The outcomes measured and reported in observational studies of incidental and untreated intracranial meningioma: A systematic review.

Background: The clinical management of patients with incidental intracranial meningioma varies markedly and is often based on clinician choice and observational data. Heterogeneous outcome measurement has likely hampered knowledge progress by preventing comparative analysis of similar cohorts of patients. This systematic review aimed to summarize the outcomes measured and reported in observational studies. Methods: A systematic literature search was performed to identify published full texts describing active monitoring of adult cohorts with incidental and untreated intracranial meningioma (PubMed, EMBASE, MEDLINE, and CINAHL via EBSCO, completed January 24, 2022). Reported outcomes were extracted verbatim, along with an associated definition and method of measurement if provided. Verbatim outcomes were de-duplicated and the resulting unique outcomes were grouped under standardized outcome terms. These were classified using the taxonomy proposed by the "Core Outcome Measures in Effectiveness Trials" (COMET) initiative. Results: Thirty-three published articles and 1 ongoing study were included describing 32 unique studies: study designs were retrospective n = 27 and prospective n = 5. In total, 268 verbatim outcomes were reported, of which 77 were defined. Following de-duplication, 178 unique verbatim outcomes remained and were grouped into 53 standardized outcome terms. These were classified using the COMET taxonomy into 9 outcome domains and 3 core areas. Conclusions: Outcome measurement across observational studies of incidental and untreated intracranial meningioma is heterogeneous. The standardized outcome terms identified will be prioritized through an eDelphi survey and consensus meeting of key stakeholders (including patients), in order to develop a Core Outcome Set for use in future observational studies.

The outcomes measured and reported in intracranial meningioma clinical trials: A systematic review.

Background: Meningioma clinical trials have assessed interventions including surgery, radiotherapy, and pharmacotherapy. However, agreement does not exist on what, how, and when outcomes of interest should be measured. To do so would allow comparative analysis of similar trials. This systematic review aimed to summarize the outcomes measured and reported in meningioma clinical trials. Methods: Systematic literature and trial registry searches were performed to identify published and ongoing intracranial meningioma clinical trials (PubMed, Embase, Medline, CINAHL via EBSCO, and Web of Science, completed January 22, 2022). Reported outcomes were extracted verbatim, along with an associated definition and method of measurement if provided. Verbatim outcomes were deduplicated and the resulting unique outcomes were grouped under standardized outcome terms. These were classified using the taxonomy proposed by the "Core Outcome Measures in Effectiveness Trials" (COMET) initiative. Results: Thirty published articles and 18 ongoing studies were included, describing 47 unique clinical trials: Phase 2 n = 33, phase 3 n = 14. Common interventions included: Surgery n = 13, radiotherapy n = 8, and pharmacotherapy n = 20. In total, 659 verbatim outcomes were reported, of which 84 were defined. Following de-duplication, 415 unique verbatim outcomes remained and were grouped into 115 standardized outcome terms. These were classified using the COMET taxonomy into 29 outcome domains and 5 core areas. Conclusions: Outcome measurement across meningioma clinical trials is heterogeneous. The standardized outcome terms identified will be prioritized through an eDelphi survey and consensus meeting of key stakeholders (including patients), in order to develop a core outcome set for use in future meningioma clinical trials.

Quantifying the carbon footprint of clinical trials: guidance development and case studies.

BACKGROUND: The urgency of the climate crisis requires attention from biomedical research, not least clinical trials which can involve significant greenhouse gas emissions. The Low Carbon Clinical Trials Working Group set out a strategy to reduce the emissions of clinical trials, starting with the development of a method to measure their carbon footprint (CO2e). METHODS: As a first step, we developed a process map defining clinical trial core activities. Corresponding emission factors were sourced to convert activity data into greenhouse gas emissions. The subsequent method was applied to two Cancer Research UK (CRUK)-funded trials (the international randomised sarcoma trial CASPS (ISRCTN63733470) and the UK cohort-based breast cancer trial PRIMETIME (ISRCTN41579286)). A guidance document defining the scope, method and assumptions was written to allow application to any publicly funded/investigator initiated clinical trial. RESULTS: Trial specific activities over and above routine care were grouped into 10 modules covering trial set up, conduct and closure. We identified emission factors for all trial activities within both trials and used them to estimate their total carbon footprint. The carbon footprint of CASPS, an international phase 2 trial of an investigational medicinal product with 47 participants, was 72 tonnes CO2e, largely attributable to clinical trials unit emissions and staff travel. PRIMETIME, a UK-based phase 3 non-investigational medicinal product trial with 1962 patients, produced 89 tonnes CO2e, largely attributable to trial-specific in-person participant assessments. CONCLUSION: We have developed a method and guidance that trialists can use to determine the carbon footprint of clinical trials. The guidance can be used to identify carbon hotspots where alternative approaches to trial design and conduct could reduce a trial footprint, and where methodology research is required to investigate the potential impact of interventions taken to reduce carbon emissions. We will continue to refine the guidance to increase the potential application and improve usability.

A Systematic Review to Evaluate Patient-Reported Outcome Measures (PROMs) for Metastatic Prostate Cancer According to the COnsensus-Based Standard for the Selection of Health Measurement INstruments (COSMIN) Methodology.

