Efficacy and Mechanism Evaluation
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A 10-year impact assessment of the Efficacy and Mechanism Evaluation (EME) programme: an independent mixed-method evaluation study
Background The Efficacy and Mechanism Evaluation (EME) programme – a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership – funds trials that evaluate the efficacy of interventions with the potential to promote health and studies that improve our understanding of the mechanisms of underlying diseases and their treatments. Objective To conduct an independent review of the EME programme’s impact and identify opportunities for future improvement. Design A mixed-methods approach, including desk research, an analysis of secondary data, stakeholder consultation and the development of impact case studies. Participants Chief investigators of EME awards, unfunded applicants to the EME programme and key opinion leaders relevant to the programme and research ecosystem. Interventions No interventions were tested, as this was a retrospective programme evaluation. Main outcome measures The evaluation was guided by a set of 15 evaluation questions. Results The EME programme bridges the gap between proof-of-concept and effectiveness studies that are located among other MRC and NIHR schemes and grants from charities in the funding landscape. Mechanistic studies alongside EME trials add value by lending confidence to trial findings and providing insights into the underlying biology. Between 2009 and September 2018, £175.7M in funding was approved for 145 EME projects. EME programme-funded research has started to deliver value to the NHS and patients by improving treatments and providing more efficient use of resources. Of the 43 completed trials, 14% (n = 6) showed that the intervention had a positive effect, whereas 74% (n = 32) of trials did not. The remaining five (12%) trials were unable to recruit participants or did not proceed to the full-trial stage. Seven projects (i.e. 16% of completed trials) have informed clinical guidelines or regulatory approval decisions and another eight projects have the potential to do so in the future, given the nature of their findings. Projects in the EME programme portfolio address a range of UK health needs and government priority areas, but they do not fully align with the level of health needs present. Commissioned calls for applications steer applicants. However, many commissioned calls do not lead to funded awards, and a better understanding of the underlying reasons for this would enable targeted supported to address key health needs. The majority of EME projects investigate existing interventions of limited commercial interest, focusing on repurposing (67/136, 49%) and informing current practice (23/136, 17%). Although there is little evidence of wider economic impact from commercial benefits, the EME programme is important in funding research in which industry is unlikely to invest. Stronger co-ordination with other funders, such as charities, could lead to synergies, enhancing the potential for health impact and influence on other funders’ agendas. The main challenges identified for EME projects were ‘complex and slow contracting processes’ (35/46, 76%), ‘setting up of study sites’ (30/46, 65%) and patient recruitment (28/46, 61%). Enablers of research included a clinical research fellow position on the project and support from Clinical Research Networks and Biomedical Research Centres. Nearly all of the chief investigators consulted had engaged in patient and public involvement at some project stage, and a lack of patient and public involvement did not emerge as a barrier to research or impact. Research ideas stemming from patients were, however, over-represented among unfunded applications, but the reason for this is unclear. Limitations Only about one-third of all studies had been completed or had published their main findings, necessitating a purposive, rather than representative, sampling of the portfolio. The COVID-19 outbreak cut short the programme of interviews, limiting the depth to which some evaluation questions could be explored. Several data sources were based on self-reporting by chief investigators; whereas key self-reported aspects were verified through desk research, this was not possible for all findings. Conclusions The EME programme plays an important role in the UK research funding landscape and has started to deliver value to the NHS and patients. Based on the evidence gathered, seven recommendations were developed to enhance the EME programme’s health and economic impact and address challenges encountered by chief investigators in implementing research projects. Funding This project was funded by the EME programme, a MRC and NIHR partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 8, No. 20. See the NIHR Journals Library website for further project information.
