Treatment Of Motor Fluctuations Research Articles

Efficacy and safety of apomorphine pump infusion in Filipino patients insufficiently controlled on oral anti-Parkinson medications: an open-label, pilot study

Background Apomorphine hydrochloride is used in the management of advanced Parkinson disease (PD), either as a rescue medication for off periods during levodopa therapy or as a maintenance pump medication. This is the first study to describe the effects of apomorphine in Filipino patients with PD. Objective To evaluate the safety and efficacy of apomorphine ampules (APO-go®) pump infusion in the treatment of motor fluctuations in patients inadequately controlled on oral anti-Parkinson medications. Methods Patients diagnosed with PD who developed motor fluctuations with levodopa were evaluated at baseline and at the end of the study using the Modified Hoehn and Yahr (H&Y) Scale, the Unified Parkinson’s Disease Rating Scale (UPDRS) and the Abnormal Involuntary Movement Scale (AIMS). After initial assessment, patients were administered 20 ampules of apomorphine hydrochloride 10 mg/mL by infusion pump over 20 days. Intention-to-treat (ITT) analysis included all patients who completed at least one posttreatment assessment. Motor disability based on modified H&Y scores, motor function and complications of therapy pre- and posttreatment were compared using Wilcoxon Signed Rank test. Chi-squared test was used to compare outcomes by age and sex. Frequencies of adverse reactions were recorded to evaluate the tolerability of the medication. Results Ten patients (mean age 63 ± 9.7 years), 3 male and 7 female, were enrolled in the study. Patients were given apomorphine for at most 16 days. The doses used were 2.5 mg/0.50 mL (n = 2), 3 mg/0.60 mL (n = 6), 4 mg/0.80 mL (n = 1) and 7 mg/1.40 mL (n = 1). After obtaining the threshold dose, two patients discontinued treatment. Eight of nine patients showed significant improvement in H&Y scores after treatment (p < 0.017). There was marked improvement after 10 days of treatment in at least five of 10 patients in terms of motor function using UPDRS, which included tremor (p < 0.034), rigidity (p < 0.002), facial expression (p < 0.014), finger taps (p < 0.008), foot taps (p < 0.014) and gait (p < 0.006). Significant changes from pre- to posttreatment scores in the frequency of dyskinesias (p < 0.010) and dystonia (p < 0.025) were observed. Nine focus areas of AIMS showed significant improvements in the muscles of facial expression (p < 0.020), upper (p < 0.016) and lower extremities (p < 0.010), incapacitation by abnormal movement (p < 0.010) and patients’ awareness of abnormal movements (p < 0.039). Six patients experienced adverse events, none of which were related to the study drug. Conclusion Apomorphine hydrochloride pump infusion therapy is potentially effective and safe in the treatment of motor fluctuations in Filipino patients with PD. This pilot study springboards safe engagements of Filipino PD patients in multicenter, large-scale trials.

Relevance of COMT inhibitors in the treatment of motor fluctuations

Catechol O‑methyltransferase (COMT) inhibitors have been established in the treatment of Parkinson's disease for more than 20years. They are considered the medication of choice for treating motor fluctuations. The available COMT inhibitors, entacapone, opicapone and tolcapone, differ pharmacokinetically in terms of their half-lives with implications for the dose frequency, in their indication requirements and in their spectrum of side effects, including diarrhea and yellow discoloration of urine. Many patients with motor fluctuations are currently not treated with COMT inhibitors and are, therefore, unlikely to receive individually optimized drug treatment. This manuscript summarizes the results of aworking group including several Parkinson's disease experts, in which the value of COMT inhibitors was critically discussed.

Influence of motor fluctuations duration, levodopa dose and duration of use in efficacy responses of Parkinson's disease patients: Post-hoc analysis from combined BIPARK-I and II

