Publications by authors named "Susan J Dutton"

56 Publications

Role of thoracic ultrasonography in pleurodesis pathways for malignant pleural effusions (SIMPLE): an open-label, randomised controlled trial.

Lancet Respir Med 2021 Oct 8. Epub 2021 Oct 8.

Academic Respiratory Unit, University of Bristol, Bristol, UK.

Background: Pleurodesis is done as an in-patient procedure to control symptomatic recurrent malignant pleural effusion (MPE) and has a success rate of 75-80%. Thoracic ultrasonography has been shown in a small study to predict pleurodesis success early by demonstrating cessation of lung sliding (a normal sign seen in healthy patients, lung sliding indicates normal movement of the lung inside the thorax). We aimed to investigate whether the use of thoracic ultrasonography in pleurodesis pathways could shorten hospital stay in patients with MPE undergoing pleurodesis.

Methods: The Efficacy of Sonographic and Biological Pleurodesis Indicators of Malignant Pleural Effusion (SIMPLE) trial was an open-label, randomised controlled trial done in ten respiratory centres in the UK and one respiratory centre in the Netherlands. Adult patients (aged ≥18 years) with confirmed MPE who required talc pleurodesis via either a chest tube or as poudrage during medical thorascopy were eligible. Patients were randomly assigned (1:1) to thoracic ultrasonography-guided care or standard care via an online platform using a minimisation algorithm. In the intervention group, daily thoracic ultrasonography examination for lung sliding in nine regions was done to derive an adherence score: present (1 point), questionable (2 points), or absent (3 points), with a lowest possible score of 9 (preserved sliding) and a highest possible score of 27 (complete absence of sliding); the chest tube was removed if the score was more than 20. In the standard care group, tube removal was based on daily output volume (per British Thoracic Society Guidelines). The primary outcome was length of hospital stay, and secondary outcomes were pleurodesis failure at 3 months, time to tube removal, all-cause mortality, symptoms and quality-of-life scores, and cost-effectiveness of thoracic ultrasonography-guided care. All outcomes were assessed in the modified intention-to-treat population (patients with missing data excluded), and a non-inferiority analysis of pleurodesis failure was done in the per-protocol population. This trial was registered with ISRCTN, ISRCTN16441661.

Findings: Between Dec 31, 2015, and Dec 17, 2019, 778 patients were assessed for eligibility and 313 participants (165 [53%] male) were recruited and randomly assigned to thoracic ultrasonography-guided care (n=159) or standard care (n=154). In the modified intention-to-treat population, the median length of hospital stay was significantly shorter in the intervention group (2 days [IQR 2-4]) than in the standard care group (3 days [2-5]; difference 1 day [95% CI 1-1]; p<0·0001). In the per-protocol analysis, thoracic ultrasonography-guided care was non-inferior to standard care in terms of pleurodesis failure at 3 months, which occurred in 27 (29·7%) of 91 patients in the intervention group versus 34 (31·2%) of 109 patients in the standard care group (risk difference -1·5% [95% CI -10·2% to 7·2%]; non-inferiority margin 15%). Mean time to chest tube removal in the intervention group was 2·4 days (SD 2·5) versus 3·1 days (2·0) in the standard care group (mean difference -0·72 days [95% CI -1·22 to -0·21]; p=0·0057). There were no significant between-group differences in all-cause mortality, symptom scores, or quality-of-life scores, except on the EQ-5D visual analogue scale, which was significantly lower in the standard care group at 3 months. Although costs were similar between the groups, thoracic ultrasonography-guided care was cost-effective compared with standard care.

Interpretation: Thoracic ultrasonography-guided care for pleurodesis in patients with MPE results in shorter hospital stay (compared with the British Thoracic Society recommendation for pleurodesis) without reducing the success rate of the procedure at 3 months. The data support consideration of standard use of thoracic ultrasonography in patients undergoing MPE-related pleurodesis.

Funding: Marie Curie Cancer Care Committee.
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http://dx.doi.org/10.1016/S2213-2600(21)00353-2DOI Listing
October 2021

Progressive exercise compared with best-practice advice, with or without corticosteroid injection, for rotator cuff disorders: the GRASP factorial RCT.

Health Technol Assess 2021 08;25(48):1-158

Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.

Background: Rotator cuff-related shoulder pain is very common, but there is uncertainty regarding which modes of exercise delivery are optimal and the long-term benefits of corticosteroid injections.

Objectives: To assess the clinical effectiveness and cost-effectiveness of progressive exercise compared with best-practice physiotherapy advice, with or without corticosteroid injection, in adults with a rotator cuff disorder.

Design: This was a pragmatic multicentre superiority randomised controlled trial (with a 2 × 2 factorial design).

Setting: Twenty NHS primary care-based musculoskeletal and related physiotherapy services.

Participants: Adults aged ≥ 18 years with a new episode of rotator cuff-related shoulder pain in the previous 6 months.

Interventions: A total of 708 participants were randomised (March 2017-May 2019) by a centralised computer-generated 1 : 1 : 1 : 1 allocation ratio to one of four interventions: (1) progressive exercise ( = 174) (six or fewer physiotherapy sessions), (2) best-practice advice ( = 174) (one physiotherapy session), (3) corticosteroid injection then progressive exercise ( = 182) (six or fewer physiotherapy sessions) or (4) corticosteroid injection then best-practice advice ( = 178) (one physiotherapy session).

Main Outcome Measures: The primary outcome was Shoulder Pain and Disability Index (SPADI) score over 12 months. Secondary outcomes included SPADI subdomains, the EuroQol 5 Dimensions, five-level version, sleep disturbance, fear avoidance, pain self-efficacy, return to activity, Global Impression of Treatment and health resource use. Outcomes were collected by postal questionnaires at 8 weeks and at 6 and 12 months. A within-trial economic evaluation was also conducted. The primary analysis was intention to treat.