Background Keratoconus is a disease of the cornea affecting vision that is usually first diagnosed in the first three decades. The abnormality of corneal shape and thickness tends to progress until the patient reaches approximately 30 years of age. Epithelium-off corneal cross-linking is a procedure that has been demonstrated to be effective in randomised trials in adults and observational studies in young patients. Objectives The KERALINK trial examined the efficacy and safety of epithelium-off corneal cross-linking, compared with standard care by spectacle or contact lens correction, for stabilisation of progressive keratoconus. Design In this observer-masked, randomised, controlled, parallel-group superiority trial, 60 participants aged 10–16 years with progressive keratoconus were randomised; 58 participants completed the study. Progression was defined as a 1.5 D increase in corneal power measured by maximum or mean power (K2) in the steepest corneal meridian in the study eye, measured by corneal tomography. Setting Referral clinics in four UK hospitals. Interventions Participants were randomised to corneal cross-linking plus standard care or standard care alone, with spectacle or contact lens correction as necessary for vision, and were monitored for 18 months. Main outcome measures The primary outcome was K2 in the study eye as a measure of the steepness of the cornea at 18 months post randomisation. Secondary outcomes included keratoconus progression, visual acuity, keratoconus apex corneal thickness and quality of life. Results Of 60 participants, 30 were randomised to the corneal cross-linking and standard-care groups. Of these, 30 patients in the corneal cross-linking group and 28 patients in the standard-care group were analysed. The mean (standard deviation) K2 in the study eye at 18 months post randomisation was 49.7 D (3.8 D) in the corneal cross-linking group and 53.4 D (5.8 D) in the standard-care group. The adjusted mean difference in K2 in the study eye was –3.0 D (95% confidence interval –4.93 D to –1.08 D; p = 0.002), favouring corneal cross-linking. Uncorrected and corrected differences in logMAR vision at 18 months were better in eyes receiving corneal cross-linking: –0.31 (95% confidence interval –0.50 to –0.11; p = 0.002) and –0.30 (95% confidence interval –0.48 to –0.11; p = 0.002). Keratoconus progression in the study eye occurred in two patients (7%) randomised to corneal cross-linking compared with 12 (43%) patients randomised to standard care. The unadjusted odds ratio suggests that, on average, patients in the corneal cross-linking group had 90% (odds ratio 0.1, 95% confidence interval 0.02 to 0.48; p = 0.004) lower odds of experiencing progression than those receiving standard care. Quality-of-life outcomes were similar in both groups. No adverse events were attributable to corneal cross-linking. Limitations Measurements of K2 in those eyes with the most significant progression were in some cases indicated as suspect by corneal topography device software. Conclusions Corneal cross-linking arrests progression of keratoconus in the great majority of young patients. These data support a consideration of a change in practice, such that corneal cross-linking could be considered as first-line treatment in progressive disease. If the arrest of keratoconus progression induced by corneal cross-linking is sustained in longer follow-up, there may be particular benefit in avoiding the later requirement for contact lens wear or corneal transplantation. However, keratoconus does not continue to progress in all patients receiving standard care. For future work, the most important questions to be answered are whether or not (1) the arrest of keratoconus progression induced by corneal cross-linking is maintained in the long term and (2) the proportion of those receiving standard care who show significant progression increases with time. Trial registration Current Controlled Trials ISRCTN17303768 and EudraCT 2016-001460-11. Funding This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 8, No. 15. See the NIHR Journals Library website for further project information. The trial sponsor is University College London. This research was otherwise supported in part by the NIHR Moorfields Biomedical Research Centre and the NIHR Moorfields Clinical Research Facility, London, United Kingdom.
Background Hyperglycaemia and hypoglycaemia are common in preterm infants and are associated with increased mortality and morbidity. Continuous glucose monitoring is widely used to target glucose control in adults and children, but not in neonates. Objective To evaluate the role of continuous glucose monitoring in the preterm infant. Design The REAl-time Continuous glucose moniToring in neonatal intensive care project combined (1) a feasibility study, (2) a multicentre randomised controlled trial and (3) a pilot of ‘closed-loop’ continuous glucose monitoring. The feasibility study comprised a single-centre study (n = 20). Eligibility criteria included a birthweight ≤ 1200 g and aged ≤ 48 hours. Continuous glucose monitoring was initiated to support glucose control. The efficacy and safety outcomes guided the design of the randomised controlled trial. The randomised controlled trial comprised a European multicentre trial (n = 182). Eligibility criteria included birthweight ≤ 1200 g and aged ≤ 24 hours. Exclusion criteria included any lethal congenital abnormality. Continuous glucose monitoring was initiated to support glucose control within 24 hours of birth. In the intervention group, the continuous glucose monitoring sensor provided real-time data on glucose levels, which guided clinical management. In control infants, the continuous glucose monitoring data were masked, and glucose level was managed in accordance with standard clinical practice and based on the blood glucose levels. The primary outcome measure was the percentage of time during which the sensor glucose level was within the target range of 2.6–10 mmol/l. Secondary outcome measures included mean sensor glucose level, the percentage of time during which the sensor glucose level was within the target range of 4–8 mmol/l, the percentage of time during which the sensor