To evaluate the impact of motor fluctuations (MF) duration, levodopa dose and levodopa duration of use (LDU) in efficacy responses of levodopa-treated Parkinson's Disease (PD) patients with MF. Opicapone (OPC), a once-daily COMT inhibitor, proved effective in the treatment of MF in PD in two large, pivotal, multinational trials (BIPARK-I and II) [[1]Ferreira et al.Lancet Neurol. 2016; 15: 154-165Google Scholar,[2]Lees et al.JAMA Neurol. 2017; 74: 197-206Google Scholar]. Patient-level data from matching treatment arms in BIPARK-I and II were combined in placebo (PLC) and OPC-50 mg groups. Studies had similar designs (primary efficacy endpoint: change from baseline in patient diaries-based absolute OFF-time) and eligibility criteria [[1]Ferreira et al.Lancet Neurol. 2016; 15: 154-165Google Scholar,[2]Lees et al.JAMA Neurol. 2017; 74: 197-206Google Scholar]. This post-hoc analysis assessed influence of MF duration (years), levodopa dose (mg) and LDU (years) in efficacy outcomes (OFF-/ON-time change from baseline). Applied linear regression's slope was statistically tested for deviation from zero. 1027 patients were randomized to BIPARK-I and II; Full Analysis Set comprised 517 [PLC (n = 255); OPC-50 mg (n = 262)]. Due to lack of matched-patients, four OPC-50 mg patients (MF > 12 years) were excluded from MF analysis and two PLC (<1 year) and five OPC-50 mg (>18 years) patients were excluded from LDU analysis. Mean baseline values were 2.4 (PLC) to 2.5 (OPC-50 mg) years of MF, 696 mg (PLC) to 698 mg (OPC-50 mg) of levodopa and 6.4 (PLC) to 6.0 (OPC-50 mg) years of use. OFF-/ON-time magnitude of responses was not influenced by any parameter. Linear regression was non-significant for each arm and variables analyzed. MF duration, levodopa dose and LDU do not appear to impact OFF-/ON-time magnitude of responses in a clinical study setting.

Influence of disease severity in the efficacy response of Parkinson's disease patients with motor fluctuations: Post-hoc analysis from combined BIPARK-I and II

To evaluate the impact of disease severity on the efficacy of opicapone (OPC) in levodopa-treated Parkinson's Disease (PD) patients with motor fluctuations. OPC, a once-daily COMT inhibitor, proved effective in the treatment of motor fluctuations in PD patients in two large, pivotal, multinational trials (BIPARK-I and II) [[1]Ferreira J.J. et al.Lancet Neurol. 2016; 15: 154-165Google Scholar,[2]Lees A.J. et al.JAMA Neurol. 2017; 74: 197-206Google Scholar]. Patient-level data from matching treatment arms in BIPARK-I and II were combined in placebo (PLC) and OPC-50 mg groups. The studies had similar designs (primary efficacy endpoint: change from baseline in patient diaries-based absolute OFF-time) and eligibility criteria [[1]Ferreira J.J. et al.Lancet Neurol. 2016; 15: 154-165Google Scholar,[2]Lees A.J. et al.JAMA Neurol. 2017; 74: 197-206Google Scholar]. An exploratory post-hoc analysis was performed to evaluate the influence of disease severity (assessed by modified Hoehn and Yahr, H&Y <2.5 vs =";≥2.5) on efficacy outcomes (i.e., change from baseline in OFF-/ON-time). Applied linear regression's slope was statistically tested for deviation from zero and linearity. In total, 1027 patients were randomized to BIPARK-I and II and 522 patients took a dose of study medication; Full Analysis Set comprised 517 [PLC (n = 255); OPC-50 mg (n = 262)]. Two PLC patients with H&Y = 4 were excluded from disease severity analysis as there were no OPC-50 mg matched-patients. For OPC-50 mg, OFF-/ON-time magnitude of responses was not influenced (non-significant linear regression). For PLC, the higher H&Y staging at baseline the greater magnitude of OFF-/ON-time response at endpoint (ending in a linear regression slope statistically significant). Disease severity impacted OFF-/ON-time magnitude of responses for PLC but not OPC-50 mg patients in a clinical study setting.

Opicapone odds ratio in relative off-time reduction: A post-hoc analysis from combined BIPARK-I and II data

