The aim of this article is to test the feasibility, in early Parkinson's disease (PD), of an overnight switch from immediate-release (IR) pramipexole to a new once-daily extended-release (ER) formulation. Nonfluctuating patients on pramipexole IR three-times daily, alone or with levodopa, for early PD were randomly switched overnight to double-blind IR three-times daily (N = 52) or ER once-daily (N = 104) at initially unchanged daily dosage. Successful switching (defined as no worsening >15% of baseline UPDRS II+III score and no drug-related adverse event withdrawal) was assessed at 9 weeks, after optional dosage adjustments (primary endpoint), and at 4 weeks, before adjustment. Other secondary endpoints included adjusted mean changes from baseline in UPDRS scores and proportion of responders based on Clinical or Patient Global Impression (CGI/PGI). Absolute difference between percentage of successful switch to ER versus IR was tested for ER noninferiority, defined as a 95% confidence-interval lower bound not exceeding -15%. At 9 weeks, 84.5% of the ER group had been successfully switched, versus 94.2% for IR. Noninferiority was not demonstrated, with a difference of -9.76% (95% CI: [-18.81%, +1.66%]). At 4 weeks, 81.6% of the ER group had been successfully switched, versus 92.3% for IR, a difference of -10.75% (95% CI: [-20.51%, +1.48%]). UPDRS changes and CGI/PGI analyses showed no differences between the groups. Both formulations were safe and well tolerated. Pramipexole ER was not equivalent to IR, but the difference was marginal. The fact that >80% of the patients successfully switched overnight at unchanged dosage shows that this practice was feasible in most patients.
Background. The minimal clinically important difference (MCID) is the smallest change in an outcome measure that is meaningful for patients. Objectives. To calculate the MCID for Unified Parkinson's Disease Rating Scale (UPDRS) scores in early Parkinson's disease (EPD) and for UPDRS scores and “OFF” time in advanced Parkinson's disease (APD). Methods. We analyzed data from two pivotal, double-blind, parallel-group trials of pramipexole ER that included pramipexole immediate release (IR) as an active comparator. We calculated MCID as the mean change in subjects who received active treatment and rated themselves “a little better” on patient global impression of improvement (PGI-I) minus the mean change in subjects who received placebo and rated themselves unchanged. Results. MCIDs in EPD (pramipexole ER, pramipexole IR) for UPDRS II were −1.8 and −2.0, for UPDRS III −6.2 and −6.1, and for UPDRS II + III −8.0 and −8.1. MCIDs in APD for UPDRS II were −1.8 and −2.3, for UPDRS III −5.2 and −6.5, and for UPDRS II + III −7.1 and −8.8. MCID for “OFF” time (pramipexole ER, pramipexole IR) was −1.0 and −1.3 hours. Conclusions. A range of MCIDs is emerging in the PD literature that provides the basis for power calculations and interpretation of clinical trials.
Depression is generally diagnosed through the core mood symptoms and a variety of associated emotional and physical symptoms that are persistent during a 2-week period. In primary care, the diagnosis of depression is complicated due to the combination of core mood symptoms and associated symptoms such as painful physical symptoms. 1,3-5 Among primary care patients, 65% of patients with MDD were shown to have some type of painful physical symptoms. 6,7 A greater severity of painful physical symptoms, including back pain, gastrointestinal pain, and headache, is associated with increased severity of depression and reduces quality of life. 8 The presence of painful physical symptoms in patients with depression impairs treatment outcome, 6,7 decreases remission rates, 9 and creates loss of productivity and quality of life. 3,4,10 Patients with residual symptoms, including painful symptoms, are more likely to relapse. 11 Pain in depression receives inadequate attention for treatment due to poor diagnosis. 12 Treatment of depression ideally should include both core mood symptoms and associated symp-
Background and purposeTo assess the long-term safety and efficacy of pramipexole as a once-daily (q.d.) extended-release oral formulation in early or advanced Parkinson's disease (PD).MethodsIn two double-blind (DB) studies of early PD and one of advanced PD, active-treatment arms received pramipexole immediate release (IR) or extended release (ER), with exposure lasting up to 33 weeks. In open-label (OL) extensions that followed immediately, subjects took ER q.d. for up to 80 weeks, with dosage adjustment permitted (range 0.375–4.5 mg q.d.).ResultsOf 590 subjects completing an early-PD DB study, 511 entered the early-PD OL extension; 408 completed it. Reported adverse events (AEs) with incidence ≥10.0% were somnolence (15.1%), peripheral edema (11.7%) and back pain (10.6%). Of 465 subjects completing the advanced-PD DB study, 391 entered the advanced-PD OL extension; 329 completed it. Reported AEs with incidence ≥10.0% were dyskinesia (27.4%) and somnolence (13.6%). Impulse control disorders were identified by semi-structured interview in 13 subjects (1.4% of 902). In exploratory analyses, adjusted mean Unified Parkinson's Disease Rating Scale (UPDRS) Parts II + III scores (excluding ex-placebo recipients) remained substantially improved from DB baseline scores prior to pramipexole introduction, at −6.6 and −6.3 points amongst ex-DB-ER and ex-DB-IR recipients after 113 weeks of pramipexole (33 DB plus 80 OL) in early PD, and −11.5 and −9.1 after up to 113 weeks (up to 33 DB plus 80 OL) in advanced PD.ConclusionsThese results support the long-term safety and efficacy of pramipexole ER in early and advanced PD. AEs were typical for dopaminergic medications, and UPDRS scores suggested sustained symptomatic benefit.
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