Results: Participants had a mean age of 55.5 (standard deviation 13.1) years and 49.3% were female. The mean baseline SPADI score was 54.1 (standard deviation 18.5). Follow-up rates were 91% at 8 weeks and 87% at 6 and 12 months. There was an overall improvement in SPADI score from baseline in each group over time. Over 12 months, there was no evidence of a difference in the SPADI scores between the progressive exercise intervention and the best-practice advice intervention in shoulder pain and function (adjusted mean difference between groups over 12 months -0.66, 99% confidence interval -4.52 to 3.20). There was also no difference in SPADI scores between the progressive exercise intervention and best-practice advice intervention when analysed at the 8-week and 6- and 12-month time points. Injection resulted in improvement in shoulder pain and function at 8 weeks compared with no injection (adjusted mean difference -5.64, 99% confidence interval -9.93 to -1.35), but not when analysed over 12 months (adjusted mean difference -1.11, 99% confidence interval -4.47 to 2.26), or at 6 and 12 months. There were no serious adverse events. In the base-case analysis, adding injection to best-practice advice gained 0.021 quality-adjusted life-years ( = 0.184) and increased the cost by £10 per participant ( = 0.747). Progressive exercise alone was £52 ( = 0.247) more expensive per participant than best-practice advice, and gained 0.019 QALYs ( = 0.220). At a ceiling ratio of £20,000 per quality-adjusted life-year, injection plus best-practice advice had a 54.93% probability of being the most cost-effective treatment.

Limitations: Participants and physiotherapists were not blinded to group allocation. Twelve-month follow-up may be insufficient for identifying all safety concerns.

Conclusions: Progressive exercise was not superior to a best-practice advice session with a physiotherapist. Subacromial corticosteroid injection improved shoulder pain and function, but provided only modest short-term benefit. Best-practice advice in combination with corticosteroid injection was expected to be most cost-effective, although there was substantial uncertainty.

Future Work: Longer-term follow-up, including any serious adverse effects of corticosteroid injection.

Trial Registration: Current Controlled Trials ISRCTN16539266 and EudraCT 2016-002991-28.

Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in ; Vol. 25, No. 48. See the NIHR Journals Library website for further project information.
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http://dx.doi.org/10.3310/hta25480DOI Listing
August 2021

Statistical analysis plan for a pragmatic phase III randomised controlled trial examining behaviour change physiotherapy intervention to increase physical activity following hip and knee replacements: the PEP-TALK trial.

Trials 2021 Jul 20;22(1):467. Epub 2021 Jul 20.

Centre for Rehabilitation Research in Oxford, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.

Background: Total hip (THR) and total knee replacements (TKR) are two highly successful orthopaedic procedures that reduce pain for people with osteoarthritis. Previous evidence suggests that physical activity, at best, remains the same pre- to post-operatively, and in some instances declines. The PEP-TALK trial evaluates the effects of a group-based, behaviour change intervention on physical activity following a THR or TKR.

Methods: PEP-TALK is an open, phase III, pragmatic, multi-centre, parallel, two-arm, two-way superiority randomised controlled trial investigating the effectiveness of usual care plus a behaviour change therapy compared with usual care alone following primary THR or TKR. The primary outcome is the UCLA Activity Score at 12 months post-randomisation which will be analysed using a linear mixed effects model. Secondary outcomes measured at 6 months and 12 months after randomisation include the UCLA Activity Score, Lower Extremity Functional Scale, Oxford Hip/Knee Score, Numerical Rating Scale for Pain, Generalised Self-Efficacy Scale, Tampa Scale for Kinesiophobia, Hospital Anxiety and Depression Scale, EuroQoL EQ-5D-5L index and EQ-VAS and complications or adverse events. Full details of the planned analysis approaches for the primary and secondary outcomes, as well as the planned sensitivity analyses to be undertaken due to the COVID-19 pandemic, are described here. The PEP-TALK study protocol has been published previously.

Discussion: This paper provides details of the planned statistical analyses for the PEP-TALK trial. This is aimed to reduce the risk of outcome reporting bias and enhance transparency in reporting.

Trial Registration: International Standard Randomised Controlled Trials database, ISRCTN Number: 29770908 . Registered on October 2018.
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http://dx.doi.org/10.1186/s13063-021-05362-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8290138PMC
July 2021

Progressive exercise compared with best practice advice, with or without corticosteroid injection, for the treatment of patients with rotator cuff disorders (GRASP): a multicentre, pragmatic, 2 × 2 factorial, randomised controlled trial.

Lancet 2021 07 12;398(10298):416-428. Epub 2021 Jul 12.

Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK; College of Medicine and Health, University of Exeter, Exeter, UK.

Background: Corticosteroid injections and physiotherapy exercise programmes are commonly used to treat rotator cuff disorders but the treatments' effectiveness is uncertain. We aimed to compare the clinical effectiveness and cost-effectiveness of a progressive exercise programme with a single session of best practice physiotherapy advice, with or without corticosteroid injection, in adults with a rotator cuff disorder.

Methods: In this pragmatic, multicentre, superiority, randomised controlled trial (2 × 2 factorial), we recruited patients from 20 UK National Health Service trusts. We included patients aged 18 years or older with a rotator cuff disorder (new episode within the past 6 months). Patients were excluded if they had a history of significant shoulder trauma (eg, dislocation, fracture, or full-thickness tear requiring surgery), neurological disease affecting the shoulder, other shoulder conditions (eg, inflammatory arthritis, frozen shoulder, or glenohumeral joint instability), received corticosteroid injection or physiotherapy for shoulder pain in the past 6 months, or were being considered for surgery. Patients were randomly assigned (centralised computer-generated system, 1:1:1:1) to progressive exercise (≤6 sessions), best practice advice (one session), corticosteroid injection then progressive exercise, or corticosteroid injection then best practice advice. The primary outcome was the Shoulder Pain and Disability Index (SPADI) score over 12 months, analysed on an intention-to-treat basis (statistical significance set at 1%). The trial was registered with the International Standard Randomised Controlled Trial Register, ISRCTN16539266, and EuDRACT, 2016-002991-28.