INTRODUCTION: Patient-reported outcome measures (PROMs) represent important endpoints in metastatic prostate cancer (mPCa). However, the clinically valid and accurate measurement of health-related quality of life depends on the psychometric properties of the PROMs considered. OBJECTIVE: To appraise, compare, and summarize the properties of PROMs in mPCa. EVIDENCE ACQUISITION: We performed a review of PROMs used in RCTs, including patients with mPCa, using Medline in September 2021, according to the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) criteria. This systematic review is part of PIONEER (an IMI2 European network of excellence for big data in PCa). RESULTS: The most frequently used PROMs in RCTs of patients with mPCa were the Functional Assessment for Cancer Therapy-Prostate (FACT-P) (n = 18), the Brief Pain Inventory-Short Form (BPI-SF) (n = 8), and the European Organization for Research and Treatment of Cancer quality of life core 30 (EORTC QLQ-C30) (n = 6). A total of 283 abstracts were screened and 12 full-text studies were evaluated. A total of two, one, and two studies reported the psychometric proprieties of FACT-P, Brief Pain Inventory (BPI), and BPI-SF, respectively. FACT-P and BPI showed a high content validity, while BPI-SF showed a moderate content validity. FACT-P and BPI showed a high internal consistency (summarized by Cronbach's α 0.70-0.95). CONCLUSIONS: The use of BPI and FACT-P in mPCa patients is supported by their high content validity and internal consistency. Since BPI is focused on pain assessment, we recommend FACT-P, which provides a broader assessment of QoL and wellbeing, for the clinical evaluation of mPCa patients. However, these considerations have been elaborated on in a very limited number of studies. PATIENT SUMMARY: In this paper, we review the psychometric properties of PROMs used with patients with mPCa to find the questionnaires that best assess patients' QoL, in order to help professionals in their intervention and improve patients' QoL. We recommend the use of BPI and FACT-P for their high content validity and internal consistency despite the limited number of studies considered.

Development of 'Core Outcome Sets' for Meningioma in Clinical Studies (The COSMIC Project): protocol for two systematic literature reviews, eDelphi surveys and online consensus meetings.

INTRODUCTION: Meningioma is the most common primary intracranial tumour in adults. The majority are non-malignant, but a proportion behave more aggressively. Incidental/minimally symptomatic meningioma are often managed by serial imaging. Symptomatic meningioma, those that threaten neurovascular structures, or demonstrate radiological growth, are usually resected as first-line management strategy. For patients in poor clinical condition, or with inoperable, residual or recurrent disease, radiotherapy is often used as primary or adjuvant treatment. Effective pharmacotherapy treatments do not currently exist. There is heterogeneity in the outcomes measured and reported in meningioma clinical studies. Two 'Core Outcome Sets' (COS) will be developed: (COSMIC: Intervention) for use in meningioma clinical effectiveness trials and (COSMIC: Observation) for use in clinical studies of incidental/untreated meningioma. METHODS AND ANALYSIS: Two systematic literature reviews and trial registry searches will identify outcomes measured and reported in published and ongoing (1) meningioma clinical effectiveness trials, and (2) clinical studies of incidental/untreated meningioma. Outcomes include those that are clinician reported, patient reported, caregiver reported and based on objective tests (eg, neurocognitive tests), as well as measures of progression and survival. Outcomes will be deduplicated and categorised to generate two long lists. The two long lists will be prioritised through two, two-round, international, modified eDelphi surveys including patients with meningioma, healthcare professionals, researchers and those in caring/supporting roles. The two final COS will be ratified through two 1-day online consensus meetings, with representation from all stakeholder groups. ETHICS AND DISSEMINATION: Institutional review board (University of Liverpool) approval was obtained for the conduct of this study. Participant eConsent will be obtained prior to participation in the eDelphi surveys and consensus meetings. The two systematic literature reviews and two final COS will be published and freely available. TRIAL REGISTRATION NUMBER: COMET study ID 1508.

The British Orthopaedic Surgery Surveillance study: Perthes' disease: the epidemiology and two-year outcomes from a prospective cohort in Great Britain.

AIMS: The aim of this study was to evaluate the epidemiology and treatment of Perthes' disease of the hip. METHODS: This was an anonymized comprehensive cohort study of Perthes' disease, with a nested consented cohort. A total of 143 of 144 hospitals treating children's hip disease in the UK participated over an 18-month period. Cases were cross-checked using a secondary independent reporting network of trainee surgeons to minimize those missing. Clinician-reported outcomes were collected until two years. Patient-reported outcome measures (PROMs) were collected for a subset of participants. RESULTS: Overall, 371 children (396 hips) were newly affected by Perthes' disease arising from 63 hospitals, with a median of two patients (interquartile range 1.0 to 5.5) per hospital. The annual incidence was 2.48 patients (95% confidence interval (CI) 2.20 to 2.76) per 100,000 zero- to 14-year-olds. Of these, 117 hips (36.4%) were treated surgically. There was considerable variation in the treatment strategy, and an optimized decision tree identified joint stiffness and age above eight years as the key determinants for containment surgery. A total of 348 hips (88.5%) had outcomes to two years, of which 227 were in the late reossification stage for which a hip shape outcome (Stulberg grade) was assigned. The independent predictors of a poorer radiological outcome were female sex (odds ratio (OR) 2.27 (95% CI 1.19 to 4.35)), age above six years (OR 2.62 (95% CI (1.30 to 5.28)), and over 50% radiological collapse at inclusion (OR 2.19 (95% CI 0.99 to 4.83)). Surgery had no effect on radiological outcomes (OR 1.03 (95% CI 0.55 to 1.96)). PROMs indicated the marked effect of the disease on the child, which persisted at two years. CONCLUSION: Despite the frequency of containment surgery, we found no evidence of improved outcomes. There appears to be a sufficient case volume and community equipoise among surgeons to embark on a randomized clinical trial to definitively investigate the effectiveness of containment surgery. Cite this article: Bone Joint J 2022;104-B(4):510-518.

