Modified-release morphine or placebo for chronic breathlessness: the MABEL trial protocol.

Chronic breathlessness, a persistent and disabling symptom despite optimal treatment of underlying causes, is a frightening symptom with serious and widespread impact on patients and their carers. Clinical guidelines support the use of morphine for the relief of chronic breathlessness in common long-term conditions, but questions remain around clinical effectiveness, safety and longer term (>7 days) administration. This trial will evaluate the effectiveness of low-dose oral modified-release morphine in chronic breathlessness. This is a multicentre, parallel group, double-blind, randomised, placebo-controlled trial. Participants (n=158) will be opioid-naïve with chronic breathlessness due to heart or lung disease, cancer or post-coronavirus disease 2019. Participants will be randomised 1:1 to 5 mg oral modified-release morphine/placebo twice daily and docusate/placebo 100 mg twice daily for 56 days. Non-responders at Day 7 will dose escalate to 10 mg morphine/placebo twice daily at Day 15. The primary end-point (Day 28) measure will be worst breathlessness severity (previous 24 h). Secondary outcome measures include worst cough, distress, pain, functional status, physical activity, quality of life, and early identification and management of morphine-related side-effects. At Day 56, participants may opt to take open-label, oral modified-release morphine as part of usual care and complete quarterly breathlessness and toxicity questionnaires. The study is powered to be able to reject the null hypothesis and an embedded normalisation process theory-informed qualitative substudy will explore the adoption of morphine as a first-line pharmacological treatment for chronic breathlessness in clinical practice if effective.

Review of investigational medical devices' clinical trials and regulations in Africa as a benchmark for new innovations.

Medical technologies present a huge potential in improving global health playing a key role toward achieving Sustainable Development Goal 3 by 2030. A number of clinicians, innovators, business entities and biomedical engineers among others have developed a number of innovative medical devices and technologies to address the healthcare challenges especially in Africa. Globally, medical devices clinical trials present the most acceptable method for determining the risks and benefits of medical device innovations with the aim of ascertaining their effectiveness and safety as compared with established medical practice. However, there are very few medical device clinical trials reported in Africa compared to other regions like USA, UK and Europe. Most of the medical device clinical trials reported in Africa are addressing challenges around HIV/AIDS, maternal health and NCDs. In this mini review, we report about some of the published medical device clinical trials in Africa PubMed and Google Scholar and their associated challenges.

Systems and processes for regulation of investigational medical devices in Uganda.

Background: In many parts of the world, medical devices and the processes of their development are tightly regulated. However, the current regulatory landscape in Uganda like other developing countries is weak and poorly defined, which creates significant barriers to innovation, clinical evaluation, and translation of medical devices. Aim: To evaluate current knowledge, systems and infrastructure for medical devices regulation and innovation in Uganda. Methods: A mixed methods study design using the methods triangulation strategy was employed in this study. Data of equal weight were collected sequentially. First, a digital structured questionnaire was sent out to innovators to establish individual knowledge and experience with medical device innovation and regulation. Then, a single focus group discussion involving both medical device innovators and regulators to collect data about the current regulatory practices for medical devices in Uganda. Univariate and bivariate analysis was done for the quantitative data to summarize results in graphs and tables. Qualitative data was analyzed using thematic analysis. Ethical review and approval were obtained from the Makerere University School of Biomedical Sciences, Research and Ethics Committee, and the Uganda National Council for Science and Technology. Results: A total of 47 innovators responded to the questionnaire. 14 respondents were excluded since they were not medical device innovators. Majority (76%) of individuals had been innovators for more than a year, held a bachelor's degree with a background in Engineering and applied sciences, and worked in an academic research institute. 22 of the 33 medical device innovators had stopped working on their innovations and had stalled at the proof-of-concept stage. Insufficient funding, inadequate technical expertise and confusing regulatory landscape were major challenges to innovation. The two themes that emerged from the discussion were "developing standards for medical devices regulation" and "implementation of regulations in practical processes". Legal limitations, lengthy processes, and low demand were identified as challenges to developing medical device regulations. Conclusions: Efforts have been taken by government to create a pathway for medical device innovations to be translated to the market. More work needs to be done to coordinate efforts among stakeholders to build effective medical device regulations in Uganda.

A randomized, feasibility trial of an exercise and nutrition-based rehabilitation programme (ENeRgy) in people with cancer.