Findings: Between March 10, 2017, and May 2, 2019, we screened 2287 patients. 708 patients were randomly assigned to progressive exercise (n=174), best practice advice (n=174), corticosteroid injection then progressive exercise (n=182), or corticosteroid injection then best practice advice (n=178). Over 12 months, SPADI data were available for 166 (95%) patients in the progressive exercise group, 164 (94%) in the best practice advice group, 177 (97%) in the corticosteroid injection then progressive exercise group, and 175 (98%) in the corticosteroid injection then best practice advice group. We found no evidence of a difference in SPADI score between progressive exercise and best practice advice when analysed over 12 months (adjusted mean difference -0·66 [99% CI -4·52 to 3·20]). We also found no evidence of a difference between corticosteroid injection compared with no injection when analysed over 12 months (-1·11 [-4·47 to 2·26]). No serious adverse events were reported.

Interpretation: Progressive exercise was not superior to a best practice advice session with a physiotherapist in improving shoulder pain and function. Subacromial corticosteroid injection provided no long-term benefit in patients with rotator cuff disorders.

Funding: UK National Institute for Health Research Technology Assessment Programme.
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http://dx.doi.org/10.1016/S0140-6736(21)00846-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8343092PMC
July 2021

Azithromycin versus standard care in patients with mild-to-moderate COVID-19 (ATOMIC2): an open-label, randomised trial.

Lancet Respir Med 2021 10 9;9(10):1130-1140. Epub 2021 Jul 9.

Oxford Clinical Trials Research Unit, Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Oxford, UK.

Background: The antibacterial, anti-inflammatory, and antiviral properties of azithromycin suggest therapeutic potential against COVID-19. Randomised data in mild-to-moderate disease are not available. We assessed whether azithromycin is effective in reducing hospital admission in patients with mild-to-moderate COVID-19.

Methods: This prospective, open-label, randomised superiority trial was done at 19 hospitals in the UK. We enrolled adults aged at least 18 years presenting to hospitals with clinically diagnosed, highly probable or confirmed COVID-19 infection, with fewer than 14 days of symptoms, who were considered suitable for initial ambulatory management. Patients were randomly assigned (1:1) to azithromycin (500 mg once daily orally for 14 days) plus standard care or to standard care alone. The primary outcome was death or hospital admission from any cause over the 28 days from randomisation. The primary and safety outcomes were assessed according to the intention-to-treat principle. This trial is registered at ClinicalTrials.gov (NCT04381962) and recruitment is closed.

Findings: 298 participants were enrolled from June 3, 2020, to Jan 29, 2021. Three participants withdrew consent and requested removal of all data, and three further participants withdrew consent after randomisation, thus, the primary outcome was assessed in 292 participants (145 in the azithromycin group and 147 in the standard care group). The mean age of the participants was 45·9 years (SD 14·9). 15 (10%) participants in the azithromycin group and 17 (12%) in the standard care group were admitted to hospital or died during the study (adjusted OR 0·91 [95% CI 0·43-1·92], p=0·80). No serious adverse events were reported.

Interpretation: In patients with mild-to-moderate COVID-19 managed without hospital admission, adding azithromycin to standard care treatment did not reduce the risk of subsequent hospital admission or death. Our findings do not support the use of azithromycin in patients with mild-to-moderate COVID-19.

Funding: National Institute for Health Research Oxford Biomedical Research Centre, University of Oxford and Pfizer.
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http://dx.doi.org/10.1016/S2213-2600(21)00263-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270523PMC
October 2021

Progression from external pilot to definitive randomised controlled trial: a methodological review of progression criteria reporting.

BMJ Open 2021 06 28;11(6):e048178. Epub 2021 Jun 28.

Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.

Objectives: Prespecified progression criteria can inform the decision to progress from an external randomised pilot trial to a definitive randomised controlled trial. We assessed the characteristics of progression criteria reported in external randomised pilot trial protocols and results publications, including whether progression criteria were specified a priori and mentioned in prepublication peer reviewer reports.

Study Design: Methodological review.

Methods: We searched four journals through PubMed: , , and . Eligible publications reported external randomised pilot trial protocols or results, were published between January 2018 and December 2019 and reported progression criteria. We double data extracted 25% of the included publications. Here we report the progression criteria characteristics.

Results: We included 160 publications (123 protocols and 37 completed trials). Recruitment and retention were the most frequent indicators contributing to progression criteria. Progression criteria were mostly reported as distinct thresholds (eg, achieving a specific target; 133/160, 83%). Less than a third of the planned and completed pilot trials that included qualitative research reported how these findings would contribute towards progression criteria (34/108, 31%). The publications seldom stated who established the progression criteria (12/160, 7.5%) or provided rationale or justification for progression criteria (44/160, 28%). Most completed pilot trials reported the intention to proceed to a definitive trial (30/37, 81%), but less than half strictly met all of their progression criteria (17/37, 46%). Prepublication peer reviewer reports were available for 153/160 publications (96%). Peer reviewer reports for 86/153 (56%) publications mentioned progression criteria, with peer reviewers of 35 publications commenting that progression criteria appeared not to be specified.

Conclusions: Many external randomised pilot trial publications did not adequately report or propose prespecified progression criteria to inform whether to proceed to a future definitive randomised controlled trial.
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http://dx.doi.org/10.1136/bmjopen-2020-048178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240572PMC
June 2021

Hand Osteoarthritis: investigating Pain Effects of estrogen-containing therapy (HOPE-e): a protocol for a feasibility randomised placebo-controlled trial.

Pilot Feasibility Stud 2021 Jun 24;7(1):133. Epub 2021 Jun 24.

Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, UK.

Background: Hand osteoarthritis (OA) is a common condition, causing pain, stiffness and reduced quality of life. Incidence is higher amongst women, particularly around the age of the menopause. Whilst the relationship between sex hormones and OA has been studied in vitro, in epidemiological studies and in clinical trials of hormone replacement therapy (HRT), this study is the first to investigate the effect of estrogen-containing therapy on hand pain in post-menopausal women with symptomatic hand OA in a randomised study design.