glucose level was in the hyperglycaemic range (i.e. > 15 mmol/l) and sensor glucose level variability. Safety outcomes included hypoglycaemia exposure. Acceptability assessment and health economic analyses were carried out and further exploratory health outcomes were explored. The mean percentage of time in glucose target range of 2.6–10 mmol/l was 9% higher in infants in the continuous glucose monitoring group (95% confidence interval 3% to 14%; p = 0.002), and the mean time in the target range of 4–8 mmol/l was 12% higher in this group (95% confidence interval 4% to 19%; p = 0.004). There was no difference in the number of episodes of hypoglycaemia. Exploratory outcomes showed a reduced risk of necrotising enterocolitis in the intervention arm (odds ratio 0.33, 95% confidence interval 0.13 to 0.78; p = 0.01). Health economic analyses demonstrated that continuous glucose monitoring was cost-effective on the basis of the cost per additional case of adequate glucose control between 2.6 and 10 mmol/l. The ‘closed-loop’ study was a single-center pilot study, with eligibility criteria including a birthweight of ≤ 1200 g and aged ≤ 48 hours. Infants underwent continuous glucose monitoring for the first week of life (n = 21), with those in the intervention group receiving closed-loop insulin delivery between 48 and 72 hours of age. The primary outcome of percentage of time in the target range (i.e. sensor glucose 4–8 mmol/l) increased from a median of 26% (interquartile range 6–64%) to 91% (interquartile range 78–99%) during closed-loop insulin delivery (p < 0.001). Limitations These studies have not defined the optimal targets for glucose control or the best strategies to achieve them in these infants. Future work Studies are needed to evaluate the longer-term impact of targeting glucose control on clinical outcomes. Conclusions Continuous glucose monitoring in extremely preterm infants can improve glucose control, with closed-loop insulin delivery having further potential to target glucose levels. Staff and parents felt that the use of continuous glucose monitoring improved care and the results of the health economic evaluation favours the use of continuous glucose monitoring. Trial registration Current Controlled Trials ISRCTN12793535. Funding This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a MRC and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 8, No. 16. See the NIHR Journals Library website for further project information. Medtronic plc provided some MiniMed™ 640G systems and Nova Biomedical (Waltham, MA, USA) provided point-of-care devices.
Background High cure rates with licensed durations of therapy for chronic hepatitis C virus suggest that many patients are overtreated. New strategies in individuals who find it challenging to adhere to standard treatment courses could significantly contribute to the elimination agenda. Objectives To compare cure rates using variable ultrashort first-line treatment stratified by baseline viral load followed by retreatment, with a fixed 8-week first-line treatment with retreatment with or without adjunctive ribavirin. Design An open-label, multicentre, factorial randomised controlled trial. Randomisation Randomisation was computer generated, with patients allocated in a 1 : 1 ratio using a factorial design to each of biomarker-stratified variable ultrashort strategy or fixed duration and adjunctive ribavirin (or not), using a minimisation algorithm with a probabilistic element. Setting NHS. Participants A total of 202 adults (aged ≥ 18 years) infected with chronic hepatitis C virus genotype 1a/1b or 4 for ≥ 6 months, with a detectable plasma hepatitis C viral load and no significant fibrosis [FibroScan® (Echosens, Paris, France) score F0–F1 or biopsy-proven minimal fibrosis], a hepatitis C virus viral load < 10,000,000 IU/ml, no previous exposure to direct-acting antiviral therapy for this infection and not pregnant. Patients co-infected with human immunodeficiency virus were eligible if human immunodeficiency virus viral load had been < 50 copies/ml for > 24 weeks on anti-human immunodeficiency virus drugs. Interventions Fixed-duration 8-week first-line therapy compared with variable ultrashort first-line therapy, initially for 4–6 weeks (continuous scale) stratified by screening viral load (variable ultrashort strategy 1, mean 32 days of treatment) and then, subsequently, for 4–7 weeks (variable ultrashort strategy 2 mean 39 days of duration), predominantly with ombitasvir, paritaprevir, ritonavir (Viekirax®; AbbVie, Chicago, IL, USA), and dasabuvir (Exviera®; AbbVie, Chicago, IL, USA) or ritonavir. All patients in whom first-line treatment was unsuccessful were immediately retreated with 12 weeks’ sofosbuvir, ledipasvir (Harvoni®, Gilead Sciences, Inc., Foster City, CA, USA) and ribavirin. Main outcome measure The primary outcome was overall sustained virological response (persistently undetectable) 12 weeks after the end of therapy (SVR12). Results A total of 202 patients were analysed. All patients in whom the primary outcome was evaluable achieved SVR12 overall [100% (197/197), 95% confidence interval 86% to 100%], demonstrating non-inferiority between fixed- and variable-duration strategies (difference 0%, 95% confidence interval –3.8% to 3.7%, prespecified non-inferiority margin 4%). A SVR12 following first-line treatment was achieved in 91% (92/101; 95% confidence interval 86% to 97%) of participants randomised to the fixed-duration strategy and by 48% (47/98; 95% confidence interval 39% to 57%) allocated to the variable-duration strategy. However, the proportion achieving SVR12 was significantly higher among those allocated to variable ultrashort strategy 2 [72% (23/32), 95% confidence interval 56% to 87%] than among those allocated to variable ultrashort strategy 1 [36% (24/66), 95% confidence interval 25% to 48%]. Overall, a SVR12 following first-line treatment was achieved by 72% (70/101) (95% confidence interval 65% to 78%) of patients treated with ribavirin and by 68% (69/98) (95% confidence interval 61% to 76%) of those not treated with ribavirin. A SVR12 with variable ultrashort strategies 1 and 2 was 52% (25/48) (95% confidence interval 38% to 65%) with