BACKGROUND: Despite rehabilitation being increasingly advocated for people living with incurable cancer, there is limited evidence supporting efficacy or component parts. The progressive decline in function and nutritional in this population would support an approach that targets these factors. This trial aimed to assess the feasibility of an exercise and nutrition based rehabilitation programme in people with incurable cancer. METHODS: We randomized community dwelling adults with incurable cancer to either a personalized exercise and nutrition based programme (experimental arm) or standard care (control arm) for 8 weeks. Endpoints included feasibility, quality of life, physical activity (step count), and body weight. Qualitative and health economic analyses were also included. RESULTS: Forty-five patients were recruited (23 experimental arm, 22 control arm). There were 26 men (58%), and the median age was 78 years (IQR 69-84). At baseline, the median BMI was 26 kg/m2 (IQR: 22-29), and median weight loss in the previous 6 months was 5% (IQR: -12% to 0%). Adherence to the experimental arm was >80% in 16/21 (76%) patients. There was no statistically significant difference in the following between trial arms: step count - median % change from baseline to endpoint, per trial arm (experimental -18.5% [IQR: -61 to 65], control 5% [IQR: -32 to 50], P = 0.548); weight - median % change from baseline to endpoint, per trial arm (experimental 1%[IQR: -3 to 3], control -0.5% [IQR: -3 to 1], P = 0.184); overall quality of life - median % change from baseline to endpoint, per trial arm (experimental 0% [IQR: -20 to 19], control 0% [IQR: -23 to 33], P = 0.846). Qualitative findings observed themes of capability, opportunity, and motivation amongst patients in the experimental arm. The mean incremental cost of the experimental arm versus control was £-319.51 [CI -7593.53 to 6581.91], suggesting the experimental arm was less costly. CONCLUSIONS: An exercise and nutritional rehabilitation intervention is feasible and has potential benefits for people with incurable cancer. A larger trial is now warranted to test the efficacy of this approach.

A phase 2 randomised controlled trial of serelaxin to lower portal pressure in cirrhosis (STOPP).

BACKGROUND: In preclinical models, recombinant human relaxin-2 (serelaxin) had anti-fibrotic effects and ameliorated portal hypertension (PH). A small exploratory study in patients with cirrhosis also suggested that serelaxin could reduce portal pressure. METHODS: In a phase 2, double-blind, randomised controlled study conducted in a single centre (Royal Infirmary of Edinburgh, UK), male and female adult participants with cirrhosis and clinically significant PH (CSPH; hepatic venous pressure gradient (HVPG) > 10 mmHg) were enrolled. Participants were allocated to serelaxin or placebo in a 3:1 ratio. The placebo was matched to serelaxin on appearance and administration protocol to create and maintain blinding. The primary endpoint was the change from baseline in fasting HVPG after 2 h of peripheral i.v. serelaxin infusion (80 µg/kg/day for 60 min followed by 30 µg/kg/day for at least 60 min). Secondary endpoints included the change from baseline in hepatic blood flow and systemic haemodynamics (cardiac index, systemic vascular resistance index and aortic pulse wave velocity). Short-term safety and tolerability of serelaxin were assessed. RESULTS: A total of 17 participants were screened, 15 were randomised and 11 completed the study (n = 9 serelaxin, n = 2 placebo). Reasons for withdrawal were baseline HVPG < 10 mmHg (n = 2) and technical failure (n = 2). The trial ended early due to manufacturer discontinuation of the study drug. The median age was 56 (range 43-69) years and 73% of participants were male. Alcohol was the commonest cirrhosis aetiology (n = 10). Participants had a median Model for End-Stage Liver Disease score of 10 (range 6-14). The mean baseline HVPG was 16.3 (range 10.3-21.7) mmHg. Individual responses were variable, but overall there was no statistically significant change in HVPG after 2 h of i.v. serelaxin (arithmetic mean of difference ± SD was 0.4 ± 3.5 mmHg (95% CI -2.3, 3.1; p = 0.76)). There were also no substantial changes from baseline in hepatic or systemic haemodynamics. We recorded 12 adverse events in 7 participants treated with serelaxin; none were significant, and most were unrelated to the investigational medicinal product. There were no serious adverse events. CONCLUSION: In a small randomised, phase 2, proof-of-concept study in patients with cirrhosis and CSPH, serelaxin infusion was safe and well-tolerated but had a neutral effect on HVPG. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02669875. Registered on 1 February 2016.