The British Orthopaedic Surgery Surveillance study: slipped capital femoral epiphysis: the epidemiology and two-year outcomes from a prospective cohort in Great Britain.

AIMS: The aim of this study was to inform the epidemiology and treatment of slipped capital femoral epiphysis (SCFE). METHODS: This was an anonymized comprehensive cohort study, with a nested consented cohort, following the the Idea, Development, Exploration, Assessment, Long-term study (IDEAL) framework. A total of 143 of 144 hospitals treating SCFE in Great Britain participated over an 18-month period. Patients were cross-checked against national administrative data and potential missing patients were identified. Clinician-reported outcomes were collected until two years. Patient-reported outcome measures (PROMs) were collected for a subset of participants. RESULTS: A total of 486 children (513 hips) were newly affected, with a median of two patients (interquartile range 0 to 4) per hospital. The annual incidence was 3.34 (95% confidence interval (CI) 3.01 to 3.67) per 100,000 six- to 18-year-olds. Time to diagnosis in stable disease was increased in severe deformity. There was considerable variation in surgical strategy among those unable to walk at diagnosis (66 urgent surgery vs 43 surgery after interval delay), those with severe radiological deformity (34 fixation with deformity correction vs 36 without correction) and those with unaffected opposite hips (120 prophylactic fixation vs 286 no fixation). Independent risk factors for avascular necrosis (AVN) were the inability of the child to walk at presentation to hospital (adjusted odds ratio (aOR) 4.4 (95% CI 1.7 to 11.4)) and surgical technique of open reduction and internal fixation (aOR 7.5 (95% CI 2.4 to 23.2)). Overall, 33 unaffected untreated opposite hips (11.5%) were treated for SCFE by two-year follow-up. Age was the only independent risk factor for contralateral SCFE, with age under 12.5 years the optimal cut-off to define 'at risk'. Of hips treated with prophylactic fixation, none had SCFE, though complications included femoral fracture, AVN, and revision surgery. PROMs demonstrated the marked impact on quality of life on the child because of SCFE. CONCLUSION: The experience of individual hospitals is limited and mechanisms to consolidate learning may enhance care. Diagnostic delays were common and radiological severity worsened with increasing time to diagnosis. There was unexplained variation in treatment, some of which exposes children to significant risks that should be evaluated through randomized controlled trials. Cite this article: Bone Joint J 2022;104-B(4):519-528.

Opportunities and challenges for the development of "core outcome sets" in neuro-oncology.

Core Outcome Sets (COS) define minimum outcomes to be measured and reported in clinical effectiveness trials for a particular health condition/health area. Despite recognition as critical to clinical research design for other health areas, none have been developed for neuro-oncology. COS development projects should carefully consider: scope (how the COS should be used), stakeholders involved in development (including patients as both research partners and participants), and consensus methodologies used (typically a Delphi survey and consensus meeting), as well as dissemination plans. Developing COS for neuro-oncology is potentially challenging due to extensive tumor subclassification (including molecular stratification), different symptoms related to anatomical tumor location, and variation in treatment options. Development of a COS specific to tumor subtype, in a specific location, for a particular intervention may be too narrow and would be unlikely to be used. Equally, a COS that is applicable across a wider area of neuro-oncology may be too broad and therefore lack specificity. This review describes why and how a COS may be developed, and discusses challenges for their development, specific to neuro-oncology. The COS under development are briefly described, including: adult glioma, incidental/untreated meningioma, meningioma requiring intervention, and adverse events from surgical intervention for pediatric brain tumors.

Updating and Integrating Core Outcome Sets for Localised, Locally Advanced, Metastatic, and Nonmetastatic Castration-resistant Prostate Cancer: An Update from the PIONEER Consortium.

CONTEXT: Harmonisation of outcome reporting and definitions for clinical trials and routine patient records can enable health care systems to provide more efficient outcome-driven and patient-centred interventions. We report on the work of the PIONEER Consortium in this context for prostate cancer (PCa). OBJECTIVE: To update and integrate existing core outcome sets (COS) for PCa for the different stages of the disease, assess their applicability, and develop standardised definitions of prioritised outcomes. EVIDENCE ACQUISITION: We followed a four-stage process involving: (1) systematic reviews; (2) qualitative interviews; (3) expert group meetings to agree standardised terminologies; and (4) recommendations for the most appropriate definitions of clinician-reported outcomes. EVIDENCE SYNTHESIS: Following four systematic reviews, a multinational interview study, and expert group consensus meetings, we defined the most clinically suitable definitions for (1) COS for localised and locally advanced PCa and (2) COS for metastatic and nonmetastatic castration-resistant PCa. No new outcomes were identified in our COS for localised and locally advanced PCa. For our COS for metastatic and nonmetastatic castration-resistant PCa, nine new core outcomes were identified. CONCLUSIONS: These are the first COS for PCa for which the definitions of prioritised outcomes have been surveyed in a systematic, transparent, and replicable way. This is also the first time that outcome definitions across all prostate cancer COS have been agreed on by a multidisciplinary expert group and recommended for use in research and clinical practice. To limit heterogeneity across research, these COS should be recommended for future effectiveness trials, systematic reviews, guidelines and clinical practice of localised and metastatic PCa. PATIENT SUMMARY: Patient outcomes after treatment for prostate cancer (PCa) are difficult to compare because of variability. To allow better use of data from patients with PCa, the PIONEER Consortium has standardised and recommended outcomes (and their definitions) that should be collected as a minimum in all future studies.