Methods: This is a feasibility study of a double-blinded placebo-controlled intervention with 1:1 randomisation to either a combination of conjugated estrogens 0.45 mg and bazedoxifene acetate 20 mg (Duavive) or placebo. The target population is post-menopausal women with symptomatic hand OA, aiming to recruit 60-90 study participants. The primary objective is to assess the feasibility of a future fully powered randomised controlled trial (RCT). Participants will take the study medication for 24 weeks and be followed up for 28 weeks after randomisation. The primary outcomes used to determine feasibility are eligible participant identification rates and routes; recruitment, randomisation and retention rates of eligible participants; study medication compliance; and the likelihood of unintentional unblinding. Secondary outcomes include measures of hand pain, function, appearance and menopausal symptoms. An end of study questionnaire and focus groups will help to refine the final protocol for a full study.

Discussion: Identifying new treatments for symptomatic hand OA is a recognised research priority. The study will help us to understand whether there are sufficient interested and eligible individuals in this target population who would consider HRT for their hand symptoms. It will provide proof-of-concept RCT data on the effects of HRT on hand pain and other clinically relevant outcomes in this population. The study will gain valuable information on the feasibility of a full RCT and how best to run this. The findings will be published in a peer-reviewed journal and presented at a relevant conference.

Trial Registration: ISRCTN12196200 registered on 15 January 2019.
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http://dx.doi.org/10.1186/s40814-021-00869-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223359PMC
June 2021

Chronic pain with neuropathic characteristics after surgery for major trauma to the lower limb: prevalence, predictors, and association with pain severity, disability, and quality of life in the UK WHiST trial.

Bone Joint J 2021 Jun 27;103-B(6):1047-1054. Epub 2021 Apr 27.

Kadoorie Research Centre, Oxford Trauma and Emergency Care, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.

Aims: To identify the prevalence of neuropathic pain after lower limb fracture surgery, assess associations with pain severity, quality of life and disability, and determine baseline predictors of chronic neuropathic pain at three and at six months post-injury.

Methods: Secondary analysis of a UK multicentre randomized controlled trial (Wound Healing in Surgery for Trauma; WHiST) dataset including adults aged 16 years or over following surgery for lower limb major trauma. The trial recruited 1,547 participants from 24 trauma centres. Neuropathic pain was measured at three and six months using the Doleur Neuropathique Questionnaire (DN4); 701 participants provided a DN4 score at three months and 781 at six months. Overall, 933 participants provided DN4 for at least one time point. Physical disability (Disability Rating Index (DRI) 0 to 100) and health-related quality-of-life (EuroQol five-dimension five-level; EQ-5D-5L) were measured. Candidate predictors of neuropathic pain included sex, age, BMI, injury mechanism, concurrent injury, diabetes, smoking, alcohol, analgaesia use pre-injury, index surgery location, fixation type, Injury Severity Score, open injury, and wound care.

Results: The median age of the participants was 51 years (interquartile range 35 to 64). At three and six months post-injury respectively, 32% (222/702) and 30% (234/787) had neuropathic pain, 56% (396/702) and 53% (413/787) had chronic pain without neuropathic characteristics, and the remainder were pain-free. Pain severity was higher among those with neuropathic pain. Linear regression analyses found that those with neuropathic pain at six months post-injury had more physical disability (DRI adjusted mean difference 11.49 (95% confidence interval (CI) 7.84 to 15.14; p < 0.001) and poorer quality of life (EQ-5D utility -0.15 (95% CI -0.19 to -0.11); p < 0.001) compared to those without neuropathic characteristics. Logistic regression identified that prognostic factors of younger age, current smoker, below knee fracture, concurrent injuries, and regular analgaesia pre-injury were associated with higher odds of post-injury neuropathic pain.

Conclusion: Pain with neuropathic characteristics is common after lower limb fracture surgery and persists to six months post-injury. Persistent neuropathic pain is associated with substantially poorer recovery. Further attention to identify neuropathic pain post-lower limb injury, predicting patients at risk, and targeting interventions, is indicated. Cite this article:  2021;103-B(6):1047-1054.
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http://dx.doi.org/10.1302/0301-620X.103B.BJJ-2020-2204.R1DOI Listing
June 2021

Treating to target in psoriatic arthritis: assessing real-world outcomes and optimising therapeutic strategy for adults with psoriatic arthritis-study protocol for the MONITOR-PsA study, a trials within cohorts study design.

Trials 2021 Mar 4;22(1):185. Epub 2021 Mar 4.

Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.

Background: The Tight Control of psoriatic arthritis (TICOPA) trial confirmed improved clinical outcomes with a treat to target (T2T) strategy in psoriatic arthritis (PsA). This consisted of 4-weekly review and escalation of 'step up' therapy (single disease modifying therapy (DMARD), combination DMARDs and then biologics) based on remission criteria. Based on this, a T2T approach is supported by European PsA treatment recommendations. However, it is not commonly implemented in routine care primarily due to feasibility and cost concerns. In the TICOPA trial, the same treatment regime was used for all participants regardless of their disease profile. Despite the recognition of PsA as a highly heterogeneous condition, no studies have tailored which drugs are used depending on disease severity. The cohort will establish real world outcomes for the T2T approach in PsA and also form the basis of a trials within cohorts (TWiCs) design to test alternative therapeutic approaches within embedded clinical trials providing an evidence base for treatment strategy in PsA.

Methods: The Multicentre Observational Initiative in Treat to target Outcomes in Psoriatic Arthritis (MONITOR-PsA) cohort will apply a T2T approach within routine care. It will recruit newly diagnosed adult patients with PsA starting systemic therapies. The cohort is observational allowing routine therapeutic care within NHS clinics but a T2T approach will be supported when monitoring treatment within the cohort. Eligible participants will be adults (≥18 years) with active PsA with ≥ 1 tender or swollen joints or enthesis who have not previously had treatment with DMARDs for articular disease.

Discussion: This study is the first TWiC designed to support a fully powered randomised drug trial. The results from the observational cohort will be compared with those observed in the TICOPA trial investigating the clinical effectiveness and health care costs of the pragmatic T2T approach. Nested trials will provide definitive RCT evidence establishing the optimal management of PsA within the T2T approach. The TWiCs design allows robust generalizability to routine healthcare, avoids disappointment bias, aids recruitment and in future will allow assessment of longer-term outcomes.

