Juergen Koester

Efficacy of pramipexole in restless legs syndrome: A six‐week, multicenter, randomized, double‐blind study (effect‐RLS study)

We evaluated the efficacy of pramipexole versus placebo in restless legs syndrome (RLS) for 6 weeks. Overall, 345 patients were randomly assigned in a 1:2 ratio to receive either placebo (n = 115) or pramipexole (n = 230) with a starting dose of 0.125 mg/day. The dose was individually optimized according to the Patient Global Impression (PGI) assessment, up to a maximum of 0.75 mg/day. The primary endpoint consisted of two assessments: the change from baseline in the International RLS Study Group Rating Scale (IRLS) and the proportion of patients with Clinical Global Impressions‐Improvement (CGI‐I) assessments of “much/very much improved” (CGI‐I responders) at week 6. Secondary endpoints included PGI and IRLS responder rates. Patient demographics and baseline characteristics were comparable between treatment groups. At baseline, mean IRLS scores were 24.9 (placebo) and 24.7 (pramipexole), representing severely affected patients. After 6 weeks, adjusted mean reductions (±SE) in IRLS score were 5.7 (±0.9) for placebo (median dose 0.47 mg/day) and 12.3 (±0.6) for pramipexole (median dose 0.35 mg/day; P < 0.0001). CGI‐I responder rates were 32.5% (placebo) and 62.9% (pramipexole) (P < 0.0001). For all secondary endpoints, pramipexole showed superior results. Pramipexole was well tolerated throughout the study.

Effects of the dopamine agonist pramipexole on depression, anhedonia and motor functioning in Parkinson's disease

Depression affects approximately 45% of all patients with Parkinsons disease, reduces quality of live independent of motor symptoms and seems to be underrated and undertreated. Pramipexole shows D(3)- versus D(2)-receptor preference at cortico-frontal dopamine receptors and neurotrophic effects which seem to relate to its antidepressant and anti-anhedonic properties in Parkinsons disease and bipolar depression found in controlled studies. In the present study, effects of pramipexole were investigated under routine clinical conditions. Anhedonia was measured in patients with Parkinsons disease (n=657) using the self-rated Snaith-Hamilton-Pleasure-Scale (SHAPS-D), depression was assessed by the observer-rated Short-Parkinsons-Evaluation Scale (SPES). Anhedonia was present in 45.7% of all patients and in 79.7% of the depressed patients with Parkinsons disease. Mild depression was present in 47%, moderate to severe depression in 22% of the patients. At the end of the study period of 9 weeks on an average, the mean dosage of pramipexole was 1.0+/-0.6 mg/d (range 0.3 to 4.2). Frequency of depression (moderate to severe: 6.8%, mild: 37.6%) and anhedonia (25.5%) as well as motor deficits were significantly reduced during treatment with pramipexole. Drop-outs due to adverse events occurred in 3.5%. Future studies should investigate specificity of anti-anhedonic and antidepressive properties of pramipexole.

Controlled withdrawal of pramipexole after 6 months of open-label treatment in patients with restless legs syndrome.

Although dopamine agonists are becoming first‐line therapy for restless legs syndrome (RLS), few reports describe treatment periods exceeding 12 weeks. Here, 150 RLS patients who had responded to pramipexole during a 6‐month run‐in period (mean dose, 0.50 mg) were randomly assigned to receive placebo or continue receiving pramipexole at an individually optimized dose of 0.125 to 0.75 mg/day for a further 3 months. Patients switched to placebo reached the primary endpoint (a predefined worsening on both the Clinical Global Impressions‐Global Improvement scale and the International RLS Study Group Rating Scale) significantly more often than patients who continued to receive pramipexole (85.5% vs. 20.5%; P < 0.0001). They also reached the primary endpoint faster, in 5 versus 42 days to a Kaplan–Meier survival estimate of 0.85 and 7 versus > 84 days to an estimate of 0.5. Over the total 9 months, clinician and patient ratings of symptoms, sleep, and quality of life identified no decline in pramipexoles benefit or tolerability. The great majority of adverse events (AEs) were mild or moderate, and of expected types. Augmentation was considered an AE, but in this population of responders it did not occur.

Randomized trial of pramipexole for patients with restless legs syndrome (RLS) and RLS-related impairment of mood

OBJECTIVES Patients with restless legs syndrome (RLS) have an elevated prevalence of mood disorders compared with the general population. We investigated the change of RLS-related mood impairment during treatment of RLS with pramipexole, a dopamine D(3)/D(2) agonist. METHODS Adults with moderate to very severe RLS were enrolled in a 12-week, double-blind, placebo-controlled Phase IV pramipexole trial. A moderate to very severe RLS-related mood disturbance at baseline (score ≥2 on Item 10 of the International RLS Study Group Rating Scale [IRLS]) was also required. Pramipexole (0.125 to 0.75 mg once daily) was flexibly titrated over the first 4 weeks. RESULTS The intent-to-treat population comprised 199 patients on placebo and 203 on pramipexole. At week 12, adjusted mean total-score changes on IRLS were -14.2±0.7 for pramipexole and -8.1±0.7 for placebo (p<0.0001), and on the Beck Depression Inventory version II, -7.3±0.4 for pramipexole and -5.8±0.5 for placebo (p=0.0199). For IRLS item 10, the 12-week responder rate (reduction to no or mild mood disturbance) was 75.9% for pramipexole and 57.3% for placebo (p<0.0001). Study withdrawal rates were higher for placebo (20.5%) than for pramipexole (12.8%). CONCLUSIONS In patients with RLS-related mood disturbance, pramipexole improved RLS while also improving RLS-related mood impairment. Tolerability of pramipexole was similar to that in previous studies.