Laurence Salin

Randomized, Double-Blind, Multicenter Evaluation of Pramipexole Extended Release Once Daily in Early Parkinson's Disease

The objective of this study was to evaluate the efficacy and safety of pramipexole extended release (ER) administered once daily in early Parkinsons disease (PD). Pramipexole immediate release (IR) administered three times daily (TID) is an efficacious and generally well‐tolerated treatment for PD. A pramipexole ER formulation is now available. We performed a randomized, double‐blind, placebo and active comparator–controlled trial in subjects with early PD. The primary efficacy and safety evaluation of pramipexole ER compared with placebo took place at week 18. Two hundred fifty‐nine subjects were randomized 2:2:1 to treatment with pramipexole ER once daily, pramipexole IR TID, or placebo. Levodopa rescue was required by 7 subjects in the placebo group (14%), 3 subjects in the pramipexole ER group (2.9%, P = 0.0160), and 1 subject in the pramipexole IR group (1.0%, P = 0.0017). Adjusted mean [standard error (SE)] change in Unified Parkinson Disease Rating Scale (UPDRS) II [activities of daily living (ADL)] + III (motor) scores from baseline to week 18, including post‐levodopa rescue evaluations, was −5.1 (1.3) in the placebo group, −8.1 (1.1) in the pramipexole ER group (P = 0.0282), and −8.4 (1.1) in the pramipexole IR group (P = 0.0153). Adjusted mean (SE) change in UPDRS ADL + motor scores, censoring post‐levodopa rescue data, was −2.7 (1.3) in the placebo group, −7.4 (1.1) in the pramipexole ER group (P = 0.0010), and −7.5 (1.1) in the pramipexole IR group (P = 0.0006). Adverse events more common with pramipexole ER than placebo included somnolence, nausea, constipation, and fatigue. Pramipexole ER administered once daily was demonstrated to be efficacious compared with placebo and provided similar efficacy and tolerability as pramipexole IR administered TID.

Prospective randomized study comparing the medicoeconomic benefits of Hylan GF-20 vs. conventional treatment in knee osteoarthritis

OBJECTIVES In a previous study, we determined the costs over 6 months to the French public health insurance system of Hylan GF-20 (Synvisc) in 66 patients with knee osteoarthritis. Here, we compared the medicoeconomic benefits over 9 months in 506 patients given Hylan GF-20 or conventional treatment for knee osteoarthritis. PATIENTS AND METHODS This prospective randomized study was conducted from October 1998 to February 2000. Clinical status was evaluated using the Lequesne index, the WOMAC index, and the SF12 quality-of-life questionnaire. Medical and sick leave costs to the public health insurance system were determined. RESULTS Effectiveness criteria were evaluable in all 506 patients. Significant clinical improvements were noted from the first month to the end of the 9-month study period in the Synvisc group. A mean 2-point difference in the Lequesne index area-under-the-curve was found in favor of Synvisc (P < 0.0001). Mean medical and sick leave costs per patient over 9 months were 829.10 in the Synvisc group and 829.40 in the conventional treatment group. CONCLUSION This study carried out over 9 months in a large population confirms that Synvisc viscosupplementation is more effective than conventional treatment, at no additional cost. It takes a step toward answering the request of international experts for medicoeconomic data on viscosupplementation for osteoarthritis.

Extended-release pramipexole in advanced Parkinson disease A randomized controlled trial

Background: In advanced Parkinson disease (PD), immediate-release pramipexole, taken 3 times daily, improves symptoms and quality of life. A once-daily extended-release formulation may be an effective and simple alternative therapy. Methods: For a multicenter randomized, double-blind, parallel trial of extended- and immediate-release pramipexole vs placebo, patients experiencing motor fluctuations while taking levodopa underwent flexible study drug titration and then maintenance at optimized dosage (0.375–4.5 mg/day). The primary endpoint was a change in the Unified Parkinsons Disease Rating Scale (UPDRS) part II+III score at 18 weeks, with further assessments at 33 weeks in a subset of patients. Adverse events were recorded throughout. Results: Among 507 patients in the 18-week analyses, UPDRS II+III scores decreased (from baseline means of 40.0–41.7) by an adjusted mean of −11.0 for extended-release pramipexole and −12.8 for immediate-release pramipexole vs −6.1 for placebo (p = 0.0001 and p < 0.0001) and off-time decreased (from baseline means of 5.8–6.0 hours/day) by an adjusted mean of −2.1 and −2.5 vs −1.4 hours/day (p = 0.0199 and p < 0.0001). Other outcomes were largely corroborative, including a significant improvement in early morning off symptoms. Among 249 pramipexole patients completing 33 weeks, UPDRS II+III and off-time findings showed ≤10.1% change from 18-week values. Both formulations were well-tolerated. Conclusions: Extended-release pramipexole significantly improved UPDRS score and off-time compared with placebo, with similar efficacy, tolerability, and safety of immediate-release pramipexole compared with placebo. Classification of evidence: This study provides Class I evidence that the extended-release form of pramipexole, taken once daily, is efficacious as an adjunct to levodopa in advanced PD. Neurology® 2011;77:767–774

Extended-release pramipexole in early Parkinson disease A 33-week randomized controlled trial

