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Study Shows Positive Results for Pramipexole in Parkinson's Disease Patients With Depressive Symptoms

RIDGEFIELD, CT -- August 23, 2006 -- Results from a small scale, open-label, multicenter, randomized, active-controlled study demonstrated that Mirapex® (pramipexole dihydrochloride) tablets, a dopamine agonist indicated for the treatment of Parkinson's disease (PD), provided similar improvement of depressive symptoms in Parkinson's disease patients as sertraline, an established antidepressant.

This prospective study, published in the Journal of Neurology, found pramipexole to have an antidepressant effect in PD patients who had major depression and no history of motor complications and/or dyskinesia and taking stable levodopa treatment.

The study, which did not include a placebo arm, found that after 12 weeks of treatment, patients in both the Mirapex- and sertraline-treated groups achieved a significant improvement in symptoms of depression as rated by the Hamilton Depression Rating Scale (HAMD), a widely used and accepted outcome measure for evaluating depression severity and a primary endpoint for this study.

The primary outcome of the study found a statistically significant higher percentage of Mirapex-treated patients recovered (as defined by a total HAMD score ≤ 8 at endpoint) compared with those patients taking sertraline (60.6% v. 27.3%, p=0.006). Additionally, 69.7% of patients on Mirapex responded to therapy (as defined by at least a 50% reduction in HAMD total score) compared with 48.5% of patients who responded to sertraline therapy.

The Unified Parkinson's Disease Rating Scale Parts II and III was used as a secondary endpoint for activities of daily living and motor function. Only the pramipexole group experienced statistically significant changes in UPDRS scores, by a mean of 2.8 plus/minus 3.5. Because the antidepressant used in this study had no impact on motor symptoms, further studies would be required in order to differentiate between the antiparkinsonian and antidepressant effects of these medications.

Up to 50% of people with PD are estimated to experience some form of depression, yet, depression is often overlooked and under-treated, in part because many symptoms of depression overlap with the motor symptoms of PD, including lack of facial expression (hypomimia), slow, monotonic speech, and lack of energy. In PD, these symptoms can be caused by motor dysfunction and may be present whether or not the person is depressed. A growing body of evidence linking depression with worsening of the condition and increased mortality underscores the need for vigilance in recognizing and addressing depression in PD patients.

"In this study, Mirapex-treated patients experienced improved mood and fewer symptoms of depression, in addition to relief of their Parkinson's disease symptoms," said Paolo Barone, MD, PhD, University of Naples in Italy, and lead investigator of the study. "We found the results to be encouraging evidence that will likely lead to additional studies of this nature."

In addition to providing symptom improvement, Mirapex proved to be safe and well-tolerated in this study. Fewer patients taking Mirapex (9.1%) reported at least one adverse event compared with those on sertraline (24.2%). Five patients being treated with sertraline withdrew from the study due to adverse events, while no Mirapex-treated patients withdrew from the study. All reported events were characterized as mild or moderate, and mainly gastrointestinal in nature. Neither treatment produced clinically significant abnormalities in any vital signs or laboratory tests.

Study Design
In this open-label, multicenter, randomized, prospective trial, 67 patients with Parkinson's disease and no history of motor fluctuations and/or dyskinesia received either Mirapex (n=33) or sertraline (n=34) for a total of 12 weeks. The primary outcome measure was change in the HAMD total score, expressed as the difference between baseline and final visit scores. Secondary measures were changes from baseline to endpoint in the Unified Parkinson's Disease Rating Scale sub-scores for daily living and motor function (UPDRS Parts II and III), the Zung self-rating depression scale total score, the Short-Form health survey (SF-36) total score, and HAMD individual item scores.

All patients had a baseline HAMD total score of >/= 16 on the 17-item scale, indicating the presence of significant depression symptoms. During the two-week screening phase of the study, patients were discontinued on all antiparkinsonian treatments (i.e., anticholinergic agents, MAO-B or COMT inhibitors, amantadine) other than levodopa, which was continued at an equal or increased dosage at the judgment of the investigators.

Following the two-week screening phase, patients randomized to the Mirapex treatment group received seven weeks of flexible dose titration followed by a five-week maintenance period with a stable dose. During the first three weeks of titration, daily doses were started at 0.375 mg and were escalated to 1.5 mg/day. Throughout the next four weeks the dose was kept flexible with the bounds of 1.5 to 4.5 mg/day, as determined by the investigator so as to optimize each patient's clinical status. During the five-week maintenance period the dosage was kept fixed through the end of the 12-week study. Patients in the sertraline treatment group received once-daily doses of 25 mg during the first week and 50 mg from week two through to the end of the 12-week study.

About Parkinson's Disease
Parkinson's disease affects approximately one% of people over age 60, causing tremor, muscle rigidity, slowed motion, shuffling gait and a loss of facial expression. Approximately 15% of patients develop PD before the age of 50. These symptoms vary from patient to patient, but become more severe over time. PD is the second most common chronic neurological disorder in older adults after Alzheimer's.

About Pramipexole
Pramipexole, a compound from Boehringer Ingelheim research, is approved for the treatment of the signs and symptoms of idiopathic Parkinson's disease.

Pramipexole may cause patients to fall asleep without any warning, even while doing normal daily activities such as driving.

When taking pramipexole hallucinations may occur and sometimes patients may feel dizzy, sweaty or nauseated upon standing up. The most commonly reported adverse events in early and late Parkinson's disease in clinical trials were dizziness, involuntary movement, hallucinations, headache, difficulty falling asleep, sleepiness, and nausea. Patients and caregivers should be informed that impulse control disorders/compulsive behaviors may occur while taking medicines, including pramipexole, to treat Parkinson's disease.


SOURCE: Boehringer Ingelheim Pharmaceuticals, Inc.

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