Identifying a core outcome set for pulmonary sarcoidosis research - the Foundation for Sarcoidosis Research - Sarcoidosis Clinical OUtcomes Taskforce (SCOUT).

Background: Pulmonary sarcoidosis is a rare granulomatous disease of unknown aetiology. Heterogeneity in the outcomes measured in trials of treatment for pulmonary sarcoidosis has impacted on the ability to systematically compare findings, contributing to research inefficiency. The FSR-SCOUT study has aimed to address this heterogeneity by developing a core outcome set that represents a patient and health professional consensus on the most important outcomes to measure in future research for the treatment of pulmonary sarcoidosis. Research design and methods: systematic review of trial registries, narrative synthesis of published qualitative literature on the patient experience and results of a patient survey contributed to the development of a comprehensive list of outcomes that were rated in a two round online Delphi survey. The Delphi survey was completed by patients/carers and health professionals and the results discussed and ratified at an online consensus meeting. Results: 259 patients/carers and 51 health professionals completed both rounds of the Delphi survey. A pre-agreed definition of consensus was applied and the results discussed at an online consensus meeting attended by 17 patients and 7 health professionals). Fifteen outcomes, across five domains (physiological/clinical, treatment, resource use, quality of life, and death), reached the definition of consensus and were included in the core outcome set. Conclusions: The core outcome set represents a patient and health professional consensus on the most important outcomes for pulmonary sarcoidosis research. The use of the core outcome set in future trials, and efforts to validate its components, will enhance the relevance of trials to stakeholders and will increase the opportunity for the research to contribute to evidence synthesis.

Standardising the Assessment of Patient-reported Outcome Measures in Localised Prostate Cancer. A Systematic Review.

CONTEXT: Prostate cancer (PCa) is the second most common cancer among men worldwide. Urinary, bowel, and sexual function, as well as hormonal symptoms and health-related quality of life (HRQoL), were prioritised by patients and professionals as part of a core outcome set for localised PCa regardless of treatment type. OBJECTIVE: To systematically review the measurement properties of patient-reported outcome measures (PROMs) used in localised PCa and recommend PROMs for use in routine practice and research settings. EVIDENCE ACQUISITION: The psychometric properties of PROMs measuring functional and HRQoL domains used in randomised controlled trials including patients with localised PCa were assessed according to the Consensus-based Standards for the Selection of Health Measurement Instruments (COSMIN) methodology. MEDLINE and Embase were searched to identify publications evaluating psychometric properties of the PROMs. The characteristics and methodological quality of the studies included were extracted, tabulated, and assessed according to the COSMIN criteria. EVIDENCE SYNTHESIS: Overall, 27 studies evaluating psychometric properties of the Expanded Prostate Cancer Index Composite (EPIC), University of California-Los Angeles Prostate Cancer Index (UCLA-PCI), European Organisation for Research and Treatment of Cancer (EORTC) quality of life core 30 (QLQ-C30) and prostate cancer 25 (QLQ-PR25) modules, International Index of Erectile Function (IIEF), and the 36-item (SF-36) and 12-item Short-Form health survey (SF-12) PROMs were identified and included in the systematic review. EPIC and EORTC QLQ-C30, a general module that assesses patients' physical, psychological, and social functions, were characterised by high internal consistency (Cronbach's α 0.46-0.96 and 0.68-0.94 respectively) but low content validity. EORTC QLQ-PR25, which is primarily designed to assess PCa-specific HRQoL, had moderate content validity and internal consistency (Cronbach's α 0.39-0.87). UCLA-PCI was characterised by moderate content validity and high internal consistency (Cronbach's α 0.21-0.94). However, it does not directly assess hormonal symptoms, whereas EORTC QLQ-PR25 does. CONCLUSION: The tools with the best evidence for psychometric properties and feasibility for use in routine practice and research settings to assess PROMs in patients with localised PCa were EORTC QLQ-C30 and QLQ-PR25. Since EORTC QLQ-C30 is a general module that does not directly assess PCa-specific issues, it should be adopted in conjunction with the QLQ-PR25 module. PATIENT SUMMARY: We reviewed and appraised the measurement properties of patient-reported outcome measure questionnaires used for patients with localised prostate cancer. We found good evidence to suggest that two questionnaires (EORTC QLQ-C30 and QLQ-PR25) can be used to measure urinary, bowel, and sexual functions and health-related quality of life.

How are trial outcomes prioritised by stakeholders from different regions? Analysis of an international Delphi survey to develop a core outcome set in gastric cancer surgery.

