Degarelix for Treating Advanced Hormone-Dependent Prostate Cancer: An Evidence Review Group Perspective of a NICE Single Technology Appraisal

As part of its Single Technology Appraisal Process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer of degarelix (Ferring Pharmaceuticals) to submit evidence for the clinical and cost effectiveness of degarelix for the treatment of advanced hormone-dependent prostate cancer. The School of Health and Related Research Technology Appraisal Group at the University of Sheffield was commissioned to act as the independent Evidence Review Group (ERG). The ERG produced a critical review of the evidence contained within the company’s submission to NICE. The evidence, which included a randomised controlled trial (RCT) of degarelix versus leuprorelin, found that degarelix was non-inferior to leuprorelin for reduction of testosterone levels and that degarelix achieved a more rapid suppression of prostate-specific antigen levels and subsequently decreased incidences of testosterone flare associated with luteinising hormone releasing-hormone (LHRH) agonists. However, protection against testosterone flare for the comparators in the clinical trials was not employed in line with UK clinical practice. Further claims surrounding overall survival, cardiovascular adverse events and clinical equivalence of the comparator drugs from six RCTs of degarelix should be regarded with caution because of flaws and inconsistencies in the pooling of trial data to draw conclusions. The cost-effectiveness evidence included a de novo economic model. Based on the ERG’s preferred base case, the deterministic incremental cost-effectiveness analysis (ICER) for degarelix versus 3-monthly triptorelin was £14,798 per quality-adjusted life-year (QALY) gained. Additional scenario analyses undertaken by the ERG resulted in ICERs for degarelix versus 3-monthly triptorelin ranging from £17,067 to £35,589 per QALY gained. Subgroup analyses undertaken using the Appraisal Committee’s preferred assumptions suggested that degarelix was not cost effective for the subgroup with metastatic disease but could be cost effective for the subgroup with spinal metastases. The company submitted further evidence to NICE following an initial negative Appraisal Committee decision. Further analyses from the Decision Support Unit found that that, whilst some evidence indicated that degarelix could be cost effective for a small subgroup of people with spinal cord compression (SCC), data on the potential size of this subgroup and the rate of SCC were insufficient to estimate an ICER based on the evidence submitted by the company and a separately commissioned systematic review. NICE recommended degarelix as an option for treating advanced hormone-dependent prostate cancer in people with spinal metastases, only if the commissioner can achieve at least the same discounted drug cost as that available to the UK NHS in June 2016

Peer support for the maintenance of physical activity and health in cancer survivors: the PEER trial - a study protocol of a randomised controlled trial

BACKGROUND: Despite an overwhelming body of evidence showing the benefits of physical activity (PA) and exercise for cancer survivors, few survivors meet the exercise oncology guidelines. Moreover, initiating, let alone maintaining exercise programs with cancer survivors continues to have limited success. The aim of this trial is to evaluate the influence of peer support on moderate-to-vigorous PA (MVPA) and various markers of health 12 months following a brief supervised exercise intervention in cancer survivors. METHODS: Men and women previously diagnosed with histologically-confirmed breast, colorectal or prostate cancer (n = 226), who are \u3e1-month post-treatment, will be invited to participate in this trial. Once enrolled, participants will complete 4 weeks (12 sessions) of supervised high intensity interval training (HIIT). On completion of the supervised phase, both groups will be provided with written recommendations and verbally encouraged to achieve three HIIT sessions per week, or equivalent exercise that meets the exercise oncology guidelines. Participants will be randomly assigned to receive 12 months of peer support, or no peer support (control). Primary and secondary outcomes will be assessed at baseline, after the 4-week supervised HIIT phase and at 3-, 6- and 12-months. Primary outcomes will include accelerometry-derived MVPA and prescribed HIIT session adherence; whilst secondary outcomes will include cardiorespiratory fitness ([Formula: see text]), body composition, quality of life and select cytokines, myokines and inflammatory markers. Random effects mixed modelling will be used to compare mean changes in outcomes between groups at each time point. A group x time interaction will be used to formally test for differences between groups (alpha =0.05); utilising intention-to-treat analyses. DISCUSSION: If successful, peer support may be proposed, adopted and implemented as a strategy to encourage cancer survivors to maintain exercise beyond the duration of a short-term, supervised intervention. A peer support-exercise model has the long-term potential to reduce comorbidities, improve physical and mental wellbeing, and significantly reduce the burden of disease in cancer survivors. ETHICS: Human Research Ethics Committee of Bellberry Ltd. (#2015-12-840). TRIAL REGISTRATION: Australian New Zealand Clinical Trial Registry 12618001855213 . Retrospectively registered 14 November 2018. Trial registration includes all components of the WHO Trial Registration Data Set, as recommended by the ICMJE