Trial Registration: ClinicalTrials.gov NCT03531073 . Retrospectively registered on 21 May 2018.
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http://dx.doi.org/10.1186/s13063-021-05142-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7931500PMC
March 2021

A randomized clinical trial of low dose single antibiotic-loaded cement versus high dose dual antibiotic-loaded cement in patients receiving a hip hemiarthroplasty after fracture: A protocol for the WHiTE 8 COPAL study.

Bone Jt Open 2021 Feb;2(2):72-78

Trauma and Orthopaedics, Northumbria Healthcare NHS Foundation Trust, Ashington, UK.

Aims: Patients receiving cemented hemiarthroplasties after hip fracture have a significant risk of deep surgical site infection (SSI). Standard UK practice to minimize the risk of SSI includes the use of antibiotic-loaded bone cement with no consensus regarding type, dose, or antibiotic content of the cement. This is the protocol for a randomized clinical trial to investigate the clinical and cost-effectiveness of high dose dual antibiotic-loaded cement in comparison to low dose single antibiotic-loaded cement in patients 60 years and over receiving a cemented hemiarthroplasty for an intracapsular hip fracture.

Methods: The WHiTE 8 Copal Or Palacos Antibiotic Loaded bone cement trial (WHiTE 8 COPAL) is a multicentre, multi-surgeon, parallel, two-arm, randomized clinical trial. The pragmatic study will be embedded in the World Hip Trauma Evaluation (WHiTE) (ISRCTN 63982700). Participants, including those that lack capacity, will be allocated on a 1:1 basis stratified by recruitment centre to either a low dose single antibiotic-loaded bone cement or a high dose dual antibiotic-loaded bone cement. The primary analysis will compare the differences in deep SSI rate as defined by the Centers for Disease Control and Prevention within 90 days of surgery via medical record review and patient self-reported questionnaires. Secondary outcomes include UK Core Outcome Set for hip fractures, complications, rate of antibiotic prescription, resistance patterns of deep SSI, and resource use (more specifically, cost-effectiveness) up to four months post-randomization. A minimum of 4,920 patients will be recruited to obtain 90% power to detect an absolute difference of 1.5% in the rate of deep SSI at 90 days for the expected 3% deep SSI rate in the control group.

Conclusion: The results of this trial will provide evidence regarding clinical and cost-effectiveness between low dose single and high dose dual antibiotic-loaded bone cement, which will inform policy and practice guidelines such as the National Institute for Health and Care Excellence guidance on management of hip fractures. Cite this article:  2021;2(2):72-78.
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http://dx.doi.org/10.1302/2633-1462.22.BJO-2020-0174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925209PMC
February 2021

The clinical and cost effectiveness of splints for thumb base osteoarthritis: a randomized controlled clinical trial.

Rheumatology (Oxford) 2021 06;60(6):2862-2877

Primary Care Centre of Excellence Versus Arthritis, School of Primary Community and Social Care, Keele University, Staffordshire.

Objectives: To investigate the clinical effectiveness, efficacy and cost effectiveness of splints (orthoses) in people with symptomatic basal thumb joint OA (BTOA).

Methods: A pragmatic, multicentre parallel group randomized controlled trial at 17 National Health Service (NHS) hospital departments recruited adults with symptomatic BTOA and at least moderate hand pain and dysfunction. We randomized participants (1:1:1) using a computer-based minimization system to one of three treatment groups: a therapist supported self-management programme (SSM), a therapist supported self-management programme plus a verum thumb splint (SSM+S), or a therapist supported self-management programme plus a placebo thumb splint (SSM+PS). Participants were blinded to group allocation, received 90 min therapy over 8 weeks and were followed up for 12 weeks from baseline. Australian/Canadian (AUSCAN) hand pain at 8 weeks was the primary outcome, using intention to treat analysis. We calculated costs of treatment.

Results: We randomized 349 participants to SSM (n = 116), SSM+S (n = 116) or SSM+PS (n = 117) and 292 (84%) provided AUSCAN Osteoarthritis Hand Index hand pain scores at the primary end point (8 weeks). All groups improved, with no mean treatment difference between groups: SSM+S vs SSM -0.5 (95% CI: -1.4, 0.4), P = 0.255; SSM+PS vs SSM -0.1 (95% CI: -1.0, 0.8), P = 0.829; and SSM+S vs SSM+PS -0.4 (95% CI: -1.4, 0.5), P = 0.378. The average 12-week costs were: SSM £586; SSM+S £738; and SSM+PS £685.

Conclusion: There was no additional benefit of adding a thumb splint to a high-quality evidence-based, supported self-management programme for thumb OA delivered by therapists.

Trial Registration: ISRCTN 54744256 (http://www.isrctn.com/ISRCTN54744256).
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http://dx.doi.org/10.1093/rheumatology/keaa726DOI Listing
June 2021

Outpatient physiotherapy versus home-based rehabilitation for patients at risk of poor outcomes after knee arthroplasty: CORKA RCT.

Health Technol Assess 2020 11;24(65):1-116

Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.

Background: Over 100,000 primary knee arthroplasty operations are undertaken annually in the UK. Around 15-30% of patients do not report a good outcome. Better rehabilitation strategies may improve patient-reported outcomes.

Objectives: To compare the outcomes from a traditional outpatient physiotherapy model with those from a home-based rehabilitation programme for people assessed as being at risk of a poor outcome after knee arthroplasty.

Design: An individually randomised, two-arm controlled trial with a blinded outcome assessment, a parallel health economic evaluation and a nested qualitative study.

Setting: The trial took place in 14 NHS physiotherapy departments.

Participants: People identified as being at high risk of a poor outcome after knee arthroplasty.

Interventions: A multicomponent home-based rehabilitation package delivered by rehabilitation assistants with supervision from qualified therapists compared with usual-care outpatient physiotherapy.

Main Outcome Measures: The primary outcome was the Late Life Function and Disability Instrument at 12 months. Secondary outcomes were the Oxford Knee Score (a disease-specific measure of function); Knee injury and Osteoarthritis Outcome Score; Quality of Life subscale; Physical Activity Scale for the Elderly; EuroQol-5 Dimensions, five-level version; and physical function assessed using the Figure-of-8 Walk Test, 30-Second Chair Stand Test and Single Leg Stance. Data on the use of health-care services, time off work and informal care were collected using participant diaries.