Objective To evaluate the opicapone (OPC) associated patient’s odds ratio (OR) in relative OFF-time reduction. OPC, a once-daily COMT inhibitor, proved effective in the treatment of motor fluctuations in PD patients in two large, pivotal, multinational trials (BIPARK-I and II) [ 1 , 2 ]. Methods Patient-level data from matching treatment arms in BIPARK-I and II were combined in placebo (PLC) and OPC-50mg groups. The studies had similar designs (primary efficacy endpoint: change from baseline in patient diaries-based absolute OFF-time) and eligibility criteria [ 1 , 2 ]. An exploratory post hoc analysis was performed evaluating the associated patient’s OR in relative OFF-time reduction, in each treatment group, at different cut-offs, namely ≥25%, ≥50%, ≥75% and 100% (OFF-time free). Statistical analysis was performed by a pairwise Cochran-Mantel-Haenszel test stratified by study. Results In total, 535 patients were randomized; Full Analysis Set comprised 517 [PLC (n=255); OPC-50mg (n=262)]. The proportion of OFF-time responders for 50mg-OPC was higher than placebo for all different cut-offs, reaching statistical significance for both ≥25 (p = 0.0002) and ≥50% (p = 0.0223) relative OFF-time reduction. PLC proportion of responders ranged from 38.0% (≥ 25%) to 4.7% (100%). OPC-50mg proportion of responders ranged from 54.6% (≥25%) to 8.0% (100%) and presented an OR to placebo ranging from 1.94 (≥25%) to 1.75 (100%).

Efficacy of opicapone in Parkinson’s disease patients according to baseline presence of dyskinesia: A post-hoc analysis from combined BIPARK-I and II

To evaluate the efficacy of opicapone (OPC) in levodopa-treated Parkinson’s Disease (PD) patients with or without baseline presence of dyskinesia (BPDys). OPC, a once-daily COMT inhibitor, proved effective in the treatment of motor fluctuations in PD patients in two large, pivotal, multinational trials (BIPARK-I and II) [[1]Ferreira et al.Lancet Neurol. 2016; 15: 154-165Google Scholar,[2]Lees et al.JAMA Neurol. 2017; 74: 197-206Google Scholar]. Patient-level data from matching treatment arms in BIPARK-I and II were combined in placebo (PLC) and OPC-50 mg groups. Studies had similar designs (primary efficacy endpoint: change from baseline in patient diaries-based absolute OFF-time) and eligibility criteria [[1]Ferreira et al.Lancet Neurol. 2016; 15: 154-165Google Scholar,[2]Lees et al.JAMA Neurol. 2017; 74: 197-206Google Scholar]. Key secondary endpoints included analysis of responders (>1 h OFF-time reduction or >1 h ON-time increase). A post-hoc analysis was performed to evaluate OPC-50 mg and PLC efficacies in levodopa-treated PD patients according to BPDys (assessed by UPDRS question 32). In total, 535 patients were randomized; Full Analysis Set comprised 517 [PLC (n = 255); OPC-50 mg (n = 262)]. 47% (PLC) to 50% (OPC-50 mg) of patients reported BPDys. Mean placebo-adjusted OFF-time reduction was −50.5 min (p = 0.0080) and −67.3 min (p = 0.0005) for OPC-50 mg patients with and without BPDys. There was ~65% more OFF-time reduction in PLC patients with BPDys than in those without. A higher-than-PLC proportion of OPC-50 mg-receiving patients with BPDys achieved OFF- (67.9% vs. 50.8%; p < 0.0060) and ON-time (65.6% vs. 45.1%; p = 0.0011) responders’ endpoint. Consistently, a higher-than-PLC proportion of OPC-50 mg-receiving patients with absence of dyskinesia achieved OFF- (67.2% vs. 47.4%; p = 0.0010) and ON-time (61.1% vs. 45.9%; p = 0.0115) responders’ endpoint. Opicapone was effective regardless of baseline presence of dyskinesia.

Incidence of treatment-emergent adverse events in Parkinson's disease patients according to gender: Post-hoc analysis from double-blind combined BIPARK-I and II data

To evaluate the incidence of treatment-emergent adverse events (TEAEs) in levodopa-treated Parkinson's Disease (PD) patients with motor fluctuations and taking opicapone (OPC), a once-daily COMT inhibitor that proved effective in the treatment of motor fluctuations in PD patients in two large, pivotal, multinational trials (BIPARK-I and II) [1,2]. Patient-level data from matching treatment arms in BIPARK-I and II were combined in placebo (PLC) and OPC-50 mg groups. The studies had similar designs (primary efficacy endpoint: change from baseline in patient diaries-based absolute OFF-time) and eligibility criteria [1,2]. Safety was assessed by incidence of TEAEs, laboratory parameters, ECGs and vital signs. An exploratory post-hoc analysis was performed to evaluate the incidence of TEAEs according to gender. Of the 1027 patients randomized to BIPARK-I and II, 522 patients took a dose of study medication (OPC-50 mg n = 265, PLC n = 257) and were included in this analysis. Male patients represented ~58% of both OPC-50 mg and PLC groups. Overall, 64.2% of OPC-50 mg patients reported any TEAE compared to 57.2% in PLC. There was a comparable incidence of TEAEs for Male-matched user patients (65.0% vs. 56.3% for OPC-50 mg and PLC groups) and Female-matched patients (62.9% vs. 58.3% for OPC-50 mg and PLC groups). The most frequently occurring TEAE was dyskinesia in both subgroups. Opicapone appears to be equally well-tolerated in both Male and Female patients.