Testing the activitystat hypothesis: a randomised controlled trial protocol

Background: The activitystat hypothesis proposes that when physical activity or energy expenditure is increased or decreased in one domain, there will be a compensatory change in another domain to maintain an overall, stable level of physical activity or energy expenditure. To date, there has been no experimental study primarily designed to test the activitystat hypothesis in adults. The aim of this trial is to determine the effect of two different imposed exercise loads on total daily energy expenditure and physical activity levels. Methods. This study will be a randomised, multi-arm, parallel controlled trial. Insufficiently active adults (as determined by the Active Australia survey) aged 18-60 years old will be recruited for this study (n=146). Participants must also satisfy the Sports Medicine Australia Pre-Exercise Screening System and must weigh less than 150 kg. Participants will be randomly assigned to one of three groups using a computer-generated allocation sequence. Participants in the Moderate exercise group will receive an additional 150 minutes of moderate to vigorous physical activity per week for six weeks, and those in the Extensive exercise group will receive an additional 300 minutes of moderate to vigorous physical activity per week for six weeks. Exercise targets will be accumulated through both group and individual exercise sessions monitored by heart rate telemetry. Control participants will not be given any instructions regarding lifestyle. The primary outcome measures are activity energy expenditure (doubly labeled water) and physical activity (accelerometry). Secondary measures will include resting metabolic rate via indirect calorimetry, use of time, maximal oxygen consumption and several anthropometric and physiological measures. Outcome measures will be conducted at baseline (zero weeks), mid- and end-intervention (three and six weeks) with three (12 weeks) and six month (24 week) follow-up. All assessors will be blinded to group allocation. Discussion. This protocol has been specifically designed to test the activitystat hypothesis while taking into account the key conceptual and methodological considerations of testing a biologically regulated homeostatic feedback loop. Results of this study will be an important addition to the growing literature and debate concerning the possible existence of an activitystat. Trial registration. Australian New Zealand Clinical Trials Registry ACTRN12610000248066

Active children through incentive vouchers – evaluation (ACTIVE): a mixed-method feasibility study

BackgroundAdolescents face many barriers to physical activity, demonstrated by the decline in physical activity levels in teenage populations. This study aimed to assess the feasibility of overcoming such barriers via the implementation of an activity-promoting voucher scheme to teenagers in deprived areas.MethodsAll Year 9 pupils (n = 115; 13.3 ± 0.48 years; 51 % boys) from one secondary school in Wales (UK) participated. Participants received £25 of activity vouchers every month for six months for physical activity or sporting equipment. Focus groups (n = 7), with 43 pupils, and qualitative interviews with teachers (n = 2) were conducted to assess feasibility, in addition to a process evaluation utilising the RE-AIM framework. Quantitative outcomes at baseline, five months (during intervention) and twelve months (follow-up) included: physical activity (accelerometer), aerobic fitness (12 min Cooper run) and self-reported activity (PAQ-A). Motivation to exercise (BREQ-2) was measured three months post-baseline and at follow-up.ResultsQualitative findings showed that vouchers encouraged friends to socialise through activity, provided opportunities to access local activities that pupils normally could not afford, and engaged both those interested and disinterested in physical education. Improvements in weekend moderate-to-vigorous physical activity and reductions in sedentary behaviour were observed in both sexes. Boys’ fitness significantly improved during the voucher scheme. ‘Non-active’ pupils (those not meeting recommended guidelines of 60 mins∙day−1) and those with higher motivation to exercise had higher voucher use.ConclusionsAdolescents, teachers and activity providers supported the voucher scheme and felt the vouchers enabled deprived adolescents to access more physical activity opportunities. Voucher usage was associated with improved attitudes to physical activity, increased socialisation with friends and improved fitness and physical activity; presenting interesting avenues for further exploration in a larger intervention trial