ribavirin, compared with 44% (22/50) (95% confidence interval 31% to 56) without. However, at treatment failure, the emergence of viral resistance was lower with ribavirin [12% (3/26), 95% confidence interval 2% to 30%] than without [38% (11/29), 95% confidence interval 21% to 58%; p = 0.01]. All 10 individuals who became undetectable at day 3 of treatment achieved first-line SVR12 regardless of treatment duration. Five participants in the variable-duration arm and five in the fixed-duration arm experienced serious adverse events (p = 0.69), as did five participants receiving ribavirin and five participants receiving no ribavirin. Conclusions SVR12 rates were significantly higher when ultrashort treatment varied between 4 and 7 weeks, rather than between 4 and 6 weeks. We found no evidence of ribavirin significantly affecting first-line SVR12, with unsuccessful first-line short-course therapy also not compromising subsequent retreatment with sofosbuvir, ledipasvir and ribavirin. Future work A priority for future work needs to be the development and evaluation of robust predictive measures to identify those patients who can be cured with ultrashort courses of therapy. Trial registration Current Controlled Trials ISRCTN37915093, EudraCT 2015-005004-28 and CTA 19174/0370/001-0001. Funding This project was funded by the Efficacy and Mechanism Evaluation programme, a MRC and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 8, No. 17. See the NIHR Journals Library website for further project information.
Background Standalone thoracoscopic surgical ablation may be more effective than catheter ablation in patients with long-standing persistent atrial fibrillation. Objectives To determine whether or not surgical ablation is clinically superior to catheter ablation as the first-line treatment strategy in long-standing persistent atrial fibrillation. Design This was a prospective, multicentre, randomised control trial. Setting Four NHS tertiary centres in England. Participants Adults with long-standing persistent atrial fibrillation, who had European Heart Rhythm Association symptom scores > 2 and who were naive to previous catheter ablation or thoracic/cardiac surgery. Interventions Minimally invasive thoracoscopic surgical ablation and conventional catheter ablation (control intervention). Main outcome measures The primary outcome was freedom from atrial fibrillation/tachycardia ≥ 30 seconds after a single procedure without antiarrhythmic drugs (class 1C/3) at 1 year, excluding a 3-month blanking period. The secondary outcomes include the intervention-related major complication rate; clinical success (≥ 75% reduction in arrhythmia burden); and changes in symptoms, quality of life and cost-effectiveness. Methods Patients (n = 120) were randomised to surgical ablation (n = 60) or catheter ablation (n = 60). An implanted loop recorder provided continuous cardiac monitoring following ablation. Follow-up visits were at 3, 6, 9 and 12 months. Loop recorder data were reviewed monthly by a physiologist who was blinded to the randomisation outcome. Results The study treatment was received by 55 patients in the surgical ablation arm and 60 patients in the catheter ablation arm; five patients withdrew from surgical ablation before treatment. Data from randomised and treated patients were analysed as per intention to treat. Patients had a mean age of 62.3 (standard deviation 9.6) years, were predominantly male (74%), had a mean left atrial diameter of 44.6 mm (standard deviation 6 mm) and were in continuous atrial fibrillation for 22 months (range 16–31 months). At 12 months, 26% of patients in the surgical ablation arm (14/54) and 28% of patients in the catheter ablation arm (17/60) were free from atrial arrhythmias after a single procedure without antiarrhythmic drugs (odds ratio 1.13, 95% confidence interval 0.46 to 2.83; p = 0.84). An arrhythmia burden reduction of ≥ 75% was seen in 36 out of 54 (67%) patients in the surgical ablation arm, compared with 46 out of 60 (77%) patients in the catheter ablation arm (odds ratio 1.64, 95% confidence interval 0.67 to 4.08; p = 0.3). Procedure-related serious complications within 30 days of the intervention occurred in 15% (8/55) of patients in the surgical ablation arm (including one death) compared with 10% (6/60) of patients in the catheter ablation arm (p = 0.46). Surgical ablation was associated with significantly higher costs (£23,221 vs. £18,186; p = 0.02) and fewer quality-adjusted life-years than catheter ablation (0.76 vs. 0.83; p = 0.02). Limitations This study was conducted in four highly specialised cardiology centres that have substantial experience in both treatment modalities; therefore, the results may not be widely generalisable. The study was not powered to detect small differences in efficacy. Conclusions We found no evidence to suggest that standalone thoracoscopic surgical ablation outcomes were superior to catheter ablation outcomes in achieving freedom from atrial arrhythmia after a single procedure without antiarrhythmic drugs. Moreover, surgical ablation is associated with a longer hospital stay, smaller improvements in quality of life and higher health-care costs than catheter ablation (standard care therapy). Future work Evaluation of the impact of ablation treatments on sinus rhythm maintenance and quality of life with extended follow-up to 3 years. Model-based economic analysis to estimate long-term benefits, harms and costs of surgical and catheter ablation compared with antiarrhythmic drug therapy in long-standing persistent atrial fibrillation patients. Trial registration Current Controlled Trials ISRCTN18250790 and ClinicalTrials.gov NCT02755688. Funding This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership. This study was supported by the UK Clinical Research Collaboration-registered King’s Clinical Trials Unit at King’s Health Partners, which is part funded by the NIHR Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust and King’s College London and the NIHR Evaluation, Trials and Studies Coordinating Centre. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 8, No. 18. See the NIHR Journals Library website for further project information.