BACKGROUND: International stakeholder participation is important in the development of core outcome sets (COS). Stakeholders from varying regions may value health outcomes differently. Here, we explore how region, health income and participant characteristics influence prioritisation of outcomes during development of a COS for gastric cancer surgery trials (the GASTROS study). METHODS: 952 participants from 55 countries participating in a Delphi survey during COS development were eligible for inclusion. Recruits were grouped according to region (East or West), country income classification (high and low-to-middle income) and other characteristics (e.g. patients; age, sex, time since surgery, mode of treatment, surgical approach and healthcare professionals; clinical experience). Groups were compared with respect to how they categorised 56 outcomes identified as potentially important to include in the final COS ('consensus in', 'consensus out', 'no consensus'). Outcomes categorised as 'consensus in' or 'consensus out' by all 3 stakeholder groups would be automatically included in or excluded from the COS respectively. RESULTS: In total, 13 outcomes were categorised 'consensus in' (disease-free survival, disease-specific survival, surgery-related death, recurrence of cancer, completeness of tumour removal, overall quality of life, nutritional effects, all-cause complications, intraoperative complications, anaesthetic complications, anastomotic complications, multiple organ failure, and bleeding), 13 'consensus out' and 31 'no consensus'. There was little variation in prioritisation of outcomes by stakeholders from Eastern or Western countries and high or low-to-middle income countries. There was little variation in outcome prioritisation within either health professional or patient groups. CONCLUSION: Our study suggests that there is little variation in opinion within stakeholder groups when participant region and other characteristics are considered. This finding may help COS developers when designing their Delphi surveys and recruitment strategies. Further work across other clinical fields is needed before broad recommendations can be made.

Lung cancer mortality reduction by LDCT screening: UKLS randomised trial results and international meta-analysis.

BACKGROUND: The NLST reported a significant 20% reduction in lung cancer mortality with three annual low-dose CT (LDCT) screens and the Dutch-Belgian NELSON trial indicates a similar reduction. We present the results of the UKLS trial. METHODS: From October 2011 to February 2013, we randomly allocated 4 055 participants to either a single invitation to screening with LDCT or to no screening (usual care). Eligible participants (aged 50-75) had a risk score (LLPv2) ≥ 4.5% of developing lung cancer over five years. Data were collected on lung cancer cases to 31 December 2019 and deaths to 29 February 2020 through linkage to national registries. The primary outcome was mortality due to lung cancer. We included our results in a random-effects meta-analysis to provide a synthesis of the latest randomised trial evidence. FINDINGS: 1 987 participants in the intervention and 1 981 in the usual care arms were followed for a median of 7.3 years (IQR 7.1-7.6), 86 cancers were diagnosed in the LDCT arm and 75 in the control arm. 30 lung cancer deaths were reported in the screening arm, 46 in the control arm, (relative rate 0.65 [95% CI 0.41-1.02]; p=0.062). The meta-analysis indicated a significant reduction in lung cancer mortality with a pooled overall relative rate of 0.84 (95% CI 0.76-0.92) from nine eligible trials. INTERPRETATION: The UKLS trial of single LDCT indicates a reduction of lung cancer death of similar magnitude to the NELSON and NLST trials and was included in a meta-analysis of nine randomised trials which provides unequivocal support for lung cancer screening in identified risk groups. FUNDING: NIHR Health Technology Assessment programme; NIHR Policy Research programme; Roy Castle Lung Cancer Foundation.

Intravenous or oral antibiotic treatment in adults and children with cystic fibrosis and Pseudomonas aeruginosa infection: the TORPEDO-CF RCT.

BACKGROUND: People with cystic fibrosis are susceptible to pulmonary infection with Pseudomonas aeruginosa. This may become chronic and lead to increased mortality and morbidity. If treatment is commenced promptly, infection may be eradicated through prolonged antibiotic treatment. OBJECTIVE: To compare the clinical effectiveness, cost-effectiveness and safety of two eradication regimens. DESIGN: This was a Phase IV, multicentre, parallel-group, randomised controlled trial. SETTING: Seventy UK and two Italian cystic fibrosis centres. PARTICIPANTS: Participants were individuals with cystic fibrosis aged > 28 days old who had never had a P. aeruginosa infection or who had been infection free for 1 year. INTERVENTIONS: Fourteen days of intravenous ceftazidime and tobramycin or 3 months of oral ciprofloxacin. Inhaled colistimethate sodium was included in both regimens over 3 months. Consenting patients were randomly allocated to either treatment arm in a 1 : 1 ratio using simple block randomisation with random variable block length. MAIN OUTCOME MEASURES: The primary outcome was eradication of P. aeruginosa at 3 months and remaining free of infection to 15 months. Secondary outcomes included time to reoccurrence, spirometry, anthropometrics, pulmonary exacerbations and hospitalisations. Primary analysis used intention to treat (powered for superiority). Safety analysis included patients who had received at least one dose of any of the study drugs. Cost-effectiveness analysis explored the cost per successful eradication and the cost per quality-adjusted life-year. RESULTS: Between 5 October 2010 and 27 January 2017, 286 patients were randomised: 137 patients to intravenous antibiotics and 149 patients to oral antibiotics. The numbers of participants achieving the primary outcome were 55 out of 125 (44%) in the intravenous group and 68 out of 130 (52%) in the oral group. Participants randomised to the intravenous group were less likely to achieve the primary outcome; although the difference between groups was not statistically significant, the clinically important difference that the trial aimed to detect was not contained within the confidence interval (relative risk 0.84, 95% confidence interval 0.65 to 1.09; p = 0.184). Significantly fewer patients in the intravenous group (40/129, 31%) than in the oral group (61/136, 44.9%) were hospitalised in the 12 months following eradication treatment (relative risk 0.69, 95% confidence interval 0.5 to 0.95; p = 0.02). There were no clinically important differences in other secondary outcomes. There were 32 serious adverse events in 24 participants [intravenous: 10/126 (7.9%); oral: 14/146 (9.6%)]. Oral therapy led to reductions in costs compared with intravenous therapy (-£5938.50, 95% confidence interval -£7190.30 to -£4686.70). Intravenous therapy usually necessitated hospital admission, which accounted for a large part of this cost. LIMITATIONS: Only 15 out of the 286 participants recruited were adults - partly because of the smaller number of adult centres participating in the trial. The possibility that the trial participants may be different from the rest of the cystic fibrosis population and may have had a better clinical status, and so be more likely to agree to the uncertainty of trial participation, cannot be ruled out. CONCLUSIONS: Intravenous antibiotics did not achieve sustained eradication of P. aeruginosa in a greater proportion of cystic fibrosis patients. Although there were fewer hospitalisations in the intravenous group during follow-up, this confers no advantage over the oral therapy group, as intravenous eradication frequently requires hospitalisation. These results do not support the use of intravenous antibiotics to eradicate P. aeruginosa in cystic fibrosis. FUTURE WORK: Future research studies should combine long-term follow-up with regimens to reduce reoccurrence after eradication. TRIAL REGISTRATION: Current Controlled Trials ISRCTN02734162 and EudraCT 2009-012575-10. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 65. See the NIHR Journals Library website for further project information.

