Serotonin and noradrenaline reuptake inhibitor duloxetine reduces daily off time in Parkinson’s disease

Background: Istradefylline is a selective adenosine A2A receptor antagonist for the treatment of patients with Parkinson’s disease (PD) experiencing OFF episodes while on levodopa/decarboxylase inhibitor. Objective: This pooled analysis of eight randomized, placebo-controlled, double-blind phase 2b/3 studies evaluated the efficacy and safety of istradefylline. Methods: Istradefylline was evaluated in PD patients receiving levodopa with carbidopa/benserazide and experiencing motor fluctuations. Eight 12- or 16-week trials were conducted (n = 3,245); four of these studies were the basis for istradefylline’s FDA approval. Change in OFF time as assessed in patient-completed 24-h PD diaries at Week 12 was the primary endpoint. All studies were designed with common methodology, thereby permitting pooling of data. Pooled analysis results from once-daily oral istradefylline (20 and 40 mg/day) and placebo were evaluated using a mixed-model repeated-measures approach including study as a factor. Results: Among 2,719 patients (placebo, n = 992; 20 mg/day, n = 848; 40 mg/day, n = 879), OFF hours/day were reduced at Week 12 at istradefylline dosages of 20 mg/day (least-squares mean difference [LSMD] from placebo in reduction from baseline [95%CI], –0.38 h [–0.61, –0.15]) and 40 mg/day (–0.45 h [–0.68, –0.22], p < 0.0001); ON time without troublesome dyskinesia (ON-WoTD) significantly increased. Similar results were found in the four-study pool (OFF hours/day, 20 mg/day, –0.75 h [–1.10, –0.40]; 40 mg/day, –0.82 h [–1.17, –0.47]). Istradefylline was generally well-tolerated; the average study completion rate among istradefylline-treated patients across all studies was 89.2%. Dyskinesia was the most frequent adverse event (placebo, 9.6%; 20 mg/day, 16.1%; 40 mg/day, 17.7%). Conclusion: In this pooled analysis, istradefylline significantly improved OFF time and ON-WoTD relative to placebo and was well-tolerated.

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Efficacy and safety of the noradrenaline reuptake inhibitor, TAS‐303, in women with stress urinary incontinence: Results of a double‐blind, randomized, placebo‐controlled, early phase II trial

International Journal of Urology ◽

10.1111/iju.14411 ◽

2020 ◽

Author(s):

Satoru Takahashi ◽

Kumiko Kato ◽

Mineo Takei ◽

Osamu Yokoyama ◽

Momokazu Gotoh

Keyword(s):

Urinary Incontinence ◽

Stress Urinary Incontinence ◽

Phase Ii ◽

Reuptake Inhibitor ◽

Early Phase ◽

Phase Ii Trial ◽

Efficacy And Safety ◽

Double Blind ◽

Noradrenaline Reuptake ◽

Noradrenaline Reuptake Inhibitor

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Continuous Subcutaneous Levodopa Delivery for Parkinson’s Disease: A Randomized Study

Journal of Parkinson s Disease ◽

10.3233/jpd-202285 ◽

2020 ◽

pp. 1-10

Author(s):

C. Warren Olanow ◽

Alberto J. Espay ◽

Fabrizio Stocchi ◽

Aaron L. Ellenbogen ◽

Mika Leinonen ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Randomized Study ◽

Preliminary Evidence ◽

Common Adverse Event ◽

Open Label ◽

Open Label Study ◽

Dosing Regimens ◽

Optimized Treatment ◽

Off Time

Background: ND0612 is a continuous, subcutaneous levodopa/carbidopa delivery system in development for patients with Parkinson’s disease (PD) experiencing motor fluctuations Objective: Evaluate the efficacy and safety of two ND0612 dosing regimens in patients with PD. Methods: This was a 28-day open-label study (NCT02577523) in PD patients with ≥2.5 hours/day of OFF time despite optimized treatment. Patients were randomized to treatment with either a 24-hour infusion (levodopa/carbidopa dose of 720/90 mg) or a 14-hour ‘waking-day’ infusion (levodopa/carbidopa dose of 538/68 mg plus a morning oral dose of 150/15 mg). In-clinic assessments of OFF time (primary endpoint) and ON time with or without dyskinesia were determined by a blinded rater over 8 hours (normalized to 16 hours). Results: A total of 38 patients were randomized and 33 (87% ) completed the study. Compared to baseline, OFF time for the overall population was reduced by a least squares (LS) mean[95% CI] of 2.0[– 3.3, – 0.7] hours (p = 0.003). ON time with no/mild dyskinesia was increased from baseline by a LS mean of 3.3[2.0, 4.6] hours (p < 0.0001), and ON time with moderate/severe dyskinesia was reduced by a LS mean of 1.2[– 1.8, – 0.5] hours (p≤0.001). Reduction in OFF time was larger in the 24-hour group (– 2.8[– 4.6, – 0.9] hours; p = 0.004) than in the 14-hour group (– 1.3[– 3.1, 0.5] hours; p = 0.16). Complete resolution of OFF time was observed in 42% (n = 8) of patients in the 24-hour group. Infusion site reactions were the most common adverse event. Conclusion: This study demonstrates the feasibility and safety of continuous subcutaneous delivery of levodopa as a treatment for PD and provides preliminary evidence of efficacy.

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Safety of Levodopa-Carbidopa Intestinal Gel Treatment in Patients with Advanced Parkinson’s Disease Receiving ≥2000 mg Daily Dose of Levodopa

Parkinson s Disease ◽

10.1155/2020/9716317 ◽

2020 ◽

Vol 2020 ◽

pp. 1-11

Author(s):

Cindy Zadikoff ◽

Werner Poewe ◽

James T. Boyd ◽

Lars Bergmann ◽

Horia Ijacu ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Rating Scale ◽

Phase Iii ◽

High Dose ◽

Double Blind Study ◽

Dosage Group ◽

Continuous Administration ◽

Advanced Parkinson’S Disease ◽

Off Time

Background. Levodopa-carbidopa intestinal gel (LCIG) provides continuous levodopa administration and clinical benefits to patients with advanced Parkinson’s disease (PD). This report evaluates long-term safety and efficacy of high-dose LCIG in PD patients. Methods. Data were collected from several prospective, phase III clinical studies and an observational registry. The phase III program (N = 412) included four multicenter studies: a 12-week, randomized, double-blind study and three open-label studies extending ≥12 months. GLORIA (N = 375) was a 24-month, multicountry, observational registry. LCIG safety (adverse effects (AEs)/adverse drug reactions (ADRs)) and efficacy (modified Unified Parkinson’s Disease Rating Scale (UPDRS) part IV item 32 and 39 scores for “On” time with dyskinesia and “Off” time) were assessed in patients who received ≥2000 mg/day vs <2000 mg/day LCIG. Results. A total of 72 of 412 (17.5%) patients required dosages ≥2000 mg/day LCIG in the phase III program and 47 of 375 (12.5%) patients in GLORIA. Baseline demographics and disease severity were similar between dosage groups with more men in the high-dosage group. Compared with the <2000 mg/day dosage group, patients requiring ≥2000 mg/day LCIG had higher rates of AEs/ADRs including polyneuropathy; improvements in “Off” time and discontinuations due to AEs were similar between dosage groups and lower for discontinuations due to ADRs reported in GLORIA. Conclusions. Patients who require ≥2000 mg/day LCIG exhibited a safety profile comparable to the established safety/tolerability of LCIG with similar clinical improvements. Higher AEs were noted but within what is accepted for LCIG. Continuous administration of LCIG is beneficial to advanced PD patients who require very high doses of levodopa.

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