Influence of baseline off-time in the efficacy response of Parkinson's disease patients with motor fluctuations: Post-hoc analysis from combined BIPARK-I and II

To evaluate the impact of baseline OFF-time on the efficacy of opicapone (OPC) in levodopa-treated Parkinson's Disease (PD) patients with motor fluctuations. OPC, a once-daily COMT inhibitor, proved effective in the treatment of motor fluctuations in PD patients in two large, pivotal, multinational trials (BIPARK-I and II) [[1]Ferreira et al.Lancet Neurol. 2016; 15: 154-165Google Scholar,[2]Lees et al.JAMA Neurol. 2017; 74: 197-206Google Scholar]. Patient-level data from matching treatment arms in BIPARK-I and II were combined in placebo (PLC) and OPC-50 mg groups. The studies had similar designs (primary efficacy endpoint: change from baseline in patient diaries-based absolute OFF-time) and eligibility criteria [[1]Ferreira et al.Lancet Neurol. 2016; 15: 154-165Google Scholar,[2]Lees et al.JAMA Neurol. 2017; 74: 197-206Google Scholar]. An exploratory post-hoc analysis was performed to evaluate the influence of baseline OFF-time in efficacy outcomes (i.e., change from baseline in OFF-/ON-time). Linear regression was applied and the slope was statistically tested for deviation from zero. 1027 patients were randomized to BIPARK-I and II; 522 patients took a dose of study medication; Full Analysis Set comprised 517 [PLC (n = 255); OPC-50 mg (n = 262)]. As expected, both treatments arms presented the same increased dependent tendency for OFF-/ON-time at endpoint, i.e., the longer OFF-time at baseline the greater magnitude of response at endpoint (ending in a linear regression slope statistically significant). When OFF-time at endpoint was ‘normalized’ as % of change in relation to baseline, the linear regression slope was found non-significant for both treatment arms, though the increased dependent tendency was still found. Baseline OFF-time appears to impact the magnitude of both OFF- and ON-time responses in a clinical study setting.

Incidence of treatment-emergent adverse events in Parkinson's disease patients according to race: Post-hoc analysis from double-blind combined BIPARK-I and II data

To evaluate the incidence of treatment-emergent adverse events (TEAEs) in levodopa-treated Parkinson's Disease (PD) patients with motor fluctuations and taking opicapone (OPC), a once-daily COMT inhibitor that proved effective in the treatment of motor fluctuations in PD patients in two large, pivotal, multinational trials (BIPARK-I and II) [[1]Ferreira et al.Lancet Neurol. 2016; 15: 154-165Google Scholar,[2]Lees et al.JAMA Neurol. 2017; 74: 197-206Google Scholar]. Patient-level data from matching treatment arms in BIPARK-I and II were combined in placebo (PLC) and OPC-50 mg groups. The studies had similar designs (primary efficacy endpoint: change from baseline in patient diaries-based absolute OFF-time) and eligibility criteria [[1]Ferreira et al.Lancet Neurol. 2016; 15: 154-165Google Scholar,[2]Lees et al.JAMA Neurol. 2017; 74: 197-206Google Scholar]. Safety was assessed by incidence of TEAEs, laboratory parameters, ECGs and vital signs. An exploratory post-hoc analysis was performed to evaluate the incidence of TEAEs according to race (Caucasian vs Asian). Of the 1027 patients randomized to BIPARK-I and II, 522 patients took a dose of relevant study medication (OPC-50 mg n = 265, PLC n = 257) and were included in this analysis. Caucasian patients represented ~85% of both OPC-50 mg and PLC groups. Overall, 64.2% of OPC-50 mg patients reported any TEAE compared to 57.2% in PLC. There was a comparable-to-overall incidence of TEAEs for Caucasian-matched patients (65.8% vs. 58.3% for OPC-50 mg and PLC groups). In contrast, for Asian-matched patients, the incidence of TEAEs was lower in OPC treated patients (51.5%) than PLC-treated ones (52.4%). The most frequently occurring TEAE was dyskinesia in both subgroups. Opicapone appears to be well-tolerated in both Caucasian and Asian patients.