Results: In total, 621 participants were randomised. A total of 309 participants were assigned to the COmmunity based Rehabilitation after Knee Arthroplasty (CORKA) home-based rehabilitation programme, receiving a median of five treatment sessions (interquartile range 4-7 sessions). A total of 312 participants were assigned to usual care, receiving a median of four sessions (interquartile range 2-6 sessions). The primary outcome, Late Life Function and Disability Instrument function total score at 12 months, was collected for 279 participants (89%) in the home-based CORKA group and 287 participants (92%) in the usual-care group. No clinically or statistically significant difference was found between the groups (intention-to-treat adjusted difference 0.49 points, 95% confidence interval -0.89 to 1.88 points;  = 0.48). There were no statistically significant differences between the groups in any of the patient-reported or physical secondary outcome measures at 6 or 12 months post randomisation. The health economic analysis found that the CORKA intervention was cheaper to provide than usual care (£66 less per participant). Total societal costs (combining health-care costs and other costs) were lower for the CORKA intervention than usual care (£316 less per participant). Adopting a societal perspective, CORKA had a 75% probability of being cost-effective at a threshold of £30,000 per quality-adjusted life-year. Adopting the narrower health and social care perspective, CORKA had a 43% probability of being cost-effective at the same threshold.

Limitations: The interventions were of short duration and were set within current commissioning guidance for UK physiotherapy. Participants and treating therapists could not be blinded.

Conclusions: This randomised controlled trial found no important differences in outcomes when post-arthroplasty rehabilitation was delivered using a home-based, rehabilitation assistant-delivered rehabilitation package or a traditional outpatient model. However, the health economic evaluation found that when adopting a societal perspective, the CORKA home-based intervention was cost-saving and more effective than, and thus dominant over, usual care, owing to reduced time away from paid employment for this group. Further research could look at identifying the risk of poor outcome and further evaluation of a cost-effective treatment, including the workforce model to deliver it.

Trial Registration: Current Controlled Trials ISRCTN13517704.

Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in ; Vol. 24, No. 65. See the NIHR Journals Library website for further project information.
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http://dx.doi.org/10.3310/hta24650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7750865PMC
November 2020

Characteristics of L-PRP preparations for treating Achilles tendon rupture within the PATH-2 study.

Platelets 2021 Feb 26;32(2):273-279. Epub 2020 Nov 26.

Kadoorie Centre for Critical Care Research, John Radcliffe Hospital, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.

Platelet-rich plasma (PRP) is an autologous preparation that has been claimed to improve healing and mechanobiological properties of tendons both in vitro and in vivo. In this sub-study from the PATH-2 (PRP in Achilles Tendon Healing-2) trial, we report the cellular and growth factor content and quality of the Leukocyte-rich PRP (L-PRP) (N = 103) prepared using a standardized commercial preparation method across 19 different UK centers. Baseline whole blood cell counts (red cells, leukocyte and platelets) demonstrated that the two groups were well-matched. L-PRP analysis gave a mean platelet count of 852.6 x 10/L (SD 438.96), a mean leukocyte cell count of 15.13 x 10/L (SD 10.28) and a mean red blood cell count of 0.91 x 10/L (SD 1.49). The activation status of the L-PRP gave either low or high expression levels of the degranulation marker CD62p before and after ex-vivo platelet activation respectively. TGF-β, VEGF, PDGF, IGF and FGFb mean concentrations were 131.92 ng/ml, 0.98 ng/ml, 55.34 ng/ml, 78.2 ng/ml and 111.0 pg/ml respectively with expected correlations with both platelet and leukocyte counts. While PATH-2 results demonstrated that there was no evidence L-PRP is effective for improving clinical outcomes at 24 weeks after Achilles tendon rupture, our findings support that the majority of L-PRP properties were within the method specification and performance.
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February 2021

A multicentre prospective randomized equivalence trial of a soft bandage and immediate discharge versus current treatment with rigid immobilization for torus fractures of the distal radius in children: protocol for the Forearm Fracture Recovery in Children Evaluation (FORCE) trial.

Bone Jt Open 2020 Jun 8;1(6):214-221. Epub 2020 Jun 8.

Oxford Trauma, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.

Aims: Torus fractures are the most common childhood fracture, accounting for 500,000 UK emergency attendances per year. UK treatment varies widely due to lack of scientific evidence. This is the protocol for a randomized controlled equivalence trial of 'the offer of a soft bandage and immediate discharge' versus 'rigid immobilization and follow-up as per the protocol of the treating centre' in the treatment of torus fractures .

Methods: Children aged four to 15-years-old inclusive who have sustained a torus/buckle fracture of the distal radius with/without an injury to the ulna are eligible to take part. Baseline pain as measured by the Wong Baker FACES pain scale, function using the Patient-Reported Outcomes Measurement Information System (PROMIS) upper limb, and quality of life (QoL) assessed with the EuroQol EQ-5D-Y will be collected. Each patient will be randomly allocated (1:1, stratified by centre and age group (four to seven years and ≥ eight years) to either a regimen of the offer of a soft bandage and immediate discharge or rigid immobilization and follow-up as per the protocol of the treating centre.

Results: At day one, three, and seven, data on pain, function, QoL, immobilization, and analgesia will be collected. Three and six weeks after injury, the main outcomes plus data on complications, resource use, and school absence will be collected. The primary outcome is the Wong-Baker FACES pain scale at three days post-randomization. All data will be obtained through electronic questionnaires completed by the participants and/or parents/guardian.Cite this article: 2020;1-6:214-221.
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http://dx.doi.org/10.1302/2633-1462.16.BJO-2020-0014.R1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677722PMC
June 2020

The Forearm Fracture Recovery in Children Evaluation (FORCE) trial: statistical and health economic analysis plan for an equivalence randomized controlled trial of treatment for torus fractures of the distal radius in children.

Bone Jt Open 2020 Jun 9;1(6):205-213. Epub 2020 Jun 9.

Oxford Clinical Trials Research Unit, Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Botnar Research Centre, Oxford, UK.