Cystic fibrosis is a genetic condition that affects mucous glands, causing sticky mucus in the lungs and digestive system. People with cystic fibrosis are prone to lung infection with a bacterium called Pseudomonas aeruginosa, which can lead to serious long-term complications and death. It is possible to eradicate P. aeruginosa if antibiotics are started promptly and taken for several months. The Trial of Optimal TheRapy for Pseudomonas EraDicatiOn in Cystic Fibrosis (TORPEDO-CF) was designed to find out if intravenous ceftazidime and tobramycin were better at eradicating P. aeruginosa than oral ciprofloxacin. A total of 286 children, young people and adults with cystic fibrosis joined the study from 70 UK and two Italian centres. Approximately half of the participants received treatment with intravenous antibiotics and half with oral antibiotics. All participants received inhaled colistin for 3 months and were followed up for a minimum of 15 months. We studied whether or not either treatment eradicated P. aeruginosa, and if reinfection happened during follow-up. We also collected data on lung function, other chest infections and hospital admissions, and examined whether or not one treatment was more cost-effective than the other. In total, 15 adults joined TORPEDO-CF, so the study population may not totally match the wider cystic fibrosis population; however, in TORPEDO-CF, we found that intravenous antibiotics did not achieve persistent eradication of P. aeruginosa in a greater proportion of cystic fibrosis patients. We also found that oral antibiotics were more cost-effective than intravenous antibiotics. The intravenous antibiotics group had fewer hospital admissions during follow-up, but, as they were usually admitted for their initial treatment, this was not considered an advantage over the oral antibiotics group. The TORPEDO-CF results do not support the use of intravenous antibiotics to eradicate P. aeruginosa in cystic fibrosis and, when the findings of this trial are applied in routine clinical practice in the NHS, patients will most likely receive oral treatment as an outpatient, avoiding the need for hospital admission.

Inclusion of participants from low-income and middle-income countries in core outcome sets development: a systematic review.

OBJECTIVE: Our study aims to describe differences or similarities in the scope, participant characteristics and methods used in core outcome sets (COS) development when only participants from high-income countries (HICs) were involved compared with when participants from low-income and middle-income countries (LMICs) were also involved. DESIGN: Systematic review. DATA SOURCES: Annual Core Outcome Measures in Effectiveness Trials systematic reviews of COS which are updated based on SCOPUS and MEDLINE, searches. The latest systematic review included studies published up to the end of 2019. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: We included studies reporting development of a COS for use in research regardless of age, health condition or setting. Studies reporting the development of a COS for patient-reported outcomes or adverse events or complications were also included. DATA EXTRACTION AND SYNTHESIS: Data were extracted in relation to scope of the COS study, participant categories and the methods used in outcome selection. RESULTS: Studies describing 370 COS were identified in the database. Of these, 75 (20%) included participants from LMICs. Only four COS were initiated from an LMIC setting. More than half of COS with LMIC participants were developed in the last 5 years. Cancer and rheumatology were the dominant disease domains. Overall, over 259 (70%) of COS explicitly reported including clinical experts; this was higher where LMIC participants were also included 340 (92%). Most LMIC participants were from China, Brazil and South Africa. Mixed methods for consensus building were used across the two settings. CONCLUSION: Progress has been made in including LMIC participants in the development of COS, however, there is a need to explore how to enable initiation of COS development from a range of LMIC settings, how to ensure prioritisation of COS that better reflects the burden of disease in these contexts and how to improve public participation from LMICs.

Patient participation in Delphi surveys to develop core outcome sets: systematic review.

OBJECTIVES: To describe the design and conduct of core outcome set (COS) studies that have included patients as participants, exploring how study characteristics might impact their response rates. DESIGN: Systematic review of COS studies published between 2015 and 2019 that included more than one patient, carer or representative as participants (hereafter referred to as patients for brevity) in scoring outcomes in a Delphi. RESULTS: There were variations in the design and conduct of COS studies that included patients in the Delphi process, including differing: scoring and feedback systems, approaches to recruiting patients, length of time between rounds, use of reminders, incentives, patient and public involvement, and piloting. Minimal reporting of participant characteristics and a lack of translation of Delphi surveys into local languages were found. Additionally, there were indications that studies that recruited patients through treatment centres had higher round two response rates than studies recruiting through patient organisations. CONCLUSIONS: Variability was striking in how COS Delphi surveys were designed and conducted to include patient participants and other stakeholders. Future research is needed to explore what motivates patients to take part in COS studies and what factors influence COS developer recruitment strategies. Improved reporting would increase knowledge of how methods affect patient participation in COS Delphi studies.

