blind placebo-controlled study of pramipexole in 55 PD patients demonstrated significant decrease in the Unified Parkinson's Disease Rating Scale (UP-DRS) activities of daily living (ADL) subscore and a trend toward improvement in the UPDRS motor subscore over 9 weeks.¹¹ The dose of 4.5 mg/d was well tolerated in that study. We conducted the present study to assess the efficacy and tolerability of pramipexole in patients with mild to moderate PD who were not receiving levodopa.

Methods. The study design was an 18-center, randomized, double-blind, placebo-controlled, parallel-group study. We recruited patients over the age of 25 years with idiopathic PD in Hoehn and Yahr (HY) stages I(unilateral symptoms) to III (bilateral symptoms with impairment of balance)¹² who were not taking levodopa. Up to 180 days of prior levodopa exposure were allowed, although patients had to be levodopa-free for 60 days prior to study entry. Prior or current treatment with direct-acting dopamine agonists was a reason for exclusion. Other restricted medications included dopamine receptor antagonists, catecholamine depleters, amantadine (within 21 days of study entry), amphetamine derivatives, and alphamethyldopa. Selegiline use was allowed so long as the dose had been stable for 30 days and did not exceed 10 mg/d. Randomization to treatment groups was stratified by selegiline use within each study center. Patients were excluded if they had signs suggestive of atypical or secondary parkinsonism, dementia, psychosis, recent surgery or electroconvulsive therapy, supine systolic blood pressure less than 100 mm Hg, a greater than 20-mm Hg orthostatic drop in systolic blood pressure, or any significant or unstable medical illness.

All subjects were required to give informed consent by signing a consent form, the content of which was approved by each investigator's Institutional Review Board. Patients were randomly assigned to treatment with the active drug or an identical-appearing placebo. The dose was titrated over a period up to 7 weeks from 0.375 mg to a maximum of 4.5 mg daily in three divided doses. Patients entered the maintenance phase of the study once they achieved a dose of 4.5 mg daily or once dose-limiting toxicity developed, or the investigator determined there had been no further response to two successive dose increases. During the 6-month maintenance phase, they remained on the maximum dose of pramipexole or placebo achieved during the ascending-dose phase. At the end of the maintenance interval, the patients entered a 1-week dose-reduction phase.

Patients were evaluated weekly during the ascending-dose interval, biweekly during the first 3 months of maintenance, and monthly during the last 3 months of maintenance. Parkinsonism was measured using the UPDRS, a scale comprising ordinal ratings of interview-based assessments of impairments of ADL (ADL subscale, part II) and ratings of motor performance(motor subscale, part III). Each item in the UPDRS parts II and III is scored from 0 (normal or absent) to 4 (maximally severe).¹³ The HY stage was also rated.¹²

Serum chemistries, hematologic studies, urinalysis, and an ECG were obtained at regular intervals throughout the study. Orthostatic changes in blood pressure and pulse were measured 2 hours after administration of the first dose at each level of dose titration and throughout the maintenance interval. A 20-mm Hg change in systolic blood pressure was considered significant.

Statistical methods. The population used for the efficacy analysis was the intent-to-treat (ITT) population, which included all randomized patients who had received at least one dose of study medication and had at least one post-baseline follow-up evaluation. Missing data or data after dropout were estimated using the last observation carried forward(LOCF) method. This method uses the last valid assessment as an estimate for all subsequent missing values.

The primary outcome variables of the study were changes in UPDRS parts II(ADL) and III (motor) scores between baseline and the end of the maintenance period. To compare the two treatment groups, a two-way analysis of variance(ANOVA) was conducted on the change from baseline of UPDRS part II total score and UPDRS part III total score. "Change from baseline" was defined as the follow-up score minus the baseline score. Secondary outcome variables included changes from baseline in the individual components of the UPDRS, HY stage, and number of days until failure (defined as unsatisfactory benefit or progression of disease to a point requiring additional therapy, such as levodopa). Power calculations suggested a sample size of 150 subjects in each treatment arm would be required to demonstrate a mean difference of 1.8 to 3.6 units in the UPDRS scales between treatment groups with 90% probability at the 0.05 level of significance.

Results. Three hundred thirty-five patients entered the trial(203 men and 132 women). Their mean age was 62.7 years, and mean duration of disease was 1.8 years. About two-thirds in each group were taking selegiline. There were no significant differences at baseline between the pramipexole and placebo arms of the trial with respect to age, gender, or ethnic background; disease duration; selegiline use; or symptom severity as assessed by the UPDRS and HY scale. One hundred sixty-four patients were randomized to the pramipexole group and 171 to the placebo group, of whom 163 pramipexole- and 170 placebo-treated patients received at least one dose of study medication and had at least one follow-up efficacy assessment. These were considered in the ITT analysis. Eighty percent of placebo- and 83% of pramipexole-treated patients completed the study (table 1). Seventy-four percent who completed the study reached the target dose of 4.5 mg daily. The mean daily maintenance dose for patients who entered the maintenance interval was 3.8 mg.

With respect to the primary efficacy measure, at the end of the maintenance interval, the UPDRS ADL and motor subscales had decreased significantly compared with baseline in the pramipexole group (mean ADL at baseline 8.2 versus end maintenance 6.4; mean motor at baseline 18.8 versus end maintenance 14.1) and were at about the baseline level in the placebo group (mean ADL at baseline 8.3 versus end maintenance 8.7; mean motor at baseline 18.8 versus end maintenance 20.1) (p < 0.0001). Benefit was significant at all other maintenance visits as well(p ≤ 0.0001, figures 1 and 2). Throughout the maintenance period, the magnitude of benefit ranged from 22 to 29% for ADL and 25 to 31% for motor scores. There was no evidence of the development of tolerance over the treatment period. Improvements in UPDRS ADL and motor scores appeared to be global. Analysis of individual items of the UPDRS showed no preferential effects on any specific aspect of the PD symptom complex. Analysis of patient subgroups including co-treatment with selegiline showed no differences in medication benefit related to baseline variables.

