Efficacy and safety of gefapixant, a P2X3 receptor antagonist, in refractory chronic cough and unexplained chronic cough (COUGH-1 and COUGH-2): results from two double-blind, randomised, parallel-group, placebo-controlled, phase 3 trials.

BACKGROUND: Gefapixant is an oral P2X3 receptor antagonist that has previously shown efficacy and safety in refractory chronic cough and unexplained chronic cough. We therefore aim to confirm the efficacy and safety of gefapixant in participants with refractory chronic cough and unexplained chronic cough. METHODS: COUGH-1 and COUGH-2 were both double-blind, randomised, parallel-group, placebo-controlled, phase 3 trials. COUGH-1 was done in 156 sites in 17 countries and COUGH-2 in 175 sites in 20 countries. We enrolled participants who were 18 years or older with a diagnosis of refractory chronic cough or unexplained chronic cough of 1 year duration or more. Participants were also required to have a cough severity visual analogue scale score of 40 mm or more at screening and baseline. Eligible participants were randomly allocated (1:1:1), using a computer-generated allocation schedule, to one of three treatment groups: placebo, gefapixant 15 mg twice per day, or gefapixant 45 mg twice per day. All study treatments were given orally. Participants were treated over a 12-week main study period in COUGH-1 and a 24-week main study period in COUGH-2; followed by extension periods for a total of up to 52 weeks of treatment in both trials. The primary outcome was placebo-adjusted mean change in 24-h cough frequency at 12 weeks in COUGH-1 and 24 weeks in COUGH-2. Both studies were registered with ClinicalTrials.gov, NCT03449134 (COUGH-1) and NCT03449147 (COUGH-2). FINDINGS: From March 14, 2018, (first participant screened) to July 26, 2019, (last participant screened) 732 patients were recruited in COUGH-1 and 1317 in COUGH-2. COUGH-1 randomly assigned and treated 730 participants (243 [33×3%] with placebo, 244 [33×4%] with gefapixant 15 mg twice per day, and 243 [33×3%] with gefapixant 45 mg twice per day); COUGH-2 randomly assigned and treated 1314 participants (435 [33×1%] with placebo, 440 [33×5%] with gefapixant 15 mg twice per day, and 439 [33×4%] with gefapixant 45 mg twice per day). Participants were mostly female (542 [74×2%] of 730 in COUGH-1 and 984 [74×9%] of 1314 in COUGH-2). The mean age was 59×0 years (SD 12×6) in COUGH-1 and 58×1 years (12×1) in COUGH-2, and the mean cough duration was 11·6 years (SD 9·5) in COUGH-1 and 11·2 years (9·8) in COUGH-2. Gefapixant 45 mg twice per day showed significant reductions in 24-h cough frequency compared with placebo at week 12 in COUGH-1 (18·5% [95% CI 32·9-0·9]; p=0·041) and at week 24 in COUGH-2 (14·6% [26·1-1·4]; p=0·031). Gefapixant 15 mg twice per day did not show a significant reduction in cough frequency versus placebo in both studies. The most common adverse events were related to taste disturbance: ageusia (36 [4·9%] of 730 in COUGH-1 and 86 [6·5%] of 1314 in COUGH-2), dysgeusia (118 [16·2%] in COUGH-1 and 277 [21·1%] in COUGH-2), hypergeusia (3 [0·4%] in COUGH-1 and 6 [0×5%] in COUGH-2), hypogeusia (19 [2·6%] in COUGH-1 and 80 [6·1%] in COUGH-2), and taste disorder (28 [3·8%] in COUGH-1 and 46 [3·5%] in COUGH-2). INTERPRETATION: Gefapixant 45 mg twice per day is the first treatment to show efficacy with an acceptable safety profile in phase 3 clinical trials for refractory chronic cough or unexplained chronic cough. FUNDING: Merck Sharp & Dohme.

Evaluation of factors contributing to the response to fosaprepitant in a heterogeneous, moderately emetogenic chemotherapy population: an exploratory analysis of a randomized phase III trial.