Background Women whose pregnancies are affected by hypertensive disorders of pregnancy, in particular preterm pre-eclampsia, are at increased risk of long-term cardiovascular morbidity and mortality. Objectives To investigate the hypothesis that prolongation of a pregnancy affected by preterm pre-eclampsia managed by expectant management compared with planned early delivery would result in worse cardiovascular function 6 months postpartum. Design A randomised controlled trial. Setting 28 maternity hospitals in England and Wales. Participants Women who were eligible for the Pre-eclampsia in HOspital: Early iNductIon or eXpectant management (PHOENIX) study were approached and recruited for the PHOEBE study. The PHOENIX (Pre-eclampsia in HOspital: Early iNductIon or eXpectant management) study was a parallel-group, non-masked, multicentre, randomised controlled trial that was carried out in 46 maternity units across England and Wales. This study compared planned early delivery with expectant management (usual care) with individual randomisation in women with late preterm pre-eclampsia who were 34 weeks’ gestation to less than 37 weeks’ gestation and having a singleton or dichorionic diamniotic twin pregnancy. Interventions Postpartum follow-up included medical history, blood pressure assessment and echocardiography. All women had blood sampling performed on at least two time points from recruitment to the 6-month follow-up for assessment of cardiac necrosis markers. Main outcome measures Primary outcome was a composite of systolic and/or diastolic dysfunction (originally by 2009 guidelines then updated by 2016 guidelines, with an amended definition of diastolic dysfunction). Analyses were by intention to treat, together with a per-protocol analysis for the primary and secondary outcomes. Results Between 27 April 2016 and 30 November 2018, 623 women were found to be eligible, of whom 420 (67%) were recruited across 28 maternity units in England and Wales. A total of 133 women were allocated to planned delivery, 137 women were allocated to expectant management and a further 150 received non-randomised expectant management within usual care. The mean time from enrolment to delivery was 2.5 (standard deviation 1.9) days in the planned delivery group compared with 6.8 (standard deviation 5.3) days in the expectant management group. There were no differences in the primary outcome between women in the planned delivery group and those in the expectant management group using either the 2009 (risk ratio 1.06, 95% confidence interval 0.80 to 1.40) or the 2016 definition (risk ratio 0.78, 95% confidence interval 0.33 to 1.86). Overall, 10% (31/321) of women had a left ventricular ejection fraction < 55% and 71% of the cohort remained hypertensive at 6 months postpartum. No differences were observed between groups in cardiorespiratory outcomes prior to discharge from hospital or in systolic or diastolic blood pressure measurements. Variables associated with the primary outcome (2009 definition) at 6 months postpartum were maternal body mass index (adjusted odds ratio 1.33 per 5 kg/m2, 95% confidence interval 1.12 to 1.59 per 5 kg/m2) and maternal age (adjusted odds ratio 2.16, 95% confidence interval 1.44 to 3.22 per 10 years). Limitations include changing definitions regarding systolic and/or diastolic dysfunction. Conclusions Preterm pre-eclampsia results in persistence of hypertension in the majority of women with late preterm pre-eclampsia at 6 months postpartum and systolic dysfunction in 10%. Pre-eclampsia should not be considered a self-limiting disease of pregnancy alone. Future work Interventions aimed at reducing cardiovascular dysfunction. Trial registration Current Controlled Trials ISRCTN01879376. Funding This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 8, No. 12. See the NIHR Journals Library website for further project information.
