Effectiveness and safety of opicapone in Parkinson’s disease patients with motor fluctuations: the OPTIPARK open-label study

Background The efficacy and safety of opicapone, a once-daily catechol-O-methyltransferase inhibitor, have been established in two large randomized, placebo-controlled, multinational pivotal trials. Still, clinical evidence from routine practice is needed to complement the data from the pivotal trials. Methods OPTIPARK (NCT02847442) was a prospective, open-label, single-arm trial conducted in Germany and the UK under clinical practice conditions. Patients with Parkinson’s disease and motor fluctuations were treated with opicapone 50 mg for 3 (Germany) or 6 (UK) months in addition to their current levodopa and other antiparkinsonian treatments. The primary endpoint was the Clinician’s Global Impression of Change (CGI-C) after 3 months. Secondary assessments included Patient Global Impressions of Change (PGI-C), the Unified Parkinson’s Disease Rating Scale (UPDRS), Parkinson’s Disease Questionnaire (PDQ-8), and the Non-Motor Symptoms Scale (NMSS). Safety assessments included evaluation of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs). Results Of the 506 patients enrolled, 495 (97.8%) took at least one dose of opicapone. Of these, 393 (79.4%) patients completed 3 months of treatment. Overall, 71.3 and 76.9% of patients experienced any improvement on CGI-C and PGI-C after 3 months, respectively (full analysis set). At 6 months, for UK subgroup only (n = 95), 85.3% of patients were judged by investigators as improved since commencing treatment. UPDRS scores at 3 months showed statistically significant improvements in activities of daily living during OFF (mean ± SD change from baseline: − 3.0 ± 4.6, p < 0.0001) and motor scores during ON (− 4.6 ± 8.1, p < 0.0001). The mean ± SD improvements of − 3.4 ± 12.8 points for PDQ-8 and -6.8 ± 19.7 points for NMSS were statistically significant versus baseline (both p < 0.0001). Most of TEAEs (94.8% of events) were of mild or moderate intensity. TEAEs considered to be at least possibly related to opicapone were reported for 45.1% of patients, with dyskinesia (11.5%) and dry mouth (6.5%) being the most frequently reported. Serious TEAEs considered at least possibly related to opicapone were reported for 1.4% of patients. Conclusions Opicapone 50 mg was effective and generally well-tolerated in PD patients with motor fluctuations treated in clinical practice. Trial registration Registered in July 2016 at clinicaltrials.gov (NCT02847442)

Genotypic Diversity within a Single Pseudomonas aeruginosa Strain Commonly Shared by Australian Patients with Cystic Fibrosis

In cystic fibrosis (CF), Pseudomonas aeruginosa undergoes intra-strain genotypic and phenotypic diversification while establishing and maintaining chronic lung infections. As the clinical significance of these changes is uncertain, we investigated intra-strain diversity in commonly shared strains from CF patients to determine if specific gene mutations were associated with increased antibiotic resistance and worse clinical outcomes. Two-hundred-and-one P. aeruginosa isolates (163 represented a dominant Australian shared strain, AUST-02) from two Queensland CF centres over two distinct time-periods (2001-2002 and 2007-2009) underwent mexZ and lasR sequencing. Broth microdilution antibiotic susceptibility testing in a subset of isolates was also performed. We identified a novel AUST-02 subtype (M3L7) in adults attending a single Queensland CF centre. This M3L7 subtype was multi-drug resistant and had significantly higher antibiotic minimum inhibitory concentrations than other AUST-02 sub-types. Prospective molecular surveillance using polymerase chain reaction assays determined the prevalence of the 'M3L7' subtype at this centre during 2007-2009 (170 patients) and 2011 (173 patients). Three-year clinical outcomes of patients harbouring different strains and subtypes were compared. MexZ and LasR sequences from AUST-02 isolates were more likely in 2007-2009 than 2001-2002 to exhibit mutations (mexZ: odds ratio (OR) = 3.8; 95% confidence interval (CI): 1.1-13.5 and LasR: OR = 2.5; 95% CI: 1.3-5.0). Surveillance at the adult centre in 2007-2009 identified M3L7 in 28/509 (5.5%) P. aeruginosa isolates from 13/170 (7.6%) patients. A repeat survey in 2011 identified M3L7 in 21/519 (4.0%) P. aeruginosa isolates from 11/173 (6.4%) patients. The M3L7 subtype was associated with greater intravenous antibiotic and hospitalisation requirements, and a higher 3-year risk of death/lung transplantation, than other AUST-02 subtypes (adjusted hazard ratio [HR] = 9.4; 95% CI: 2.2-39.2) and non-AUST-02 strains (adjusted HR = 4.8; 95% CI: 1.4-16.2). This suggests ongoing microevolution of the shared CF strain, AUST-02, was associated with an emerging multi-drug resistant subtype and possibly poorer clinical outcomes

Flow diagram demonstrating patient and isolate selection for initial assessment of <i>mexZ</i> and <i>lasR</i> sequence diversity and antibiotic susceptibility.

<p>Flow diagram demonstrating patient and isolate selection for initial assessment of <i>mexZ</i> and <i>lasR</i> sequence diversity and antibiotic susceptibility.</p

Baseline clinical characteristics of the 166 patients with cystic fibrosis and <i>Pseudomonas aeruginosa</i> infection from The Prince Charles Hospital surveyed in 2007–2009. ^a

<p>Baseline clinical characteristics of the 166 patients with cystic fibrosis and <i>Pseudomonas aeruginosa</i> infection from The Prince Charles Hospital surveyed in 2007–2009. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0144022#t003fn001" target="_blank">^a</a></p

Clinical outcome of 166 TPCH adult patients within 3-years of participating in the 2007–2009 survey.

<p>Clinical outcome of 166 TPCH adult patients within 3-years of participating in the 2007–2009 survey.</p

Flow diagram showing patients included in the two cross-sectional surveys for ‘M3L7’ AUST-02 subtype at TPCH.

<p>Flow diagram showing patients included in the two cross-sectional surveys for ‘M3L7’ AUST-02 subtype at TPCH.</p

Summary of longitudinal within-patient changes involving shared and unique <i>Pseudomonas aeruginosa</i> strains, including their subtypes^a.

<p>Summary of longitudinal within-patient changes involving shared and unique <i>Pseudomonas aeruginosa</i> strains, including their subtypes<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0144022#t002fn001" target="_blank">^a</a>.</p

Disease progression and treatment burden (2007–2009 and 2011) by <i>Pseudomonas aeruginosa</i> strain and subtype groupings.

<p>Disease progression and treatment burden (2007–2009 and 2011) by <i>Pseudomonas aeruginosa</i> strain and subtype groupings.</p