Objective: To assess the clinical efficacy of a novel once-daily extended-release (ER) formulation of the dopamine agonist pramipexole as monotherapy in patients with early Parkinson disease (PD) and establish its noninferiority vs standard immediate-release (IR) pramipexole. Methods: This was a multicenter, double-blind, parallel study of patients with early PD not receiving levodopa or dopamine agonists, randomly assigned to pramipexole IR, pramipexole ER, or placebo. Seven-week flexible titration was followed by 26-week maintenance, with levodopa permitted as rescue medication. The primary analysis was to test pramipexole ER noninferiority to pramipexole IR based on a change in the Unified Parkinsons Disease Rating Scale (UPDRS) part II+III score at 33 weeks, with noninferiority predefined as a treatment group difference for which the lower bound of the 95% confidence interval (CI) did not exceed −3 points. Results: Among 213 ER and 207 IR recipients, the adjusted mean 33-week UPDRS II+III change (excluding levodopa rescue effects) was −8.2 for ER and −8.7 for IR, a difference of −0.5 with a 95% CI of −2.3 to 1.3. Compared with placebo (n = 103), pramipexole ER and pramipexole IR were significantly superior on UPDRS II+III score, all key secondary outcomes, and almost all other endpoints. On the 39-item Parkinson Disease Questionnaire, superiority of pramipexole ER failed to reach statistical significance. Both formulations were equally safe and well-tolerated. Conclusions: As monotherapy for early PD, pramipexole ER was noninferior to pramipexole IR and significantly more effective than placebo. Tolerability and safety did not differ between the formulations. Classification of evidence: This study provides Class I evidence that pramipexole ER is not inferior to pramipexole IR in patients with early PD. Neurology® 2011;77:759–766

Randomized trial of the triple monoamine reuptake inhibitor NS 2330 (tesofensine) in early Parkinson's disease

The objective of this study was to evaluate the efficacy and safety of three daily dosages of the triple monoamine reuptake inhibitor NS 2330 (tesofensine) compared to placebo as monotherapy in early Parkinsons disease (PD). In MPTP (1‐methyl 4‐phenyl‐tetrahydropyridine 1,2,3,6)‐lesioned marmosets, dopamine reuptake inhibitors have been demonstrated to reverse parkinsonian signs without evoking established dyskinesia. NS 2330 inhibits reuptake of dopamine, serotonin, and norepinephrine. We performed a proof‐of‐concept, randomized, double‐blind trial of NS 2330. Two hundred sixty‐one subjects with PD < 5 years and not receiving dopaminergic treatment were randomly assigned to daily treatment with NS 2330 at 0.25 mg, 0.5 mg, 1.0 mg, or placebo. Adjusted mean difference in total Unified Parkinsons Disease Rating Scale (UPDRS) scores from baseline to week 14 was −0.7 (P = 0.64) in the 0.25‐mg group, −1.3 (P = 0.41) in the 0.5‐mg group, and −1.7 (P = 0.27) in the 1.0‐mg group. The adjusted mean difference in total UPDRS score for the highest dose group (1.0 mg/day) was superior to placebo at week 6 (−3.1; P = 0.02), but this effect was not sustained. NS 2330 was generally well tolerated and the most commonly reported adverse events were constipation, insomnia, and dry mouth. Decreased body weight and elevated heart rate were common in the 1.0‐mg dosage group. At the dosages tested, NS 2330 did not provide significantly greater benefit than placebo. It is possible that inhibition of dopamine reuptake alone does not provide clinical benefit in early PD, adequate inhibition of dopamine reuptake was not achieved in this study, or countervailing physiologic mechanisms offset the potential benefit.

Efficacy, Safety, and Tolerability of Overnight Switching from Immediate- to Once Daily Extended-Release Pramipexole in Early Parkinson's Disease

The aim of this article is to test the feasibility, in early Parkinsons 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.

Étude prospective randomisée comparant le bénéfice médico-économique de Synvisc® à celui des traitements usuels chez des patients souffrant de gonarthrose

Resume Objectifs. – Une 1re etude avait evalue sur 6 mois, les couts a la charge de la Securite Sociale lors du traitement par Synvisc® (hylane G-F 20) de 66 patients souffrant de gonarthrose. L’etude actuelle a evalue ces couts sur 9 mois chez 506 patients traites par Synvisc® ou traitements usuels. Patients et methodes. – Etude prospective, randomisee, menee d’octobre 1998 a fevrier 2000, comparant le rapport cout-efficacite de Synvisc® a celui des traitements usuels de la gonarthrose. L’evaluation clinique reposait sur l’indice de Lequesne, l’indice de Womac, le questionnaire de qualite de vie SF12 et l’evaluation medico-economique reposait sur les couts medicaux et non medicaux a la charge de la Securite Sociale. Resultats. – Cinq cent six patients etaient evaluables pour les criteres d’efficacite. L’amelioration clinique significative notee des le 1er mois dans le groupe Synvisc® s’est poursuivie jusqu’a 9 mois. Une difference moyenne de 2 points pour l’aire sous la courbe de l’indice de Lequesne a ete notee en faveur du groupe Synvisc® (p Conclusion. – L’etude confirme, sur une duree de 9 mois et une population importante de patients, l’efficacite et l’absence de surcout d’une visco-supplementation par Synvisc®, comparativement aux traitements usuels. Elle apporte une 1re reponse pertinente a la demande des experts internationaux qui soulignaient la necessite de disposer de donnees medico-economiques dans l’evaluation des produits de visco-supplementation.