Influence of demographic characteristics in the efficacy response of Parkinson’s disease patients with motor fluctuations: Post-hoc analysis from combined BIPARK-I and II

To evaluate the impact of demographic characteristics in the efficacy response of levodopa-treated Parkinson’s Disease (PD) patients with motor fluctuations. Opicapone (OPC), a once-daily COMT inhibitor, proved effective in the treatment of motor fluctuations in PD patients in two large, pivotal, multinational trials (BIPARK-I and II) [[1]Ferreira et al.Lancet Neurol. 2016; 15: 154-165Google Scholar,[2]Lees et al.JAMA Neurol. 2017; 74: 197-206Google Scholar]. Patient-level data from matching treatment arms in BIPARK-I and II were combined in placebo (PLC) and OPC-50 mg groups. The studies had similar designs (primary efficacy endpoint: change from baseline in patient diaries-based absolute OFF-time) and eligibility criteria [[1]Ferreira et al.Lancet Neurol. 2016; 15: 154-165Google Scholar,[2]Lees et al.JAMA Neurol. 2017; 74: 197-206Google Scholar]. An exploratory post-hoc analysis was performed to evaluate the influence of demographic characteristics [i.e., age, gender, race (Caucasian vs. Asian), weight and Body Mass Index (BMI)] in efficacy outcomes (i.e., change from baseline in OFF-/ON-time). Linear regression was applied and the slope was statistically tested for deviation from zero. In total, 1027 patients were randomized to BIPARK-I and II and 522 patients took a dose of study medication; Full Analysis Set comprised 517 [PLC (n = 255); OPC-50 mg (n = 262)]. Neither OFF- nor ON-time magnitude of responses were influenced by age, gender, race, weight and BMI at baseline. Linear regression applied was found to be non-significant for both treatment arms and all variables analyzed. Demographic characteristics (i.e., age, gender, race, weight and BMI) do not appear to impact either OFF- or ON-time magnitude of responses in a clinical study setting.

Incidence of treatment-emergent adverse events in Parkinson's disease patients according to baseline mao-b inhibitors use: Post-hoc analysis from double-blind combined BIPARK-I and II data

To evaluate the incidence of treatment-emergent adverse events (TEAEs) in levodopa-treated Parkinson's Disease (PD) patients with motor fluctuations and taking opicapone (OPC), a once-daily COMT inhibitor that proved effective in the treatment of motor fluctuations in PD patients in two large, pivotal, multinational trials (BIPARK-I and II) [[1]Ferreira et al.Lancet Neurol. 2016; 15: 154-165Google Scholar,[2]Lees et al.JAMA Neurol. 2017; 74: 197-206Google Scholar]. Patient-level data from matching treatment arms in BIPARK-I and II were combined in placebo (PLC) and OPC-50 mg groups. The studies had similar designs (primary efficacy endpoint: change from baseline in patient diaries-based absolute OFF-time) and eligibility criteria [[1]Ferreira et al.Lancet Neurol. 2016; 15: 154-165Google Scholar,[2]Lees et al.JAMA Neurol. 2017; 74: 197-206Google Scholar]. Safety was assessed by incidence of TEAEs, laboratory parameters, ECGs and vital signs. An exploratory post-hoc analysis was performed to evaluate the incidence of TEAEs according to baseline MAO-B inhibitors (MAOBi) use. Of the 1027 patients randomized to BIPARK-I and II, 522 patients took a dose of relevant study medication (OPC-50 mg n = 265, PLC n = 257) and were included in this analysis. Non-MAOBi user patients represented ~80% of both OPC-50 mg and PLC groups. In total, 64.2% of OPC-50 mg patients reported any TEAE compared to 57.2% in PLC. There was a comparable-to-overall incidence of TEAEs for non-MAOBi matched user patients (62.5% vs. 53.8% for OPC-50 mg and PLC groups). In contrast, for MAOBi-matched patients, incidence of TEAEs was lower in OPC-treated patients (70.2%) than PLC-treated ones (71.4%), but overall higher. Most frequently occurring TEAE was dyskinesia in both subgroups. Opicapone appears to be well-tolerated in both MAOBi and non-MAOBi user patients.