• Download figure
• Open in new tab
• Download powerpoint

Figure 1. Mean ADL subscore of the UPDRS scale at each visit in the ascending-dose (A1-A7) and maintenance phase (M0-M24). Compared with placebo, there is a significant decrease in the ADL score at each visit (p < 0.001) beginning with week 3 of the ascending-dose interval.

• Download figure
• Open in new tab
• Download powerpoint

Figure 2. Mean motor UPDRS subscore at each visit in the ascending-dose (A1-A7) and maintenance phase (M0-M24). Compared with placebo, there is a significant decrease in the motor UPDRS score at each visit (p < 0.001) beginning with week 3 (A3) of the ascending-dose phase.

During the course of the study, potential adverse events were reported in 95% of pramipexole-treated and 91% of placebo-treated patients. Of all reported adverse events, only nausea, insomnia, constipation, somnolence, and visual hallucinations occurred significantly more frequently in the pramipexole-treated patients compared with placebo patients(table 2). Visual and auditory hallucinations were seen in about 10% and 2%, respectively, of pramipexole-treated patients compared with 2% and 0%, respectively, of placebo-treated patients. Forty percent of patients who hallucinated on pramipexole had to discontinue the study drug; hallucinations resolved in the remaining patients with dose reduction. Sedation or fatigue occurred in 18.3% and 14.6%, respectively, of pramipexole-treated patients compared with 8.8% and 8.8%, respectively, of placebo-treated patients. Adverse events led to discontinuation of the study medication in 18 pramipexole- and 8 placebo-treated patients. Specific adverse events leading to discontinuation of the study medication are listed in table 3. Most pramipexole-treated patients had multiple reasons for discontinuation, the most common of which were gastrointestinal complaints (10 patients), hallucinations (7 patients), and sleepiness or fatigue (5 patients). Orthostatic hypotension was seen in 10% of pramipexole- and 6% of placebo-treated subjects, but was most often asymptomatic. The occurrence of symptomatic orthostatic hypotension did not differ between the two groups. Overall, pramipexole was not associated with significant changes in blood pressure, pulse, ECG, or any hematologic or serum chemistry test.

Discussion. This study demonstrates that pramipexole, a synthetic D₃-preferring D2 dopamine agonist, has potent antiparkinsonian effects in patients with mild to moderate PD who are not receiving levodopa therapy. Significant improvements in the primary efficacy measures were apparent throughout the 24-week maintenance period. The drug was generally well tolerated. Only nausea, insomnia, constipation, somnolence, and visual hallucinations occurred significantly more often in the pramipexole-treated group. Hallucinations occurred in approximately 10% of pramipexole-treated patients, but often resolved with reduction in drug dose. Sedation was seen in about 20% of patients. Symptomatic orthostatic hypotension, a troublesome side effect of dopamine agonists, was notably absent.

The primary goal of early dopamine agonist monotherapy in PD is adequate control of parkinsonian symptoms without intolerable adverse effects. The extent to which this can be accomplished is likely to be determined at least in part by the drug's affinities for dopamine and other neurotransmitter receptors. D₂-receptor agonism is associated with antiparkinsonian benefit in animal models of PD as well as in human studies.^2,14 Both bromocriptine and pergolide are believed to exert their major therapeutic effects at the D₂ receptor and effectively ameliorate parkinsonian symptoms in 20 to 83% of patients treated.^5,6,9,15-23 D₃-receptor agonism has been shown effective in animal models of parkinsonism³ and early human studies (unpublished data, Elvin 1994, Tregunno 1995, Peters 1995, Denahan 1995, Lesko 1995). Pergolide has some selectivity for the D₃ receptor, which may contribute to its overall usefulness. Pramipexole has marked selectivity for the D₃ receptor, and the present study confirms the utility of selective D₃ agonism in the treatment of PD. The role of D₁ agonism is less well understood. Although early animal studies of selective D₁ agonists suggested no antiparkinsonian efficacy, more recently developed selective D₁ agonists have shown some promise in animal models of PD, particularly in combination with D₂ agonist therapy.²⁴ D₁-receptor agonism has been associated with the development of dyskinesias in the MPTP-treated primate.^14,25 Although pergolide acts at both the D₁ and D₂ receptor, there is as yet no compelling evidence that D₁ agonism contributes to its short- or long-term efficacy. The lack of significant D₁. activity does not appear to detract from the efficacy of pramipexole. The tolerability of pramipexole compares favorably with available dopamine agonists. Hallucinations occurred in about 10% of patients compared with up to 10% in pergolide-treated⁷ and 20% in bromocriptine-treated²⁶ de novo patients. Orthostatic hypotension, reported to complicate therapy in 16% of bromocriptine-treated⁷ and 25% of pergolide-treated²⁶ patients, occurred in only 10% of pramipexole-treated patients, a number that did not differ significantly from the control group.

We did not directly compare pramipexole monotherapy with levodopa monotherapy or with other available dopamine agonists, although such studies would be useful in defining the roles of each of these agents in the treatment of PD. Nevertheless, we conclude that the D₃ receptor is an appropriate target for dopamine agonist therapy and that pramipexole appears to have a clear role in the treatment of early PD.

Acknowledgment

This study was supported by Pharmacia & Upjohn, Inc., Kalamazoo, MI.

Appendix