PURPOSE: Fosaprepitant improved prevention of chemotherapy-induced nausea and vomiting (CINV) in a randomized, double-blind phase III trial (PN031). This post hoc analysis explored factors that may have influenced response. METHODS: Adult subjects (N = 1000) scheduled to receive non-anthracycline and cyclophosphamide (AC) moderately emetogenic chemotherapy (MEC) on day 1 were randomly assigned 1:1 to a single-dose, 150-mg intravenous fosaprepitant regimen or a control regimen. Both regimens included dexamethasone and ondansetron on day 1, with ondansetron continuing through day 3 in the control arm only. Complete response (CR; no vomiting and no rescue medication) rates in the acute, delayed, and overall phases (0-25, 25-120, and 0-120 h, respectively) were analyzed by chemotherapy type (carboplatin-based vs non-carboplatin-based), chemotherapy duration (single-day vs multiple-day), and baseline characteristics. RESULTS: Most subjects received single-day chemotherapeutic regimens (70.6%), which were mainly carboplatin-based (67.6%). CR with fosaprepitant was consistent (76-80%) during the delayed and overall phases in carboplatin-based and non-carboplatin-based subgroups and in subgroups receiving single-day or multiple-day MEC regimens. Treatment effects favored fosaprepitant for the carboplatin-based versus the non-carboplatin-based group during the delayed phase (14.1 vs 6.5%; p = 0.06), and for the single-day versus the multiple-day subgroup during the delayed (13.2 vs 3.2%; p = 0.02) and overall phases (12.8 vs 4.0%; p = 0.06). CONCLUSIONS: This exploratory analysis confirms that single-dose fosaprepitant is effective for the prevention of CINV in subjects receiving carboplatin or non-carboplatin in both single- and multiple-day non-AC MEC chemotherapy regimens. This trial is registered at ClinicalTrials.gov , number NCT01594749.

The Evolution of Remote-Controlled Intramedullary Lengthening and Compression Nails.

The operative elongation of limbs has long been a goal of orthopaedic surgeons. Indeed, the very first external skeletal fixators, although designed for stabilization of displaced fractures, were also used to overcome the posttrauma shortening that so commonly accompanies fracture deformities.

Identification of factors that support successful implementation of care bundles in the acute medical setting: a qualitative study.

BACKGROUND: Clinical guidelines offer an accessible synthesis of the best evidence of effectiveness of interventions, providing recommendations and standards for clinical practice. Many guidelines are relevant to the diagnosis and management of the acutely unwell patient during the first 24-48 h of admission. Care bundles are comprised of a small number of evidence-based interventions that when implemented together aim to achieve better outcomes than when implemented individually. Care bundles that are explicitly developed from guidelines to provide a set of related evidence-based actions have been shown to improve the care of many conditions in emergency, acute and critical care settings. This study aimed to review the implementation of two distinct care bundles in the acute medical setting and identify the factors that supported successful implementation. METHODS: Two initiatives that had used a systematic approach to quality improvement to successfully implement care bundles within the acute medical setting were selected as case studies. Contemporaneous data generated during the initiatives included the review reports, review minutes and audio recordings of the review meetings at different time points. Data were subject to deductive analysis using three domains of the Consolidated Framework for Implementation Research to identify factors that were important in the implementation of the care bundles. RESULTS: Several factors were identified that directly influenced the implementation of the care bundles. Firstly, the availability of resources to support initiatives, which included training to develop quality improvement skills within the team and building capacity within the organisation more generally. Secondly, the perceived sustainability of changes by stakeholders influenced the embedding new care processes into existing clinical systems, maximising their chance of being sustained. Thirdly, senior leadership support was seen as critical not just in supporting implementation but also in sustaining longer-term changes brought about by the initiative. Lastly, practitioner incentives were identified as potential levers to engage junior doctors, a crucial part of the acute medical work force and essential to the initiatives, as there is currently little recognition or reward for involvement CONCLUSIONS: The factors identified have been shown to be supportive in the successful implementation of care bundles as a mechanism for implementing clinical guidelines. Addressing these factors at a practitioner and organisational level, alongside the use of a systematic quality improvement approach, should increase the likelihood that care bundles will be implemented successfully to deliver evidence based changes in the acute medical setting.

PRECICE® magnetically-driven, telescopic, intramedullary lengthening nail: pre-clinical testing and first 30 patients.