Efficacy of opicapone in Parkinson’s disease patients according to baseline rasagiline use: A post-hoc analysis from combined BIPARK-I and II

To evaluate opicapone’s (OPC) efficacy in levodopa-treated Parkinson’s Disease (PD) patients with or without concurrent rasagiline use (CRU). OPC, a once-daily COMT inhibitor, proved effective in the treatment of motor fluctuations in PD patients in two large, pivotal, multinational trials (BIPARK-I and II) [[1]Ferreira et al.Lancet Neurol. 2016; 15: 154-165Google Scholar,[2]Lees et al.JAMA Neurol. 2017; 74: 197-206Google Scholar]. Patient-level data from matching treatment arms in BIPARK-I and II were combined in placebo (PLC) and OPC-50 mg groups. Studies had similar designs (primary efficacy endpoint: change from baseline in patient diaries-based absolute OFF-time) and eligibility criteria [[1]Ferreira et al.Lancet Neurol. 2016; 15: 154-165Google Scholar,[2]Lees et al.JAMA Neurol. 2017; 74: 197-206Google Scholar]. This exploratory post-hoc analysis was performed to evaluate OPC-50 mg and PLC efficacies in levodopa-treated PD patients with or without baseline CRU (the most commonly used MAO-B inhibitor). In total, 535 patients were randomized; Full Analysis Set comprised 517 [PLC (n = 255); OPC-50 mg (n = 262)]. 12 (PLC) to 15% (OPC-50 mg) of patients were using rasagiline at baseline. Mean placebo-adjusted OFF-time reductions were −81.1 min (p = 0.0469) and −54.2 min (p = 0.0002) for OPC-50 mg patients with and without CRU. There was ~35% more OFF-time reduction in PLC patients without CRU than in those with, but ~9% less OFF-time reduction in OPC-50 mg patients without CRU than in those with. A higher-than-PLC proportion of OPC-50 mg-receiving patients with CRU achieved OFF- (40.0% vs. 66.7%; p = 0.0283) and ON-time (40.0% vs. 64.1%; p = 0.0491) responders’ endpoint. Consistently, a higher-than-PLC proportion of OPC-50 mg-receiving patients without CRU achieved OFF- (50.2% vs. 67.7%; p = 0.0002) and ON-time (46.2% vs. 63.2%; p = 0.0003) responders’ endpoint. Opicapone was effective regardless of concurrent rasagiline use.

Efficacy of opicapone in Parkinson’s disease patients according to baseline pramipexole use: A post-hoc analysis from combined BIPARK-I and II

To evaluate opicapone’s (OPC) efficacy in levodopa-treated Parkinson’s Disease (PD) patients with or without concurrent pramipexole use (CPU). OPC, a once-daily COMT inhibitor, proved effective in the treatment of motor fluctuations in PD patients in two large, pivotal, multinational trials (BIPARK-I and II) [[1]Ferreira et al.Lancet Neurol. 2016; 15: 154-165Google Scholar,[2]Lees et al.JAMA Neurol. 2017; 74: 197-206Google Scholar]. Patient-level data from matching treatment arms in BIPARK-I and II were combined in placebo (PLC) and OPC-50 mg groups. Studies had similar designs (primary efficacy endpoint: change from baseline in patient diaries-based absolute OFF-time) and eligibility criteria [[1]Ferreira et al.Lancet Neurol. 2016; 15: 154-165Google Scholar,[2]Lees et al.JAMA Neurol. 2017; 74: 197-206Google Scholar]. This exploratory post-hoc analysis was performed to evaluate OPC-50 mg and PLC efficacies in levodopa-treated PD patients with or without baseline CPU (the most commonly used dopamine agonist). In total, 535 patients were randomized; Full Analysis Set comprised 517 [PLC (n = 255); OPC-50 mg (n = 262)]. About 37% of patients in each arm were using pramipexole at baseline. Mean placebo-adjusted OFF-time reductions were −89.0 min (p = 0.0001) and −39.8 min (p = 0.0165) for OPC-50 mg patients with and without CPU. There was ~45% more OFF-time reduction in PLC patients without CPU than in those with, but ~20% less OFF-time reduction in OPC-50 mg patients without CPU than in those with. A higher-than-PLC proportion of OPC-50 mg-receiving patients with CPU achieved OFF- (72.9% vs. 40.4%; p < 0.0001) and ON-time (68.8% vs. 42.6%; p = 0.0003) responders’ endpoint. Consistently, a higher-than-PLC proportion of OPC-50 mg-receiving patients without CPU achieved OFF- (64.5% vs. 54.0%; p = 0.0551) and ON-time (60.2% vs. 47.2%; p = 0.0169) responders’ endpoint. Opicapone was effective regardless of concurrent pramipexole use.