Multi-centre Randomised Controlled Trial of a Smartphone-based Event Recorder Alongside Standard Care Versus Standard Care for Patients Presenting to the Emergency Department with Palpitations and Pre-syncope: The IPED (Investigation of Palpitations in the ED) study.

BACKGROUND: Patients with palpitations and pre-syncope commonly present to Emergency Departments (EDs) but underlying rhythm diagnosis is often not possible during the initial presentation. This trial compares the symptomatic rhythm detection rate of a smartphone-based event recorder (AliveCor) alongside standard care versus standard care alone, for participants presenting to the ED with palpitations and pre-syncope with no obvious cause evident at initial consultation. METHODS: Multi-centre open label, randomised controlled trial. Participants ≥ 16 years old presenting to 10 UK hospital EDs were included. Participants were randomised to either (a) intervention group; standard care plus the use of a smartphone-based event recorder or (b) control group; standard care alone. Primary endpoint was symptomatic rhythm detection rate at 90 days. Trial registration number NCT02783898 (ClinicalTrials.gov). FINDINGS: Two hundred forty-three participants were recruited over an 18-month period. A symptomatic rhythm was detected at 90 days in 69 (n = 124; 55.6%; 95% CI 46.9-64.4%) participants in the intervention group versus 11 (n = 116; 9.5%; 95% CI 4.2-14.8) in the control group (RR 5.9, 95% CI 3.3-10.5; p < 0.0001). Mean time to symptomatic rhythm detection in the intervention group was 9.5 days (SD 16.1, range 0-83) versus 42.9 days (SD 16.0, range 12-66; p < 0.0001) in the control group. The commonest symptomatic rhythms detected were sinus rhythm, sinus tachycardia and ectopic beats. A symptomatic cardiac arrhythmia was detected at 90 days in 11 (n = 124; 8.9%; 95% CI 3.9-13.9%) participants in the intervention group versus 1 (n = 116; 0.9%; 95% CI 0.0-2.5%) in the control group (RR 10.3, 95% CI 1.3-78.5; p = 0.006). INTERPRETATION: Use of a smartphone-based event recorder increased the number of patients in whom an ECG was captured during symptoms over five-fold to more than 55% at 90 days. This safe, non-invasive and easy to use device should be considered part of on-going care to all patients presenting acutely with unexplained palpitations or pre-syncope. FUNDING: This study was funded by research awards from Chest, Heart and Stroke Scotland (CHSS) and British Heart Foundation (BHF) which included funding for purchasing the devices. MR was supported by an NHS Research Scotland Career Researcher Clinician award.

"How Long Have I Got?"-A Prospective Cohort Study Comparing Validated Prognostic Factors for Use in Patients with Advanced Cancer.

BACKGROUND: The optimal prognostic factors in patients with advanced cancer are not known, as a comparison of these is lacking. The aim of the present study was to determine the optimal prognostic factors by comparing validated factors. MATERIALS AND METHODS: A multicenter, prospective observational cohort study recruited patients over 18 years with advanced cancer. The following were assessed: clinician-predicted survival (CPS), Eastern Cooperative Oncology Group performance status (ECOG-PS), patient reported outcome measures (anorexia, cognitive impairment, dyspnea, global health), metastatic disease, weight loss, modified Glasgow Prognostic Score (mGPS) based on C-reactive protein and albumin, lactate dehydrogenase (LDH), and white (WCC), neutrophil (NC), and lymphocyte cell counts. Survival at 1 and 3 months was assessed using area under the receiver operating curve and logistic regression analysis. RESULTS: Data were available on 478 patients, and the median survival was 4.27 (1.86-7.03) months. On univariate analysis, the following factors predicted death at 1 and 3 months: CPS, ECOG-PS, mGPS, WCC, NC (all p < .001), dyspnea, global health (both p ≤ .001), cognitive impairment, anorexia, LDH (all p < .01), and weight loss (p < .05). On multivariate analysis ECOG-PS, mGPS, and NC were independent predictors of survival at 1 and 3 months (all p < .01). CONCLUSION: The simple combination of ECOG-PS and mGPS is an important novel prognostic framework which can alert clinicians to patients with good performance status who are at increased risk of having a higher symptom burden and dying at 3 months. From the recent literature it is likely that this framework will also be useful in referral for early palliative care with 6-24 months survival. IMPLICATIONS FOR PRACTICE: This large cohort study examined all validated prognostic factors in a head-to-head comparison and demonstrated the superior prognostic value of the Eastern Cooperative Oncology Group performance status (ECOG-PS)/modified Glasgow Prognostic Score (mGPS) combination over other prognostic factors. This combination is simple, accurate, and also relates to quality of life. It may be useful in identifying patients who may benefit from early referral to palliative care. It is proposed ECOG-PS/mGPS as the new prognostic domain in patients with advanced cancer.