Methods for conducting international Delphi surveys to optimise global participation in core outcome set development: a case study in gastric cancer informed by a comprehensive literature review.

BACKGROUND: Core outcome sets (COS) should be relevant to key stakeholders and widely applicable and usable. Ideally, they are developed for international use to allow optimal data synthesis from trials. Electronic Delphi surveys are commonly used to facilitate global participation; however, this has limitations. It is common for these surveys to be conducted in a single language potentially excluding those not fluent in that tongue. The aim of this study is to summarise current approaches for optimising international participation in Delphi studies and make recommendations for future practice. METHODS: A comprehensive literature review of current approaches to translating Delphi surveys for COS development was undertaken. A standardised methodology adapted from international guidance derived from 12 major sets of translation guidelines in the field of outcome reporting was developed. As a case study, this was applied to a COS project for surgical trials in gastric cancer to translate a Delphi survey into 7 target languages from regions active in gastric cancer research. RESULTS: Three hundred thirty-two abstracts were screened and four studies addressing COS development in rheumatoid and osteoarthritis, vascular malformations and polypharmacy were eligible for inclusion. There was wide variation in methodological approaches to translation, including the number of forward translations, the inclusion of back translation, the employment of cognitive debriefing and how discrepancies and disagreements were handled. Important considerations were identified during the development of the gastric cancer survey including establishing translation groups, timelines, understanding financial implications, strategies to maximise recruitment and regulatory approvals. The methodological approach to translating the Delphi surveys was easily reproducible by local collaborators and resulted in an additional 637 participants to the 315 recruited to complete the source language survey. Ninety-nine per cent of patients and 97% of healthcare professionals from non-English-speaking regions used translated surveys. CONCLUSION: Consideration of the issues described will improve planning by other COS developers and can be used to widen international participation from both patients and healthcare professionals.

Surgical microdiscectomy versus transforaminal epidural steroid injection in patients with sciatica secondary to herniated lumbar disc (NERVES): a phase 3, multicentre, open-label, randomised controlled trial and economic evaluation.

BACKGROUND: The optimal invasive treatment for sciatica secondary to herniated lumbar disc remains controversial, with a paucity of evidence for use of non-surgical treatments such as transforaminal epidural steroid injection (TFESI) over surgical microdiscectomy. We aimed to investigate the clinical and cost-effectiveness of these options for management of radicular pain secondary to herniated lumbar disc. METHODS: We did a pragmatic, multicentre, phase 3, open-label, randomised controlled trial at 11 spinal units across the UK. Eligible patients were aged 16-65 years, had MRI-confirmed non-emergency sciatica secondary to herniated lumbar disc with symptom duration between 6 weeks and 12 months, and had leg pain that was not responsive to non-invasive management. Participants were randomly assigned (1:1) to receive either TFESI or surgical microdiscectomy by an online randomisation system that was stratified by centre with random permuted blocks. The primary outcome was Oswestry Disability Questionnaire (ODQ) score at 18 weeks. All randomly assigned participants who completed a valid ODQ at baseline and at 18 weeks were included in the analysis. Safety analysis included all treated participants. Cost-effectiveness was estimated from the EuroQol-5D-5L, Hospital Episode Statistics, medication usage, and self-reported resource-use data. This trial was registered with ISRCTN, number ISRCTN04820368, and EudraCT, number 2014-002751-25. FINDINGS: Between March 6, 2015, and Dec 21, 2017, 163 (15%) of 1055 screened patients were enrolled, with 80 participants (49%) randomly assigned to the TFESI group and 83 participants (51%) to the surgery group. At week 18, ODQ scores were 30·02 (SD 24·38) for 63 assessed patients in the TFESI group and 22·30 (19·83) for 61 assessed patients in the surgery group. Mean improvement was 24·52 points (18·89) for the TFESI group and 26·74 points (21·35) for the surgery group, with an estimated treatment difference of -4·25 (95% CI -11·09 to 2·59; p=0·22). There were four serious adverse events in four participants associated with surgery, and none with TFESI. Compared with TFESI, surgery had an incremental cost-effectiveness ratio of £38 737 per quality-adjusted life-year gained, and a 0·17 probability of being cost-effective at a willingness-to-pay threshold of £20 000 per quality-adjusted life-year. INTERPRETATION: For patients with sciatica secondary to herniated lumbar disc, with symptom duration of up to 12 months, TFESI should be considered as a first invasive treatment option. Surgery is unlikely to be a cost-effective alternative to TFESI. FUNDING: Health Technology Assessment programme of the National Institute for Health Research (NIHR), UK.

Microdiscectomy compared with transforaminal epidural steroid injection for persistent radicular pain caused by prolapsed intervertebral disc: the NERVES RCT.