Impact of solitary pulmonary nodule size on qualitative and quantitative assessment using 18F-fluorodeoxyglucose PET/CT: the SPUTNIK trial

Purpose: To compare qualitative and semi-quantitative PET/CT criteria, and the impact of nodule size on the diagnosis of solitary pulmonary nodules in a prospective multicentre trial. / Methods: Patients with an SPN on CT ≥ 8 and ≤ 30 mm were recruited to the SPUTNIK trial at 16 sites accredited by the UK PET Core Lab. Qualitative assessment used a five-point ordinal PET-grade compared to the mediastinal blood pool, and a combined PET/CT grade using the CT features. Semi-quantitative measures included SUVmax of the nodule, and as an uptake ratio to the mediastinal blood pool (SURBLOOD) or liver (SURLIVER). The endpoints were diagnosis of lung cancer via biopsy/histology or completion of 2-year follow-up. Impact of nodule size was analysed by comparison between nodule size tertiles. / Results: Three hundred fifty-five participants completed PET/CT and 2-year follow-up, with 59% (209/355) malignant nodules. The AUCs of the three techniques were SUVmax 0.87 (95% CI 0.83;0.91); SURBLOOD 0.87 (95% CI 0.83; 0.91, p = 0.30 versus SUVmax); and SURLIVER 0.87 (95% CI 0.83; 0.91, p = 0.09 vs. SUVmax). The AUCs for all techniques remained stable across size tertiles (p > 0.1 for difference), although the optimal diagnostic threshold varied by size. For nodules  16 mm, an SUVmax ≥ 3.6 or visual PET uptake greater than the mediastinum was the most accurate. / Conclusion: In this multicentre trial, SUVmax was the most accurate technique for the diagnosis of solitary pulmonary nodules. Diagnostic thresholds should be altered according to nodule size. / Trial registration: ISRCTN - ISRCTN30784948. ClinicalTrials.gov - NCT0201306

The role for high flow nasal cannula as a respiratory support strategy in adults: a clinical practice guideline

Purpose: High flow nasal cannula (HFNC) is a relatively recent respiratory support technique which delivers high flow, heated and humidified controlled concentration of oxygen via the nasal route. Recently, its use has increased for a variety of clinical indications. To guide clinical practice, we developed evidence-based recommendations regarding use of HFNC in various clinical settings. Methods: We formed a guideline panel composed of clinicians, methodologists and experts in respiratory medicine. Using GRADE, the panel developed recommendations for four actionable questions. Results: The guideline panel made a strong recommendation for HFNC in hypoxemic respiratory failure compared to conventional oxygen therapy (COT) (moderate certainty), a conditional recommendation for HFNC following extubation (moderate certainty), no recommendation regarding HFNC in the peri-intubation period (moderate certainty), and a conditional recommendation for postoperative HFNC in high risk and/or obese patients following cardiac or thoracic surgery (moderate certainty). Conclusions: This clinical practice guideline synthesizes current best-evidence into four recommendations for HFNC use in patients with hypoxemic respiratory failure, following extubation, in the peri-intubation period, and postoperatively for bedside clinicians

Diabetes self-management arrangements in Europe: a realist review to facilitate a project implemented in six countries

