Nolwenn Juhel

Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis.

BACKGROUND Idiopathic pulmonary fibrosis is a progressive lung disease with a high mortality rate. Because the signaling pathways activated by several tyrosine kinase receptors have been shown to be involved in lung fibrosis, it has been suggested that the inhibition of these receptors may slow the progression of idiopathic pulmonary fibrosis. METHODS In a 12-month, phase 2 trial, we assessed the efficacy and safety of four different oral doses of the tyrosine kinase inhibitor BIBF 1120 as compared with placebo in patients with idiopathic pulmonary fibrosis. The primary end point was the annual rate of decline in forced vital capacity (FVC). Secondary end points included acute exacerbations, quality of life (measured with the St. Georges Respiratory Questionnaire [SGRQ]), and total lung capacity. RESULTS A total of 432 patients underwent randomization to receive one of four doses of BIBF 1120 (50 mg once a day, 50 mg twice a day, 100 mg twice a day, or 150 mg twice a day) or placebo. In the group receiving 150 mg of BIBF 1120 twice a day, FVC declined by 0.06 liters per year, as compared with 0.19 liters per year in the placebo group, a 68.4% reduction in the rate of loss with BIBF 1120 (P = 0.06 with the closed testing procedure for multiplicity correction; P = 0.01 with the hierarchical testing procedure). This dose also resulted in a lower incidence of acute exacerbations, as compared with placebo (2.4 vs. 15.7 per 100 patient-years, P = 0.02) and a small decrease in the SGRQ score (assessed on a scale of 0 to 100, with lower scores indicating better quality of life) as compared with an increase with placebo (-0.66 vs. 5.46, P = 0.007). Gastrointestinal symptoms (which led to more discontinuations in the group receiving 150 mg twice a day than in the placebo group) and increases in levels of liver aminotransferases were more frequent in the group receiving 150 mg of BIBF 1120 twice daily than in the placebo group. CONCLUSIONS In patients with idiopathic pulmonary fibrosis, BIBF 1120 at a dose of 150 mg twice daily, as compared with placebo, was associated with a trend toward a reduction in the decline in lung function, with fewer acute exacerbations and preserved quality of life. (Funded by Boehringer Ingelheim; ClinicalTrials.gov number, NCT00514683 .).

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.

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.