Addressing Comorbidities in People with Parkinson’s Disease: Considerations From An Expert Panel

In the UK, guidance exists to aid clinicians and patients deciding when treatment for Parkinson’s disease (PD) should be initiated and which therapies to consider. National Institute for Health and Care Excellence (NICE) guidance recommends that before starting PD treatment clinicians should discuss the following: the patient’s individual clinical circumstances; lifestyle; preferences; needs and goals; as well as the potential benefits and harms of the different drug classes. Individualization of medicines and management in PD significantly improves patients’ outcomes and quality of life. This article aims to provide simple and practical guidance to help clinicians address common, but often overlooked, co-morbidities. A multi-disciplinary group of PD experts discussed areas where clinical care can be improved by addressing commonly found co-morbidities in people with Parkinson’s (PwP) based on clinical experience and existing literature, in a roundtable meeting organized and funded by Bial Pharma UK Ltd. The experts identified four core areas (bone health, cardiovascular risk, anticholinergic burden, and sleep quality) that, if further standardized may improve treatment outcomes for PwP patients. Focusing on anticholinergic burden, cardiac risk, sleep, and bone health could offer a significant contribution to personalizing regimes for PwP and improving overall patient outcomes. Within this opinion-based paper, the experts offer a list of guiding factors to help practitioners in the management of PwP

A narrative synthesis of research evidence for tinnitus-related complaints as reported by patients and their significant others

Background: There are a large number of assessment tools for tinnitus, with little consensus on what it is important to measure and no preference for a minimum reporting standard. The item content of tinnitus assessment tools should seek to capture relevant impacts of tinnitus on everyday life, but no-one has yet synthesised information about the range of tinnitus complaints. This review is thus the first comprehensive and authoritative collection and synthesis of what adults with tinnitus and their significant others report as problems in their everyday lives caused by tinnitus. Methods: Electronic searches were conducted in PubMed, Embase, CINAHL, as well as grey literature sources to identify publications from January 1980 to June 2015 in which participants were enrolled because tinnitus was their primary complaint. A manual search of seven relevant journals updated the search to December 2017. Of the 3,699 titles identified overall, 84 records (reporting 86 studies) met our inclusion criteria and were taken through to data collection. Coders collated generic and tinnitus specific complaints reported by people with tinnitus. All relevant data items were then analyzed using an iterative approach to narrative synthesis to form domain groupings representing complaints of tinnitus, which were compared patients and significant others. Results: From the 86 studies analyzed using data collected from 16,381 patients, 42 discrete complaints were identified spanning physical and psychological health, quality of life and negative attributes of the tinnitus sound. This diversity was not captured by any individual study alone. There was good convergence between complaints collected using open- and closed-format questions, with the exception of general moods and perceptual attributes of tinnitus (location, loudness, pitch and unpleasantness); reported only using closed questions. Just two studies addressed data from the perspective of significant others (n=79), but there was substantial correspondence with the patient framework, especially regarding relationships and social life. Conclusions: Our findings contribute fundamental new knowledge and a unique resource that enables investigators to appreciate the broad impacts of tinnitus on an individual. Our findings can also be used to guide questions during diagnostic assessment, to evaluate existing tinnitus-specific HR-QoL questionnaires and develop new ones, where necessary

Noninvasive options for ‘wearing-off’ in Parkinson's disease: a clinical consensus from a panel of UK Parkinson's disease specialists

In the past 4 years, two adjunctive treatment options to levodopa have been licensed for use in the UK in patients with Parkinson's disease (PD) and motor fluctuations: opicapone, a third-generation catechol-O-methyl transferase inhibitor, and safinamide, a monoamine oxidase B inhibitor. This clinical consensus outlines the practical considerations relating to motor fluctuations and managing wearing-off in patients with PD, and provides a clinical insight to adjunctive treatment options, including opicapone and safinamide. Practice-based opinion was provided from a multidisciplinary steering Group of eight UK-based movement disorder and PD specialists, including neurologists, geriatricians and a nurse specialist, from England, Scotland and Wales

Core outcome domains for early-phase clinical trials of sound-, psychology-, and pharmacology-based interventions to manage chronic subjective tinnitus in adults: the COMIT'ID study protocol for using a Delphi process and face-to-face meetings to establish consensus