Multi-centre randomised controlled trial of a smart phone-based event recorder alongside standard care versus standard care for patients presenting to the Emergency Department with palpitations and pre-syncope - the IPED (Investigation of Palpitations in the ED) study: study protocol for a randomised controlled trial.

BACKGROUND: Palpitations and pre-syncope are together responsible for 300,000 annual Emergency Department (ED) attendances in the United Kingdom (UK). Diagnosis of the underlying rhythm is difficult as many patients are fully recovered on ED arrival; and examination and presenting electrocardiogram (ECG) are commonly normal. The only way to establish the underlying heart rhythm is to capture an ECG during symptoms. Recent technology advances have led to several novel ECG monitoring devices appearing on the market. This trial aims to compare the symptomatic rhythm detection rate at 90 days of one such smart phone-based event recorder (AliveCor Heart Monitor and AliveECG) with standard care for participants presenting to the ED with palpitations and pre-syncope and no obvious cause in the ED. METHODS/DESIGN: This is a multi-centre hospital ED / Acute Medical Unit (AMU) open label, randomised controlled trial. Participants will be recruited in 10 tertiary and district general hospitals in the UK. Participants aged ≥ 16 years presenting with an episode of palpitations or pre-syncope with no obvious cause and whose underlying ECG rhythm during these episodes remains undiagnosed after clinical assessment will be included. Participants will be randomised to either: (1) the intervention arm, standard care plus the use of a smart phone-based event recorder; or (2) the control arm, standard care. Primary endpoint will be symptomatic rhythm detection rate at 90 days. A number of secondary clinical, process and cost-effectiveness endpoints will be collected and analysed. Analysis will be on an intention-to-treat basis. DISCUSSION: The Investigation of Palpitations in the ED (IPED) study aims to recruit 242 participants across 10 hospital sites. It will be the first study to investigate the ability of a smart phone-based event recorder to detect symptomatic cardiac rhythms compared to standard care for ED patients with palpitations and pre-syncope with no obvious cause in the ED. This smart phone event recorder will allow ED patients who have presented with palpitations or pre-syncope to record their ECG tracing if they have a further episode and may increase the rate of underlying rhythm diagnosis. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02783898 . Registered on 26 May 2016.

Stressful life events and maltreatment in conversion (functional neurological) disorder: systematic review and meta-analysis of case-control studies.

BACKGROUND: Stressful life events and maltreatment have traditionally been considered crucial in the development of conversion (functional neurological) disorder, but the evidence underpinning this association is not clear. We aimed to assess the association between stressors and functional neurological disorder. METHODS: We systematically reviewed controlled studies reporting stressors occurring in childhood or adulthood, such as stressful life events and maltreatment (including sexual, physical abuse, and emotional neglect) and functional neurological disorder. We did a meta-analysis, with assessments of methodology, sources of bias, and sensitivity analyses. FINDINGS: 34 case-control studies, with 1405 patients, were eligible. Studies were of moderate-to-low quality. The frequency of childhood and adulthood stressors was increased in cases compared with controls. Odds ratios (OR) were higher for emotional neglect in childhood (49% for cases vs 20% for controls; OR 5·6, 95% CI 2·4-13·1) compared with sexual abuse (24% vs 10%; 3·3, 2·2-4·8) or physical abuse (30% vs 12%; 3·9, 2·2-7·2). An association with stressful life events preceding onset (OR 2·8, 95% CI 1·4-6·0) was stronger in studies with better methods (interviews; 4·3, 1·4-13·2). Heterogeneity was significant between studies (I2 21·1-90·7%). 13 studies that specifically ascertained that the participants had not had either severe life events or any subtype of maltreatment all found a proportion of patients with functional neurological disorder reporting no stressor. INTERPRETATION: Stressful life events and maltreatment are substantially more common in people with functional neurological disorder than in healthy controls and patient controls. Emotional neglect had a higher risk than traditionally emphasised sexual and physical abuse, but many cases report no stressors. This outcome supports changes to diagnostic criteria in DSM-5; stressors, although relevant to the cause in many patients, are not a core diagnostic feature. This result has implications for ICD-11. FUNDING: None.