Background: Self-management of long term conditions can promote quality of life whilst delivering benefits to the financing of health care systems. However, rarely are the meso-level influences, likely to be of direct relevance to these desired outcomes, systematically explored. No specific international guidelines exist suggesting the features of the most appropriate structure and organisation of health care systems within which to situate self-management approaches and practices. This review aimed to identify the quantitative literature with regard to diabetes self-management arrangements currently in place within the health care systems of six countries (The United Kingdom, The Netherlands, Norway, Spain, Bulgaria, and Greece) and explore how these are integrated into the broader health care and welfare systems in each country. Methods: The methodology for a realist review was followed. Publications of interest dating from 2000 to 2013 were identified through appropriate MeSH terms by a systematic search in six bibliographic databases. A search diary was maintained and the studies were assessed for their quality and risk of bias. Results: Following the multi-step search strategy, 56 studies were included in the final review (the majority from the UK) reporting design methods and findings on 21 interventions and programmes for diabetes and chronic disease self-management. Most (11/21, 52%) of the interventions were designed to fit within the context of primary care. The majority (11/21, 52%) highlighted behavioural change as an important goal. Finally, some (5/21, 24%) referred explicitly to Internet-based tools. Conclusions: This review is based on results which are derived from a total of at least 5,500 individuals residing in the six participating countries. It indicates a policy shift towards patient-centred self-management of diabetes in a primary care context. The professional role of diabetes specialist nurses, the need for multidisciplinary approaches and a focus on patient education emerge as fundamental principles in the design of relevant programmes. Socio-economic circumstances are relevant to the capacity to self-manage and suggest that any gains and progress will be hard to maintain during economic austerity. This realist review should be interpreted within the wider context of a whole systems approach regarding self-care support and chronic illness management

Clinical review: Allocating ventilators during large-scale disasters – problems, planning, and process

Catastrophic disasters, particularly a pandemic of influenza, may force difficult allocation decisions when demand for mechanical ventilation greatly exceeds available resources. These situations demand integrated incident management responses on the part of the health care facility and community, including resource management, provider liability protection, community education and information, and health care facility decision-making processes designed to allocate resources as justly as possible. If inadequate resources are available despite optimal incident management, a process that is evidence-based and as objective as possible should be used to allocate ventilators. The process and decision tools should be codified pre-event by the local and regional healthcare entities, public health agencies, and the community. A proposed decision tool uses predictive scoring systems, disease-specific prognostic factors, response to current mechanical ventilation, duration of current and expected therapies, and underlying disease states to guide decisions about which patients will receive mechanical ventilation. Although research in the specifics of the decision tools remains nascent, critical care physicians are urged to work with their health care facilities, public health agencies, and communities to ensure that a just and clinically sound systematic approach to these situations is in place prior to their occurrence

The theory of expanded, extended, and enhanced opportunities for youth physical activity promotion

Background Physical activity interventions targeting children and adolescents (≤18 years) often focus on complex intra- and inter-personal behavioral constructs, social-ecological frameworks, or some combination of both. Recently published meta-analytical reviews and large-scale randomized controlled trials have demonstrated that these intervention approaches have largely produced minimal or no improvements in young people\u27s physical activity levels. Discussion In this paper, we propose that the main reason for previous studies\u27 limited effects is that fundamental mechanisms that lead to change in youth physical activity have often been overlooked or misunderstood. Evidence from observational and experimental studies is presented to support the development of a new theory positing that the primary mechanisms of change in many youth physical activity interventions are approaches that fall into one of the following three categories: (a) the expansion of opportunities for youth to be active by the inclusion of a new occasion to be active, (b) the extension of an existing physical activity opportunity by increasing the amount of time allocated for that opportunity, and/or (c) the enhancement of existing physical activity opportunities through strategies designed to increase physical activity above routine practice. Their application and considerations for intervention design and interpretation are presented. Summary The utility of these mechanisms, referred to as the Theory of Expanded, Extended, and Enhanced Opportunities (TEO), is demonstrated in their parsimony, logical appeal, support with empirical evidence, and the direct and immediate application to numerous settings and contexts. The TEO offers a new way to understand youth physical activity behaviors and provides a common taxonomy by which interventionists can identify appropriate targets for interventions across different settings and contexts. We believe the formalization of the TEO concepts will propel them to the forefront in the design of future intervention studies and through their use, lead to a greater impact on youth activity behaviors than what has been demonstrated in previous studies