INTRODUCTION: Femoral/tibial lengthening with a telescopic, magnetically-powered, intramedullary nail is an alternative to lengthening with external fixation. METHODS: Pre-clinical testing was conducted of the PRECICE in a human cadaver. A retrospective review of the first 30 consecutive patients who underwent unilateral lengthening was also conducted. Nail accuracy was obtained by comparing the amount of nail distraction to the final bone length achieved at the end of the distraction process. Relative standard deviation of accuracy was used to calculate nail precision. RESULTS: Devices performed successfully in a human cadaver. Thirty consecutive patients (10 females, 20 males; mean age, 23 years) with limb length discrepancy (LLD) were followed an average of 19 months (range, 12-24 months). Etiology included congenital shortening (14), posttraumatic deformities (7), Ollier disease (3), osteosarcoma resection (1), prior clubfoot (2), hip dysplasia (1), post-septic growth arrest of knee (1), and LLD after hip arthroplasty (1). Twenty-four femoral and eight tibial nails were implanted. Mean preoperative lengthening goal was 4.4 cm (range, 2-6.5 cm); mean postoperative length achieved was 4.3 cm (range, 1.5-6.5 cm). Average consolidation index was 36.4 days/cm (range, 12.8-113 days/cm). Mean nail accuracy was 97.3% with a precision of 92.4%. Average preoperative and 12-month postoperative Enneking scores were 21.5 and 25.3 (p < 0.001), respectively. The preoperative and 12-month postoperative SF-12 physical and mental component scores were not statistically different. Nine complications (nine limb segments) resolved: two partial femoral unions, two suspected deep vein thrombosis (DVT), one delayed tibial union, one fibular nonunion, one peroneal nerve irritation, one knee joint subluxation, and one confirmed DVT. Twenty-nine (91%) of 32 limb segments achieved successful bone healing without revision surgery. DISCUSSION: Limb lengthening with PRECICE is reliable, but larger trials with longer follow-up will reveal limitations. Implantable nails prevent problems associated with external fixation, such as muscle tethering and pin-site infections.

Co-production as an approach to developing stakeholder partnerships to reduce mental health inequalities: an evaluation of a pilot service.

Aim This study aimed to evaluate a pilot cross-sector initiative - bringing together public health, a community group, primary mental health teams and patients - in using co-production approaches to deliver a mental health service to meet the needs of the black and minority ethnic communities. BACKGROUND: Black and minority ethnic communities continue to face inequalities in mental health service access and provision. They are under-represented in low-level interventions as they are less likely to be referred, and more likely to disengage from mainstream mental health services. Effective models that lead to improved access and better outcomes are yet to be established. It has long been recognised that to be effective, services need to be more culturally competent, which may be achieved through a co-production approach. METHODS: This study aimed to evaluate the role of co-production in the development of a novel community mental health service for black and minority ethnic service users. Qualitative research methods, including semi-structured interviews and focus groups, were used to collect data to examine the use of co-production methods in designing and delivering an improved mental health service. Findings Twenty-five patients enrolled into the study; of these, 10 were signposted for more intensive psychological support. A 75% retention rate was recorded (higher than is generally the case for black and minority ethnic service users). Early indications are that the project has helped overcome barriers to accessing mental health services. Although small scale, this study highlights an alternative model that, if explored and developed further, could lead to delivery of patient-centred services to improve access and patient experience within mental health services, particularly for black and minority ethnic communities.

A qualitative evaluation to explore the suitability, feasibility and acceptability of using a 'celebration card' intervention in primary care to improve the uptake of childhood vaccinations.

BACKGROUND: Childhood vaccination remains a primary mechanism for reducing the burden of infectious disease. In the United Kingdom, as in many countries, a sustained effort is required to ensure that vaccination targets are met to afford protection to the whole population from vaccine preventable disease. The Celebrate and Protect programme is a collaborative partnership developed to improve the uptake of childhood vaccination across a number of boroughs within London through the use of a celebration card to encourage attendance for vaccination and enhance relationships between general practices and the parents/carers of children. METHODS: This study was undertaken to assess the suitability, feasibility and acceptability of the Celebrate and Protect programme across nine boroughs in London. Data were collected either from telephone interviews (n = 24) or from focus groups (n = 31). A total of 55 key informants were included in the study, representing strategic, commissioning or policy leads, healthcare professionals and primary care teams delivering vaccinations and parents/carers of children under five. RESULTS: The analysis of data identified that whilst parents/carers saw the celebration card positively this raised the issue of 'vaccine hesitancy' and the lack of information that parents/carers have to make informed decisions about vaccination. Similarly, healthcare professionals viewed the programme positively and felt that it was deliverable within existing resources although they raised wider questions about on-going sustainability and about quantitative data collection. In relation to the collaboration between primary care and a pharmaceutical company in developing the Celebrate and Protect programme, it was generally felt that, provided appropriate governance is in place, it was a pragmatic approach in which the benefits outweighed any perceived disadvantages. DISCUSSION: The Celebrate and Protect programme was seen as an innovative collaborative programme to engage with parents and carers of children in order to improve relationships between service users and providers and subsequently increase vaccination uptake. The analysis demonstrates that that the celebration card is suitable for its purpose, acceptable to both healthcare professionals and to parents/carers of children and the Celebrate and Protect programme has been able to deliver its aims. CONCLUSION: Whilst the delivery of the 'celebration card' intervention in primary met its objectives there are some outstanding issues in terms of the sustainability of the initiative and the ability to demonstrate quantitative improvements in vaccination uptake rates.