Using wearables to assess bradykinesia and rigidity in patients with Parkinson’s disease: a focused, narrative review of the literature

The potential of using wearable technologies for the objective assessment of motor symptoms in Parkinson's disease (PD) has gained prominence recently. Nonetheless, compared to tremor and gait impairment, less emphasis has been placed on the quantification of bradykinesia and rigidity. This review aimed to consolidate the existing research on objective measurement of bradykinesia and rigidity in PD through the use of wearables, focusing on the continuous monitoring of these two symptoms in free-living environments. A search of PubMed was conducted through a combination of keyword and MeSH searches. We also searched the IEEE, Google Scholar, Embase, and Scopus databases to ensure thorough results and to minimize the chances of missing relevant studies. Papers published after the year 2000 with sample sizes greater than five were included. Studies were assessed for quality and information was extracted regarding the devices used and their location on the body, the setting and duration of the study, the "gold standard" used as a reference for validation, the metrics used, and the results of each paper. Thirty-one and eight studies met the search criteria and evaluated bradykinesia and rigidity, respectively. Several studies reported strong associations between wearable-based measures and the gold-standard references for bradykinesia, and, to a lesser extent, rigidity. Only a few, pilot studies investigated the measurement of bradykinesia and rigidity in the home and free-living settings. While the current results are promising for the future of wearables, additional work is needed on their validation and adaptation in ecological, free-living settings. Doing so has the potential to improve the assessment and treatment of motor fluctuations and symptoms of PD more generally through real-time objective monitoring of bradykinesia and rigidity.

Real life evaluation of safinamide effectiveness in Parkinson's disease.

In this retrospective study, we evaluated both efficacy and effectiveness of safinamide 50 and 100mg in the treatment of motor fluctuations and disabling dyskinesias in a cohort of patients with idiopathic Parkinson's disease (PD). Ninety-one PD patients were evaluated during the first year of commercialization of the drug, both prior to starting safinamide and at the last available follow-up. Evaluations were based on the Unified Parkinson's Disease Scale part III (UPDRS III), Hoehn & Yahr (HY), Unified Dyskinesia Rating Scale (UDysRS) walking and balance item 9 score, daily time spent in OFF and in ON with disabling dyskinesias (1week diary), mean daily dose of levodopa (LD), dopamine-agonists (DA), catechol-O-methyl transferase inhibitor (COMT-I), monoamine oxidase B inhibitor (MAOB-I), and their LD equivalent dose (LEDD). Eight patients withdrew safinamide within the first month for minor side effects. At the follow-up evaluation, after a mean time with safinamide of 7.5months ± 3.4, all patients showed a significant improvement of all the scale scores, except for HY, and of the daily dosages of the drugs and the LEDD. The same results were shown by PD patients treated with safinamide 50mg and patients who started safinamide without switching from a previous MAOBI. PD patients with safinamide 100mg and patients who started safinamide switching from a previous MAOBI significantly improved in time spent in OFF and LEDD. In conclusion, safinamide is safe and effective in improving motor complications in patients with idiopathic PD and can be considered a useful levodopa sparing strategy.

Perceived Treatment Status of Fluctuations in Parkinson Disease Impacts Suicidality

On/off motor fluctuations in Parkinson disease (PD) can be associated with extreme mood fluctuations and severe dysphoria. The impact of these affective symptoms may be overlooked in the treatment of motor fluctuations. Our goal was to examine the relationship between motor fluctuations, their treatment status, and suicidality in PD participants. We analyzed data from the Methods of Optimal Depression Detection in Parkinson's Disease (MOOD-PD) study of 223 individuals with PD. Suicidality was measured using items from four depression scales: Hamilton Depression Rating Scale (HAM-D-17); Montgomery-Åsberg Depression Rating Scale (MADRS); Inventory for Depressive Symptomatology (IDS-C); and the self-rated Beck Depression Inventory (BDI). Multivariable Poisson regression analyses tested whether self-reported motor fluctuations and their treatment status were associated with suicidality while controlling for recognized risk factors. Thirty-seven participants (16.6%) self-reported suicidality and 89 (39.5%) self-reported motor fluctuations, of whom 21 (23.6%) perceived their fluctuations as untreated. Participants reporting untreated motor fluctuations more frequently had a current depressive disorder (p < 0.001) and endorsed suicidality (p = 0.006) than participants with treated or no fluctuations. They also had significantly higher total scores on the HAM-D-17, MADRS, IDS-C, and BDI depression scales (p < 0.001 for each). Regression analyses showed significant associations between untreated motor fluctuations and higher scores on suicide questions extracted from the HAM-D-17, MADRS, and IDS-C (p < 0.01 for each). PD patients with untreated motor fluctuations are at increased risk for suicidal thoughts and should be monitored for mood changes as treatment is adapted.