Background Reliable vascular access is essential for patients receiving haemodialysis. An arteriovenous fistula is the preferred option; however, these are prone to developing stenotic segments. These lesions are treated with angioplasty, but there is a high rate of recurrence. When the PAVE (Paclitaxel-assisted balloon Angioplasty of Venous stenosis in haEmodialysis access) trial was conceived, a number of small studies suggested that restenosis may be reduced by paclitaxel-coated balloons. Objective To test the efficacy of paclitaxel-coated balloons in arteriovenous fistulas. Design A randomised controlled trial. Setting Twenty UK centres. Participants Patients (aged ≥ 18 years) referred with a clinical indication for angioplasty of an arteriovenous fistula (212 patients in total, 106 per group). Interventions High-pressure plain balloon fistuloplasty was performed in all patients. In the intervention arm, the second component was insertion of a paclitaxel-coated balloon. In the control arm, an identical procedure was followed, but using a standard balloon. Main outcome measures The primary end point was time (days) to loss of target lesion primary patency. Secondary patency end points were time to loss of access circuit primary patency and time to loss of access circuit cumulative patency. Other secondary end points included angiographically determined late lumen loss, rate of binary angiographic restenosis, procedural success, number of thrombosis events, fistula interventions, adverse events during follow-up and patient quality of life. Results Primary analysis showed no evidence for a difference in time to end of target lesion primary patency between groups (hazard ratio 1.18, 95% confidence interval 0.78 to 1.79; p = 0.440). An adjusted secondary analysis with prespecified clinical covariates gave similar results (hazard ratio 1.11, 95% confidence interval 0.69 to 1.78; p = 0.664). Prespecified secondary outcomes included the time to intervention anywhere in the access circuit or the time until the fistula was abandoned. There were no differences in these patency-related secondary outcomes or in any other secondary outcomes, such as adverse events. Limitations The PAVE trial was not a fully blinded trial. It was impossible to ensure that treating radiologists were blinded to treatment allocation because of the appearance of the paclitaxel-coated balloon. The extent to which our findings can be generalised to patients with multiple lesions could be questioned, given the proportion randomised. However, if paclitaxel-coated balloons had been effective at a single lesion segment, then there is no plausible reason why they could not be effective in patients with multiple lesions. Conclusions There were no differences in primary or secondary outcomes. Following a plain balloon angioplasty, additional treatment with a paclitaxel-coated balloon does not provide benefit. Future work The reasons for differences between the results of the PAVE trial and of other studies deserve further analysis and consideration. Other interventions to prevent restenosis following a fistuloplasty are needed. Trial registration Current Controlled Trials ISRCTN14284759. Funding This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 8, No. 13. See the NIHR Journals Library website for further project information.
Background Preterm infants have high rates of morbidity, especially from late-onset sepsis and necrotising enterocolitis. Lactoferrin is an anti-infective milk protein that may act through effects on gut bacteria, metabolites and epithelial cell function. The impact of supplemental lactoferrin in reducing late-onset sepsis was explored in the Enteral LactoFerrin In Neonates (ELFIN) trial. Objectives The Mechanisms Affecting the Gut of Preterm Infants in Enteral feeding (MAGPIE) study was nested within the ELFIN trial and aimed to determine the impact of lactoferrin on gut microbiota and bacterial function, and changes preceding disease onset. We aimed to explore impacts on the stool bacteria and faecal/urinary metabolome using gas and liquid chromatography–mass spectrometry, and explore immunohistological pathways in resected tissue. Methods Preterm infants from 12 NHS hospitals were enrolled in the study, and daily stool and urine samples were collected. Local sample collection data were combined with ELFIN trial data from the National Perinatal Epidemiology Unit, Oxford. The longitudinal impact of lactoferrin in healthy infants was determined, and samples that were collected before disease onset were matched with samples from healthy control infants. Established, quality-controlled 16S ribonucleic acid, gas chromatography–mass spectrometry and liquid chromatography–mass spectrometry analyses were conducted. Validated databases and standardised workflows were used to identify bacteria and metabolites. Tissue samples from infants undergoing surgery and matched controls were analysed. Results We recruited 479 preterm infants (mean gestation of 28.4 ± 2.3 weeks) and collected > 33,000 usable samples from 467 infants. 16S ribonucleic acid bacterial analysis was conducted on samples from 201 infants, of whom 20 had necrotising enterocolitis and 51 had late-onset sepsis, along with samples from healthy matched controls to explore longitudinal changes. The greatest change in relative bacterial abundance over time was observed in Staphylococcus, which decreased from 42% at aged 7–9 days to only 2% at aged 30–60 days (p < 0.001). Small but significant differences in community composition were observed between samples in each ELFIN trial group (R 2 = 0.005; p = 0.04). Staphylococcus (p < 0.01), Haemophilus (p < 0.01) and Lactobacillus (p = 0.01) showed greater mean relative abundance in the placebo group than in the lactoferrin group. Gas chromatography–mass spectrometry and liquid chromatography–mass spectrometry analyses showed that lactoferrin had limited impact on the metabolome. Liquid chromatography–mass spectrometry showed significant metabolite differences between necrotising enterocolitis or late-onset sepsis infants and healthy controls. The resected gut tissue analysis revealed 82 differentially expressed genes between healthy and necrotic tissue. Limitations Although we recruited a large number of infants, collecting daily samples from every infant is challenging, especially in the few days immediately preceding disease onset. Conclusion We conducted a large mechanistic study across multiple hospital sites and showed that, although lactoferrin significantly decreased the level of Staphylococcus and other key pathogens, the impact was smaller than those of other clinical variables. Immunohistochemistry identified multiple inflammatory pathways leading to necrotising enterocolitis and showed that the use of NHS pathology archive tissue is feasible in the context of a randomised controlled trial. Future work We observed significant changes in the stool and urinary metabolome in cases preceding late-onset sepsis or necrotising enterocolitis, which provide metabolic targets for a future mechanistic and biomarker study. Trial registration Current Controlled Trials ISRCTN12554594. Funding This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 8, No. 14. See the NIHR Journals Library website for further project information.