Background: The reporting of outcomes in clinical trials of subjective tinnitus indicates that many different tinnitus-related complaints are of interest to investigators, from perceptual attributes of the sound (e.g. loudness) to psychosocial impacts (e.g. quality of life). Even when considering one type of intervention strategy for subjective tinnitus, there is no agreement about what is critically important for deciding whether a treatment is effective. The main purpose of this observational study is therefore to develop Core Outcome Domain Sets for the three different intervention strategies (sound, psychological, and pharmacological) for adults with chronic subjective tinnitus that should be measured and reported in every clinical trial of these interventions. Secondary objectives are to identify the strengths and limitations of our study design for recruiting and reducing attrition of participants, and to explore uptake of the core outcomes. Methods: The ‘Core Outcome Measures in Tinnitus: International Delphi’ (COMIT’ID) study will use a mixed methods approach that incorporates input from healthcare users at the pre-Delphi stage, a modified three round Delphi survey and final consensus meetings (one for each intervention). The meetings will generate recommendations by stakeholder representatives on agreed Core Outcome Domain Sets specific to each intervention. A subsequent step will establish a common cross-cutting Core Outcome Domain Set by identifying the common outcome domains included in all three intervention-specific Core Outcome Domain Sets. To address the secondary objectives, we will gather feedback from participants about their experience of taking part in the Delphi process. We aspire to conduct an observational cohort study to evaluate uptake of the core outcomes in published studies at 7 years following core outcome set publication. Discussion: The COMIT’ID study aims to develop a Core Outcome Domain Set that are agreed as critically important for deciding whether a treatment for subjective tinnitus is effective. Such a recommendation would help to standardise future clinical trials worldwide and so we will determine if participation increases use of the core outcome set in the long term. Trial registration: This project has been registered in the database of the Core Outcome Measures in Effectiveness Trials (COMET) initiative

Spatial and temporal variability of the concentration field from localized releases in a regular building array

Spatial and temporal fluctuations in the concentration field from an ensemble of continuous point-source releases in a regular building array are analyzed from data generated by direct numerical simulations. The release is of a passive scalar under conditions of neutral stability. Results are related to the underlying flow structure by contrasting data for an imposed wind direction of 0 deg and 45 deg relative to the buildings. Furthermore, the effects of distance from the source and vicinity to the plume centreline on the spatial and temporal variability are documented. The general picture that emerges is that this particular geometry splits the flow domain into segments (e.g. “streets” and “intersections”) in each of which the air is, to a first approximation, well mixed. Notable exceptions to this general rule include regions close to the source, near the plume edge, and in unobstructed channels when the flow is aligned. In the oblique (45 deg) case the strongly three-dimensional nature of the flow enhances mixing of a scalar within the canopy leading to reduced temporal and spatial concentration fluctuations within the plume core. These fluctuations are in general larger for the parallel flow (0 deg) case, especially so in the long unobstructed channels. Due to the more complex flow structure in the canyon-type streets behind buildings, fluctuations are lower than in the open channels, though still substantially larger than for oblique flow. These results are relevant to the formulation of simple models for dispersion in urban areas and to the quantification of the uncertainties in their predictions

A systematic review of techniques and effects of self-help interventions for tinnitus: application of taxonomies from health psychology

Objective: Self-help interventions are followed by people independently with minimal or no therapist contact. This review aims to assess the effectiveness of self-help interventions for adults with chronic tinnitus and systematically identify the self-help techniques used. Design: Systematic review and application of health psychology taxonomies. Electronic database searches were conducted, supplemented by citation searching and hand-searching of key journals. Prospective controlled trials, which used measures of tinnitus distress, functional management, anxiety, depression, and quality of life, were included. Michie et al’s behaviour change techniques (BCTs) taxonomy and Taylor et al’s PRISMS taxonomy of self-management components were applied to describe interventions. Study sample: Five studies were included, providing low-to-moderate levels of evidence. Results: Randomized controlled trial studies were too few and heterogeneous for meta-analysis to be performed. Studies comparing self-help interventions to therapist-guided interventions and assessing non tinnitus-specific psychosocial outcomes and functional management were lacking. Fifteen BCTs and eight self-management components were identified across interventions. Conclusions: A lack of high-quality and homogeneous studies meant that confident conclusions could not be drawn regarding the efficacy of self-help interventions for tinnitus. Better reporting and categorization of intervention techniques is needed for replication in research and practice and to facilitate understanding of intervention mechanisms