Off- and on-time responder post-HOC analyses of pooled opicapone phase III studies

Background: Opicapone (OPC) is a new once-daily COMT inhibitor shown to be safe and effective in the treatment of motor fluctuations in Parkinson’s disease (PD) patients in two large, pivotal, multinational trials (BIPARK-I and II)

The efficacy of apomorphine – A non-motor perspective

Non-motor features have a great impact on progression and quality of life in individuals with Parkinson's disease. Current treatments for PD are limited and apomorphine is one of the advanced therapies available with advantageous effects on motor complications. Several studies have suggested that apomorphine has potential benefits in PD patients beyond its established role in the treatment of motor fluctuations and levodopa-induced dyskinesia. This review examines the efficacy of apomorphine in the treatment of non-motor symptoms (NMS), describing recent studies that highlight its possible effect on cognition. Despite a limited number of studies, the available evidence shows that apomorphine has an overall beneficial effect on NMS of PD patients, including neuropsychiatric symptoms, sleep disturbances, pain, urinary dysfunction, and impulse control disorders. If the effects of apomorphine on amyloid deposition are confirmed in the future, its place in the armamentarium of PD treatment could see a shift towards younger and non-demented PD patients.

Carbidopa/levodopa enteral suspension in advanced Parkinson’s disease: a guide to its use

Carbidopa/levodopa enteral suspension [carbidopa/levodopa ES; Duopa™ (USA); Duodopa® (EU, where it is referred to as intestinal gel)] is indicated for the treatment of motor fluctuations in patients with advanced Parkinson’s disease (PD). Its delivery by continuous infusion into the proximal small intestine allows for rapid absorption of levodopa and helps to avoid the fluctuations in levodopa plasma concentrations that occur with oral levodopa therapy. In clinical trials in adults with advanced PD, carbidopa/levodopa ES provided significantly greater improvements in motor fluctuations and troublesome dyskinesia than oral immediate-release carbidopa/levodopa over 12 weeks, and had sustained efficacy in longer-term, open-label studies. Carbidopa/levodopa ES was generally well tolerated in these trials, although complications related to the delivery system were common.

Risk and course of motor complications in a population-based incident Parkinson's disease cohort

BackgroundMotor complications may become major challenges in the management of patients with Parkinson's disease. In this study, we sought to determine the incidence, risk factors, evolution, and treatment of motor fluctuations and dyskinesias in a population-representative, incident Parkinson's disease cohort. MethodsIn this prospective population-based 5-year longitudinal study, we followed 189 incident and initially drug-naïve Parkinson's disease patients biannually for detailed examination of dyskinesias and motor fluctuations as defined by the Unified Parkinson's disease Rating Scale. We performed Kaplan–Meier survival and Cox regression analyses to assess cumulative incidence and risk factors of these motor complications. ResultsThe 5-year cumulative incidence of motor complications was 52.4%. Motor fluctuations occurred in 42.9% and dyskinesias in 24.3%. Besides higher motor severity predicting both motor fluctuations (p = 0.016) and dyskinesias (p < 0.001), lower age at diagnosis predicted motor fluctuations (p = 0.001), whereas female gender predicted dyskinesias (p = 0.001). Actual levodopa dose at onset of motor fluctuations (p = 0.037) or dyskinesias (p < 0.001) rather than initial treatment with levodopa (p > 0.1) independently predicted development of motor complications. Motor fluctuations reversed in 37% and dyskinesias in 49% of patients on oral treatment and remained generally mild in those with persistent complications. No patients received device-aided therapies during the study. ConclusionsMore than 50% in the general Parkinson's disease population develop motor complications within 5 years of diagnosis. However, they remain mild in the vast majority and are reversible in a substantial proportion of patients.