BACKGROUND: Sciatica is a common condition reported to affect > 3% of the UK population at any time and is most often caused by a prolapsed intervertebral disc. Currently, there is no uniformly adopted treatment strategy. Invasive treatments, such as surgery (i.e. microdiscectomy) and transforaminal epidural steroid injection, are often reserved for failed conservative treatment. OBJECTIVE: To compare the clinical effectiveness and cost-effectiveness of microdiscectomy with transforaminal epidural steroid injection for the management of radicular pain secondary to lumbar prolapsed intervertebral disc for non-emergency presentation of sciatica of < 12 months' duration. INTERVENTIONS: Patients were randomised to either (1) microdiscectomy or (2) transforaminal epidural steroid injection. DESIGN: A pragmatic, multicentre, randomised prospective trial comparing microdiscectomy with transforaminal epidural steroid injection for sciatica due to prolapsed intervertebral disc with < 1 year symptom duration. SETTING: NHS services providing secondary spinal surgical care within the UK. PARTICIPANTS: A total of 163 participants (aged 16-65 years) were recruited from 11 UK NHS outpatient clinics. MAIN OUTCOME MEASURES: The primary outcome was participant-completed Oswestry Disability Questionnaire score at 18 weeks post randomisation. Secondary outcomes were visual analogue scores for leg pain and back pain; modified Roland-Morris score (for sciatica), Core Outcome Measures Index score and participant satisfaction at 12-weekly intervals. Cost-effectiveness and quality of life were assessed using the EuroQol-5 Dimensions, five-level version; Hospital Episode Statistics data; medication usage; and self-reported cost data at 12-weekly intervals. Adverse event data were collected. The economic outcome was incremental cost per quality-adjusted life-year gained from the perspective of the NHS in England. RESULTS: Eighty-three participants were allocated to transforaminal epidural steroid injection and 80 participants were allocated to microdiscectomy, using an online randomisation system. At week 18, Oswestry Disability Questionnaire scores had decreased, relative to baseline, by 26.7 points in the microdiscectomy group and by 24.5 points in the transforaminal epidural steroid injection. The difference between the treatments was not statistically significant (estimated treatment effect -4.25 points, 95% confidence interval -11.09 to 2.59 points). Nor were there significant differences between treatments in any of the secondary outcomes: Oswestry Disability Questionnaire scores, visual analogue scores for leg pain and back pain, modified Roland-Morris score and Core Outcome Measures Index score up to 54 weeks. There were four (3.8%) serious adverse events in the microdiscectomy group, including one nerve palsy (foot drop), and none in the transforaminal epidural steroid injection group. Compared with transforaminal epidural steroid injection, microdiscectomy had an incremental cost-effectiveness ratio of £38,737 per quality-adjusted life-year gained and a probability of 0.17 of being cost-effective at a willingness to pay threshold of £20,000 per quality-adjusted life-year. LIMITATIONS: Primary outcome data was invalid or incomplete for 24% of participants. Sensitivity analyses demonstrated robustness to assumptions made regarding missing data. Eighteen per cent of participants in the transforaminal epidural steroid injection group subsequently received microdiscectomy prior to their primary outcome assessment. CONCLUSIONS: To the best of our knowledge, the NErve Root Block VErsus Surgery trial is the first trial to evaluate the comparative clinical effectiveness and cost-effectiveness of microdiscectomy and transforaminal epidural steroid injection. No statistically significant difference was found between the two treatments for the primary outcome. It is unlikely that microdiscectomy is cost-effective compared with transforaminal epidural steroid injection at a threshold of £20,000 per quality-adjusted life-year for sciatica secondary to prolapsed intervertebral disc. FUTURE WORK: These results will lead to further studies in the streamlining and earlier management of discogenic sciatica. TRIAL REGISTRATION: Current Controlled Trials ISRCTN04820368 and EudraCT 2014-002751-25. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 24. See the NIHR Journals Library website for further project information.

WHAT IS THE PROBLEM?: Sciatica or pain related to nerve irritation travelling down the leg is common in young working adults and most likely to be caused by a 'slipped' (prolapsed) disc. Although the majority of cases get better on their own and within 4­6 weeks, a significant group of patients struggle with disabling symptoms sometimes beyond 1 year. Consequently, patients struggle to maintain their home and working lives. Many treatments are available for sciatica, but simpler treatments (e.g. pain tablets, physiotherapy and changing one's lifestyle) are often not very effective and patients have often tried all of them by the time they are seen in hospital to have tests, such as scans, done. Surgery to remove part of the disc is recommended in cases where the pain is accompanied by severe weakness in one or both legs, or where doctors think that nerves may be damaged because patients have bladder, bowel and sexual functioning difficulties (i.e. red flag symptoms). Surgery works well in alleviation of referred leg pain and also to relieve pressure on a physically compressed nerve that may be showing clinical sign of injury/weakness. An alternative to surgery is to inject a mixture of anaesthetic and steroid close to the site of the disc injury and nerve, but at the moment we do not know whether or not these injections work in the long term. They are cheaper and less invasive, with fewer risks than surgery, such as from anaesthetic or infection. WHAT DID OUR STUDY INVESTIGATE?: This study compared the usefulness of surgery with injections for patients who have had sciatica for < 1 year and who have tried simple remedies but are still in pain. Patients were allocated to have either surgery or the injection. Symptoms (e.g. pain) were assessed after 18 weeks. WHAT DID WE FIND?: We found that there was no significant difference between surgery and injection at the primary end point. Surgery was not significantly different from injection in terms of clinical outcome and was not cost-effective compared with injection. OUR CONCLUSION AND RECOMMENDATION: Given the cost of surgery and the risks to patients, we suggest that further studies should be carried out to explore whether or not all patients with sciatica due to a slipped disc should be considered suitable for an injection, unless there is a good reason not to.