Quality of Life in Men With Prostate Cancer Randomly Allocated to Receive Docetaxel or Abiraterone in the STAMPEDE Trial

PURPOSE: Docetaxel and abiraterone acetate plus prednisone or prednisolone (AAP) both improve survival when commenced alongside standard of care (SOC) androgen deprivation therapy in locally advanced or metastatic hormone-sensitive prostate cancer. Thus, patient-reported quality of life (QOL) data may guide treatment choices. METHODS: A group of patients within the STAMPEDE trial were contemporaneously enrolled with the possibility of being randomly allocated to receive either docetaxel + SOC or AAP + SOC. A mixed-model assessed QOL in those who had completed at least one QLQ-C30 + PR25 questionnaire. The primary outcome measure was difference in global-QOL (QLQ-C30 Q29&30) between patients allocated to docetaxel + SOC or AAP + SOC over the 2 years after random assignment, with a predefined criterion for clinically meaningful difference of > 4.0 points. Secondary outcome measures included longitudinal comparison of functional domains, pain, and fatigue, plus global-QOL at defined timepoints. RESULTS: Five hundred fifteen patients (173 docetaxel + SOC and 342 AAP + SOC) were included. Baseline characteristics, proportion of missing data, and mean baseline global-QOL scores (docetaxel + SOC 77.8 and AAP + SOC 78.0) were similar. Over the 2 years following random assignment, the mean modeled global-QOL score was +3.9 points (95% CI, +0.5 to +7.2; P = .022) higher in patients allocated to AAP + SOC. Global-QOL was higher for patients allocated to AAP + SOC over the first year (+5.7 points, 95% CI, +3.0 to +8.5; P < .001), particularly at 12 (+7.0 points, 95% CI, +3.0 to +11.0; P = .001) and 24 weeks (+8.3 points, 95% CI, +4.0 to +12.6; P < .001). CONCLUSION: Patient-reported QOL was superior for patients allocated to receive AAP + SOC, compared with docetaxel + SOC over a 2-year period, narrowly missing the predefined value for clinical significance. Patients receiving AAP + SOC reported clinically meaningful higher global-QOL scores throughout the first year following random assignment

Systematic review of outcome domains and instruments used in clinical trials of tinnitus treatments in adults

BACKGROUND: There is no evidence-based guidance to facilitate design decisions for confirmatory trials or systematic reviews investigating treatment efficacy for adults with tinnitus. This systematic review therefore seeks to ascertain the current status of trial designs by identifying and evaluating the reporting of outcome domains and instruments in the treatment of adults with tinnitus. METHODS: Records were identified by searching PubMed, EMBASE CINAHL, EBSCO, and CENTRAL clinical trial registries (ClinicalTrials.gov, ISRCTN, ICTRP) and the Cochrane Database of Systematic Reviews. Eligible records were those published from 1 July 2006 to 12 March 2015. Included studies were those reporting adults aged 18 years or older who reported tinnitus as a primary complaint, and who were enrolled into a randomised controlled trial, a before and after study, a non-randomised controlled trial, a case-controlled study or a cohort study, and written in English. Studies with fewer than 20 participants were excluded. RESULTS: Two hundred and twenty-eight studies were included. Thirty-five different primary outcome domains were identified spanning seven categories (tinnitus percept, impact of tinnitus, co-occurring complaints, quality of life, body structures and function, treatment-related outcomes and unclear or not specified). Over half the studies (55 %) did not clearly define the complaint of interest. Tinnitus loudness was the domain most often reported (14 %), followed by tinnitus distress (7 %). Seventy-eight different primary outcome instruments were identified. Instruments assessing multiple attributes of the impact of tinnitus were most common (34 %). Overall, 24 different patient-reported tools were used, predominantly the Tinnitus Handicap Inventory (15 %). Loudness was measured in diverse ways including a numerical rating scale (8 %), loudness matching (4 %), minimum masking level (1 %) and loudness discomfort level (1 %). Ten percent of studies did not clearly report the instrument used. CONCLUSIONS: Our findings indicate poor appreciation of the basic principles of good trial design, particularly the importance of specifying what aspect of therapeutic benefit is the main outcome. No single outcome was reported in all studies and there was a broad diversity of outcome instruments. PROSPERO REGISTRATION: The systematic review protocol is registered on PROSPERO (International Prospective Register of Systematic Reviews): CRD42015017525. Registered on 12 March 2015 revised on 15 March 2016. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13063-016-1399-9) contains supplementary material, which is available to authorized users