Background Reasoning may play a causal role in paranoid delusions in psychosis. SlowMo, a new digitally supported cognitive–behavioural therapy, targets reasoning to reduce paranoia. Objectives To examine the effectiveness of SlowMo therapy in reducing paranoia and in improving reasoning, quality of life and well-being, and to examine its mechanisms of action, moderators of effects and acceptability. Design A parallel-arm, assessor-blind, randomised controlled trial comparing SlowMo plus treatment as usual with treatment as usual alone. An online independent system randomised eligible participants (1 : 1) using randomly varying permuted blocks, stratified by site and paranoia severity. Setting Community mental health services in three NHS mental health trusts in England, plus patient identification centres. Participants A total of 362 participants with schizophrenia-spectrum psychosis. Eligibility criteria comprised distressing and persistent (≥ 3 months) paranoia. Interventions Eight face-to-face SlowMo sessions over 12 weeks plus treatment as usual, or treatment as usual alone (control group). Main outcome measures The primary outcome measure was paranoia measured by the Green Paranoid Thoughts Scale and its revised version, together with observer-rated measures of persecutory delusions (The Psychotic Symptom Rating Scales delusion scale and delusion items from the Scale for the Assessment of Positive Symptoms). The secondary outcome measures were reasoning (measures of belief flexibility, jumping to conclusions, and fast and slow thinking), well-being, quality of life, schemas, service use and worry. Results A total of 362 participants were recruited between 1 May 2017 and 14 May 2019: 181 in the SlowMo intervention group and 181 in the treatment-as-usual (control) group. One control participant subsequently withdrew. In total, 325 (90%) participants provided primary Green Paranoid Thoughts Scale outcome data at 12 weeks (SlowMo, n = 162; treatment as usual, n = 163). A total of 145 (80%) participants in the SlowMo group completed all eight therapy sessions. SlowMo was superior to treatment as usual in reducing paranoia on all three measures used: Green Paranoid Thoughts Scale total at 12 weeks (Cohen’s d = 0.30, 95% confidence interval 0.09 to 0.51; p = 0.005) and 24 weeks (Cohen’s d = 0.20, 95% confidence interval –0.02 to 0.40; p = 0.063); Psychotic Symptom Rating Scales delusions at 12 weeks (Cohen’s d = 0.47, 95% confidence interval 0.17 to 0.78; p = 0.002) and 24 weeks (Cohen’s d = 0.50, 95% confidence interval 0.20 to 0.80; p = 0.001); and Scale for the Assessment of Positive Symptoms persecutory delusions at 12 weeks (Cohen’s d = 0.43, 95% confidence interval 0.03 to 0.84; p = 0.035) and 24 weeks (Cohen’s d = 0.54, 95% confidence interval 0.14 to 0.94; p = 0.009). Reasoning (belief flexibility, possibility of being mistaken and Fast and Slow Thinking Questionnaire measure) improved, but jumping to conclusions did not improve. Worry, quality of life, well-being and self-concept also improved, improving most strongly at 24 weeks. Baseline characteristics did not moderate treatment effects. Changes in belief flexibility and worry mediated changes in paranoia. Peer researcher-led qualitative interviews confirmed positive experiences of the therapy and technology. Nineteen participants in the SlowMo group and 21 participants in the treatment-as-usual group reported 54 adverse events (51 serious events, no deaths). Limitations The trial included treatment as usual as the comparator and, thus, the trial design did not control for the effects of time with a therapist. Conclusions To the best of our knowledge, this is the largest trial of a psychological therapy for paranoia in people with psychosis and the first trial using a brief targeted digitally supported therapy. High rates of therapy uptake demonstrated acceptability. It was effective for paranoia, comparable to longer therapy, and equally effective for people with different levels of negative symptoms and working memory. Mediators were improvements in belief flexibility and worry. Our results suggest that targeting reasoning helps paranoia. Future work Further examination of SlowMo mechanisms of action and implementation. Trial registration Current Controlled Trials ISRCTN32448671. Funding This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a MRC and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 8, No. 11. See the NIHR Journals Library website for further project information.