Aims: Torus fractures of the distal radius are the most common fractures in children. The NICE non-complex fracture guidelines recently concluded that bandaging was probably the optimal treatment for these injuries. However, across the UK current treatment varies widely due to a lack of evidence underpinning the guidelines. The Forearm Fracture Recovery in Children Evaluation (FORCE) trial evaluates the effect of a soft bandage and immediate discharge compared with rigid immobilization.

Methods: FORCE is a multicentre, parallel group randomized controlled equivalence trial. The primary outcome is the Wong-Baker FACES pain score at three days after randomization and the primary analysis of this outcome will use a multivariate linear regression model to compare the two groups. Secondary outcomes are measured at one and seven days, and three and six-weeks post-randomization and include the Patient Reported Outcome Measurement Information System (PROMIS) upper extremity limb score, EuroQoL EQ-5D-Y, analgesia use, school absence, complications, and healthcare resource use. The planned statistical and health economic analyses for this trial are described here. The FORCE trial protocol has been published separately.

Conclusion: This paper provides details of the planned analyses for this trial, and will reduce the risks of outcome reporting bias and data driven results.Cite this article: 2020;1-6:205-213.
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http://dx.doi.org/10.1302/2633-1462.16.BJO-2020-0015.R1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677725PMC
June 2020

Progressive exercise compared with best practice advice, with or without corticosteroid injection, for the treatment of rotator cuff disorders: statistical analysis plan for the Getting it Right: Addressing Shoulder Pain (GRASP) 2 × 2 factorial multicentre randomised controlled trial.

Trials 2020 Sep 7;21(1):767. Epub 2020 Sep 7.

Oxford Clinical Trials Research Unit, Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Botnar Research Centre, Old Road, Oxford, OX3 7LD, UK.

Background: The Getting it Right: Addressing Shoulder Pain (GRASP) trial assesses the clinical and cost-effectiveness of individually tailored, progressive exercise compared with best practice advice, with or without corticosteroid injection, in adults with a rotator cuff disorder. This article describes the statistical analysis plan for the GRASP randomised controlled trial.

Methods/design: GRASP is a multicentre randomised controlled trial using a 2 × 2 factorial design. Adults aged ≥ 18 years with a new episode of shoulder pain related to a rotator cuff disorder, not currently receiving physiotherapy or being considered for surgery, are randomised (centralised computer-generated 1:1:1:1 allocation ratio) to one of four interventions: (1) progressive exercise (up to 6 physiotherapy sessions), (2) best practice advice (one physiotherapy session), (3) subacromial corticosteroid injection then progressive exercise and (4) subacromial corticosteroid injection then best practice advice. The primary outcome is the mean difference in Shoulder Pain and Disability Index (SPADI) total score over 12 months. Secondary outcomes are as follows: pain and function SPADI subdomains, health-related quality of life (EuroQol EQ-5D-5L), sleep disturbance, return to activity, global impression of change, health resource use, out-of-pocket expenses and work disability. Here, we describe in detail the following: sample size calculation, descriptive statistics of the primary and secondary outcomes, statistical models used for the analysis of the main outcomes, handling of missing data, planned sensitivity and subgroup analyses. This pre-specified statistical analysis plan was written and submitted without prior knowledge of the trial results.

Discussion: Publication of the statistical analysis plan for the GRASP trial aims to reduce the risk of outcome reporting bias and increase transparency of the data analysis. Any deviations or changes to the current SAP will be described and justified in the final study report and any results publications.

Trial Registration: International Standard Randomised Controlled Trial Number ISRCTN16539266 . Registered on 14 June 2016. EudraCT number 2016-002991-28. Registered on 12 June 2016.
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http://dx.doi.org/10.1186/s13063-020-04704-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487843PMC
September 2020

A multi-centre open-label two-arm randomised superiority clinical trial of azithromycin versus usual care in ambulatory COVID-19: study protocol for the ATOMIC2 trial.

Trials 2020 Aug 17;21(1):718. Epub 2020 Aug 17.

Respiratory Medicine Unit and National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC), Nuffield Department of Medicine Experimental Medicine, University of Oxford, Oxfordshire, OX3 9DU, UK.

Background: Azithromycin is an orally active synthetic macrolide antibiotic with a wide range of anti-bacterial, anti-inflammatory and antiviral properties. It is a safe, inexpensive, generic licenced drug available worldwide and manufactured to scale and is a potential candidate therapy for pandemic coronavirus disease 2019 (COVID-19). Azithromycin was widely used to treat severe SARS-CoV and MERS-CoV, but to date, no randomised data are available in any coronavirus infections. Other ongoing trials are exploring short courses of azithromycin either in early disease, within the first 7 days of symptoms, when azithromycin's antiviral properties may be important, or late in disease when anti-bacterial properties may reduce the risk of secondary bacterial infection. However, the molecule's anti-inflammatory properties, including suppression of pulmonary macrophage-derived pro-inflammatory cytokines such as interleukins-1β, -6, -8, and -18 and cytokines G-CSF and GM-CSF may provide a distinct therapeutic benefit if given in as a prolonged course during the period of progression from moderate to severe disease.

Methods: ATOMIC2 is a phase II/III, multi-centre, prospective, open-label, two-arm randomised superiority clinical trial of azithromycin versus standard care for adults presenting to hospital with COVID-19 symptoms who are not admitted at initial presentation. We will enrol adults, ≥ 18 years of age assessed in acute hospitals in the UK with clinical diagnosis of COVID-19 infection where management on an ambulatory care pathway is deemed appropriate. Participants will be randomised in a 1:1 ratio to usual care or to azithromycin 500 mg orally daily for 14 days with telephone follow-up at days 14 and 28. The primary objective is to compare the proportion with either death or respiratory failure requiring invasive or non-invasive mechanical ventilation over 28 days from randomisation. Secondary objectives include mortality/respiratory failure in those with a PCR-confirmed diagnosis; all-cause mortality; progression to pneumonia; progression to severe pneumonia; peak severity of illness and mechanistic analysis of blood and nasal biomarkers.