Prognostic Tools in Patients With Advanced Cancer: A Systematic Review.

PURPOSE: In 2005, the European Association for Palliative Care made recommendations for prognostic markers in advanced cancer. Since then, prognostic tools have been developed, evolved, and validated. The aim of this systematic review was to examine the progress in the development and validation of prognostic tools. METHODS: Medline, Embase Classic and Embase were searched. Eligible studies met the following criteria: patients with incurable cancer, >18 years, original studies, population n ≥100, and published after 2003. Descriptive and quantitative statistical analyses were performed. RESULTS: Forty-nine studies were eligible, assessing seven prognostic tools across different care settings, primary cancer types, and statistically assessed survival prediction. The Palliative Performance Scale was the most studied (n = 21,082), comprising six parameters (six subjective), was externally validated, and predicted survival. The Palliative Prognostic Score composed of six parameters (four subjective and two objective), the Palliative Prognostic Index composed of nine parameters (nine subjective), and the Glasgow Prognostic Score composed of two parameters (two objective) and were all externally validated in more than 2000 patients with advanced cancer and predicted survival. CONCLUSION: Various prognostic tools have been validated but vary in their complexity, subjectivity, and therefore clinical utility. The Glasgow Prognostic Score would seem the most favorable as it uses only two parameters (both objective) and has prognostic value complementary to the gold standard measure, which is performance status. Further studies comparing all proved prognostic markers in a single cohort of patients with advanced cancer are needed to determine the optimal prognostic tool.

Optimization and Reproducibility of Aortic Valve 18F-Fluoride Positron Emission Tomography in Patients With Aortic Stenosis.

BACKGROUND: 18F-Fluoride positron emission tomography (PET) and computed tomography (CT) can measure disease activity and progression in aortic stenosis. Our objectives were to optimize the methodology, analysis, and scan-rescan reproducibility of aortic valve 18F-fluoride PET-CT imaging. METHODS AND RESULTS: Fifteen patients with aortic stenosis underwent repeated 18F-fluoride PET-CT. We compared nongated PET and noncontrast CT, with a modified approach that incorporated contrast CT and ECG-gated PET. We explored a range of image analysis techniques, including estimation of blood-pool activity at differing vascular sites and a most diseased segment approach. Contrast-enhanced ECG-gated PET-CT permitted localization of 18F-fluoride uptake to individual valve leaflets. Uptake was most commonly observed at sites of maximal mechanical stress: the leaflet tips and the commissures. Scan-rescan reproducibility was markedly improved using enhanced analysis techniques leading to a reduction in percentage error from ±63% to ±10% (tissue to background ratio MDS mean of 1.55, bias -0.05, limits of agreement -0·20 to +0·11). CONCLUSIONS: Optimized 18F-fluoride PET-CT allows reproducible localization of calcification activity to different regions of the aortic valve leaflet and commonly to areas of increased mechanical stress. This technique holds major promise in improving our understanding of the pathophysiology of aortic stenosis and as a biomarker end point in clinical trials of novel therapies. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02132026.

Quality of Life in Patients With Advanced Cancer: Differential Association With Performance Status and Systemic Inflammatory Response.

PURPOSE: Quality of life is a key component of cancer care; however, the factors that determine quality of life are not well understood. The aim of this study was to examine the relationship between quality of life parameters, performance status (PS), and the systemic inflammatory response in patients with advanced cancer. METHODS: An international biobank of patients with advanced cancer was analyzed. Quality of life was assessed at a single time point by using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C-30 (EORTC QLQ-C30). PS was assessed by using the Eastern Cooperative Oncology Group (ECOG) classification. Systemic inflammation was assessed by using the modified Glasgow Prognostic Score (mGPS), which combines C-reactive protein and albumin. The relationship between quality of life parameters, ECOG PS, and the mGPS was examined. RESULTS: Data were available for 2,520 patients, and the most common cancers were GI (585 patients [22.2%]) and pulmonary (443 patients [17.6%]). The median survival was 4.25 months (interquartile range, 1.36 to 12.9 months). Increasing mGPS (systemic inflammation) and deteriorating PS were associated with deterioration in quality-of-life parameters (P < .001). Increasing systemic inflammation was associated with deterioration in quality-of-life parameters independent of PS. CONCLUSION: Systemic inflammation was associated with quality-of-life parameters independent of PS in patients with advanced cancer. Further investigation of these relationships in longitudinal studies and investigations of possible effects of attenuating systemic inflammation are now warranted.