Background Idiopathic pulmonary fibrosis is an irreversible fibrosing lung disorder with a poor prognosis. Current treatments slow the rate of decline in lung function and may influence survival, but they have a significant side-effect profile and so additional therapeutic options are required. People with idiopathic pulmonary fibrosis have altered innate immunity and altered lung microbiota, with the bacterial burden relating to mortality. Two randomised controlled trials have demonstrated beneficial effects with co-trimoxazole (SEPTRIN®; Essential Generics Ltd, Egham, UK; Chemidex Generics Ltd, Egham, UK), with the suggestion of an improvement in rates of survival. Objectives To determine the clinical efficacy of co-trimoxazole in people with moderate to severe idiopathic pulmonary fibrosis. Design A Phase II, double-blind, placebo-controlled, parallel-group, randomised multicentre study. Setting UK specialist interstitial lung disease centres. Participants Patients who were randomised had idiopathic pulmonary fibrosis diagnosed by a multidisciplinary team. In addition, patients had significant breathlessness (i.e. a Medical Research Council Dyspnoea Scale score of > 1) and impaired lung function (i.e. a forced vital capacity of < 75% predicted). Patients could be taking licensed medication for idiopathic pulmonary fibrosis, but were excluded if they had significant comorbidities, including airflow obstruction. Intervention Oral co-trimoxazole, 960 mg twice per day (two 480-mg tablets twice per day), compared with placebo tablets (two tablets twice per day) for a median of 27 months (range 12–42 months). Otherwise, both trial groups had standard care. Main outcome measures The primary outcome was the time to death (all causes), transplant or first non-elective hospital admission. Secondary outcomes were the individual components of the primary end point and the number of respiratory-related events. Questionnaires (the King’s Brief Interstitial Lung Disease questionnaire; the Medical Research Council Dyspnoea Scale; EuroQol-5 Dimensions, five-level version; the Leicester Cough Questionnaire; and the Cough Symptom Score) and lung function tests (forced vital capacity and diffusing capacity for carbon monoxide) were undertaken at baseline and at 12 months. Results The trial randomised a total of 342 (295 male) patients (active treatment group, n = 170; placebo group, n = 172), using minimisation for hospital and receipt of licensed antifibrotic medication, from 39 UK hospitals. The patients had a mean (standard deviation) age of 71.3 years (7.47 years) and a mean forced vital capacity of 2.25 l (0.56 l). A total of 137 (40%) patients were taking pirfenidone (Esbriet, Roche Holding AG, Basel, Switzerland) and 116 (34%) were taking nintedanib (Ofev®, Boehringer Ingelheim, Brackness, UK). There was one post-randomisation exclusion from the co-trimoxazole group, but no withdrawals. There was no difference in the time to event for the composite primary end point (co-trimoxazole: hazard ratio 1.2, 95% confidence interval 0.9 to 1.6; p = 0.319). Likewise, there was no difference in other event outcomes, lung function measurements or patient-reported outcomes, other than a beneficial effect on the total Leicester Cough Questionnaire score, the social domain of the Leicester Cough Questionnaire score and the chest domain of the King’s Brief Interstitial Lung Disease questionnaire in the adjusted analysis. The repeated-measures analysis showed a significant overall difference in Cough Symptom Score. There were significantly more reports of nausea, but fewer reports of diarrhoea, with co-trimoxazole; however, differences in frequency of hyperkalaemia, rash and headache were not significant. The limitations of the trial were that it was not possible to evaluate the lung microbiota, there were missing data for secondary end points and there was no health economic analysis. Conclusion These results suggest that co-trimoxazole does not reduce the likelihood of death or number of hospitalisations among people with idiopathic pulmonary fibrosis with moderate to severe idiopathic pulmonary fibrosis. Further work is required to evaluate the effect in subgroups of individuals with idiopathic pulmonary fibrosis or the effect of antibiotics with different antibacterial properties. Trial registration Current Controlled Trials ISRCTN17464641. Funding This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 8, No. 9. See the NIHR Journals Library for further project information.