Abiraterone acetate plus prednisolone with or without enzalutamide for patients with metastatic prostate cancer starting androgen deprivation therapy: final results from two randomised phase 3 trials of the STAMPEDE platform protocol

BACKGROUND: Abiraterone acetate plus prednisolone (herein referred to as abiraterone) or enzalutamide added at the start of androgen deprivation therapy improves outcomes for patients with metastatic prostate cancer. Here, we aimed to evaluate long-term outcomes and test whether combining enzalutamide with abiraterone and androgen deprivation therapy improves survival. METHODS: We analysed two open-label, randomised, controlled, phase 3 trials of the STAMPEDE platform protocol, with no overlapping controls, conducted at 117 sites in the UK and Switzerland. Eligible patients (no age restriction) had metastatic, histologically-confirmed prostate adenocarcinoma; a WHO performance status of 0–2; and adequate haematological, renal, and liver function. Patients were randomly assigned (1:1) using a computerised algorithm and a minimisation technique to either standard of care (androgen deprivation therapy; docetaxel 75 mg/m2 intravenously for six cycles with prednisolone 10 mg orally once per day allowed from Dec 17, 2015) or standard of care plus abiraterone acetate 1000 mg and prednisolone 5 mg (in the abiraterone trial) orally or abiraterone acetate and prednisolone plus enzalutamide 160 mg orally once a day (in the abiraterone and enzalutamide trial). Patients were stratified by centre, age, WHO performance status, type of androgen deprivation therapy, use of aspirin or non-steroidal anti-inflammatory drugs, pelvic nodal status, planned radiotherapy, and planned docetaxel use. The primary outcome was overall survival assessed in the intention-to-treat population. Safety was assessed in all patients who started treatment. A fixed-effects meta-analysis of individual patient data was used to compare differences in survival between the two trials. STAMPEDE is registered with ClinicalTrials.gov (NCT00268476) and ISRCTN (ISRCTN78818544). FINDINGS: Between Nov 15, 2011, and Jan 17, 2014, 1003 patients were randomly assigned to standard of care (n=502) or standard of care plus abiraterone (n=501) in the abiraterone trial. Between July 29, 2014, and March 31, 2016, 916 patients were randomly assigned to standard of care (n=454) or standard of care plus abiraterone and enzalutamide (n=462) in the abiraterone and enzalutamide trial. Median follow-up was 96 months (IQR 86–107) in the abiraterone trial and 72 months (61–74) in the abiraterone and enzalutamide trial. In the abiraterone trial, median overall survival was 76·6 months (95% CI 67·8–86·9) in the abiraterone group versus 45·7 months (41·6–52·0) in the standard of care group (hazard ratio [HR] 0·62 [95% CI 0·53–0·73]; p<0·0001). In the abiraterone and enzalutamide trial, median overall survival was 73·1 months (61·9–81·3) in the abiraterone and enzalutamide group versus 51·8 months (45·3–59·0) in the standard of care group (HR 0·65 [0·55–0·77]; p<0·0001). We found no difference in the treatment effect between these two trials (interaction HR 1·05 [0·83–1·32]; pinteraction=0·71) or between-trial heterogeneity (I2 p=0·70). In the first 5 years of treatment, grade 3–5 toxic effects were higher when abiraterone was added to standard of care (271 [54%] of 498 vs 192 [38%] of 502 with standard of care) and the highest toxic effects were seen when abiraterone and enzalutamide were added to standard of care (302 [68%] of 445 vs 204 [45%] of 454 with standard of care). Cardiac causes were the most common cause of death due to adverse events (five [1%] with standard of care plus abiraterone and enzalutamide [two attributed to treatment] and one (<1%) with standard of care in the abiraterone trial). INTERPRETATION: Enzalutamide and abiraterone should not be combined for patients with prostate cancer starting long-term androgen deprivation therapy. Clinically important improvements in survival from addition of abiraterone to androgen deprivation therapy are maintained for longer than 7 years. FUNDING: Cancer Research UK, UK Medical Research Council, Swiss Group for Clinical Cancer Research, Janssen, and Astellas