A retrospective observational analysis to identify patient and treatment-related predictors of outcomes in a community mental health programme.

OBJECTIVES: This study aims to identify patient and treatment factors that affect clinical outcomes of community psychological therapy through the development of a predictive model using historic data from 2 services in London. In addition, the study aims to assess the completeness of data collection, explore how treatment outcomes are discriminated using current criteria for classifying recovery, and assess the feasibility and need for undertaking a future larger population analysis. DESIGN: Observational, retrospective discriminant analysis. SETTING: 2 London community mental health services that provide psychological therapies for common mental disorders including anxiety and depression. PARTICIPANTS: A total of 7388 patients attended the services between February 2009 and May 2012, of which 4393 (59%) completed therapy, or there was an agreement to end therapy, and were included in the study. PRIMARY AND SECONDARY OUTCOME MEASURES: Different combinations of the clinical outcome scores for anxiety Generalised Anxiety Disorder-7 and depression Patient Health Questionnaire-9 were used to construct different treatment outcomes. RESULTS: The predictive models were able to assign a positive or negative clinical outcome to each patient based on 5 independent pre-treatment variables, with an accuracy of 69.4% and 79.3%, respectively: initial severity of anxiety and depression, ethnicity, deprivation and gender. The number of sessions attended/missed were also important factors identified in recovery. CONCLUSIONS: Predicting whether patients are likely to have a positive outcome following treatment at entry might allow suitable modification of scheduled treatment, possibly resulting in improvements in outcomes. The model also highlights factors not only associated with poorer outcomes but inextricably linked to prevalence of common mental disorders, emphasising the importance of social determinants not only in poor health but also poor recovery.

Using geographical information systems and cartograms as a health service quality improvement tool.

INTRODUCTION: Disease prevalence can be spatially analysed to provide support for service implementation and health care planning, these analyses often display geographic variation. A key challenge is to communicate these results to decision makers, with variable levels of Geographic Information Systems (GIS) knowledge, in a way that represents the data and allows for comprehension. The present research describes the combination of established GIS methods and software tools to produce a novel technique of visualising disease admissions and to help prevent misinterpretation of data and less optimal decision making. The aim of this paper is to provide a tool that supports the ability of decision makers and service teams within health care settings to develop services more efficiently and better cater to the population; this tool has the advantage of information on the position of populations, the size of populations and the severity of disease. METHODS: A standard choropleth of the study region, London, is used to visualise total emergency admission values for Chronic Obstructive Pulmonary Disease and bronchiectasis using ESRI's ArcGIS software. Population estimates of the Lower Super Output Areas (LSOAs) are then used with the ScapeToad cartogram software tool, with the aim of visualising geography at uniform population density. An interpolation surface, in this case ArcGIS' spline tool, allows the creation of a smooth surface over the LSOA centroids for admission values on both standard and cartogram geographies. The final product of this research is the novel Cartogram Interpolation Surface (CartIS). RESULTS: The method provides a series of outputs culminating in the CartIS, applying an interpolation surface to a uniform population density. The cartogram effectively equalises the population density to remove visual bias from areas with a smaller population, while maintaining contiguous borders. CartIS decreases the number of extreme positive values not present in the underlying data as can be found in interpolation surfaces. DISCUSSION: This methodology provides a technique for combining simple GIS tools to create a novel output, CartIS, in a health service context with the key aim of improving visualisation communication techniques which highlight variation in small scale geographies across large regions. CartIS more faithfully represents the data than interpolation, and visually highlights areas of extreme value more than cartograms, when either is used in isolation.