Discussion: This trial will determine the clinical utility of azithromycin in patients with moderately severe, clinically diagnosed COVID-19 and could be rapidly applicable worldwide.

Trial Registration: ClinicalTrials.gov NCT04381962 . Registered on 11 May 2020. EudraCT identifier 2020-001740-26 . Opened for accrual on 29 May 2020.
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http://dx.doi.org/10.1186/s13063-020-04593-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429453PMC
August 2020

Better Outcomes for Older people with Spinal Trouble (BOOST) trial: statistical analysis plan for a randomised controlled trial of a combined physical and psychological intervention for older adults with neurogenic claudication.

Trials 2020 Jul 21;21(1):667. Epub 2020 Jul 21.

Oxford Clinical Trials Research Unit, Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Old Road, Oxford, OX3 7LD, UK.

Background: Neurogenic claudication is a common spinal condition affecting older adults that has a major effect on mobility and implicitly independence. The effectiveness of conservative interventions in this population is not known. We describe the statistical analysis plan for the Better Outcomes for Older people with Spinal trouble (BOOST) randomised controlled trial.

Methods/design: BOOST is a pragmatic, multicentre, parallel, two-arm, randomised controlled trial. Participants are community-dwelling adults, 65 years or older, with neurogenic claudication, registered prospectively, and randomised 2:1 (intervention to control) to the combined physical and psychological BOOST group physiotherapy programme or best practice advice. The primary outcome is the Oswestry Disability Index at 12 months. Secondary outcomes include the Short Physical Performance Battery, Swiss Spinal Stenosis Scale, 6 Minute Walk Test, Fear Avoidance Beliefs Questionnaire, and Tilburg Frailty Indicator. Outcomes are measured at 6 and 12 months by researchers blinded to treatment allocation. The primary statistical analysis is by intention to treat. Further study design details are published in the BOOST protocol.

Discussion: The planned statistical analyses for the BOOST trial aim to reduce the risk of outcome reporting bias from prior data knowledge. Any changes or deviations from this statistical analysis plan will be described and justified in the final study report.

Trial Registration: This study has been registered in the International Standard Randomised Controlled Trial Number registry, reference number ISRCTN12698674 . Registered on 10 November 2015.
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http://dx.doi.org/10.1186/s13063-020-04590-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7372766PMC
July 2020

Interleukin-2 Therapy of Autoimmunity in Diabetes (ITAD): a phase 2, multicentre, double-blind, randomized, placebo-controlled trial.

Wellcome Open Res 2020 20;5:49. Epub 2020 Mar 20.

Islet Transplant Research Group, Nuffield Department of Surgical Sciences, Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, Oxford, OX3 9DU, UK.

Type 1 diabetes is a common autoimmune disease due to destruction of pancreatic β cells, resulting in lifelong need for insulin. Evidence suggest that maintaining residual β-cell function can improve glucose control and reduce risk of hypoglycaemia and vascular complications. Non-clinical, preclinical and some preliminary clinical data suggest that low-dose interleukin-2 (IL-2) therapy could block pancreatic β cells destruction by increasing the number of functional regulatory T cells (Tregs) that inhibit islet-specific autoreactive effector T cells (Teffs). However, there is lack of data on the effect of low-dose IL-2 in newly diagnosed children and adolescents with T1D as well as lack of specific data on its potential effect on β-cell function. The ' nterleukin-2 herapy of utoimmunity in iabetes (ITAD)' is a phase 2, multicentre, double-blind, randomised, placebo-controlled trial in children and adolescents (6-18 years; having detectable C-peptide) initiated within 6 weeks of T1D diagnosis. A total of 45 participants will be randomised in a 2:1 ratio to receive either ultra-low dose IL-2 (aldesleukin), at a dose of 0.2 x 10 IU/m twice-weekly, given subcutaneously, or placebo, for 6 months. The primary objective is to assess the effects of ultra-low dose aldesleukin administration on endogenous β-cell function as measured by frequent home dried blood spot (DBS) fasting and post-prandial C-peptide in children and adolescents with newly diagnosed T1D. The secondary objectives are: 1) to assess the efficacy of regular dosing of aldesleukin in increasing Treg levels; 2) to confirm the clinical safety and tolerability of ultra-low dose aldesleukin; 3) to assess changes in the immune system indicating benefit or potential risk for future gains/loss in β-cell function and immune function; 4) to assess treatment effect on glycaemic control. Trial registration: EudraCT 2017-002126-20 (06/02/2019).
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http://dx.doi.org/10.12688/wellcomeopenres.15697.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7194454PMC
March 2020

Plaster cast versus functional bracing for Achilles tendon rupture: the UKSTAR RCT.

Health Technol Assess 2020 02;24(8):1-86

Warwick Clinical Trials Unit, Warwick Medical School, University of Warwick, Coventry, UK.

Background: Achilles tendon rupture affects > 11,000 people each year in the UK, leading to prolonged periods away from work, sports and social activities. Traditionally, the ruptured tendon is held still in a plaster cast for ≥ 8 weeks. Functional bracing is an alternative treatment that allows patients to mobilise earlier, but there is little evidence about how bracing affects patients' recovery.

Objectives: To measure the Achilles Tendon Rupture Score, quality of life, complications and resource use of patients receiving non-operative treatment for an Achilles tendon rupture treated with plaster cast compared with those treated with functional bracing.

Design: This was a multicentre, randomised, pragmatic, two-group superiority trial.

Setting: The setting was 39 NHS hospitals.

Participants: A total of 540 adult patients treated non-operatively for Achilles tendon rupture were randomised from July 2016 to May 2018. Exclusion criteria included presenting after 14 days, having had previous rupture and being unable to complete questionnaires.

Interventions: A total of 266 participants had a plaster cast applied, with their toes initially pointing to the floor. The cast was changed over 8 weeks to bring the foot into a walking position. A total of 274 patients had a functional brace that facilitated immediate weight-bearing. The foot position was adjusted within the brace over the same 8-week period.

Main Outcome Measures: Achilles Tendon Rupture Score is patient reported and assesses symptoms and physical activity related to the Achilles tendon (score 0-100, with 100 being the best possible outcome). The secondary outcomes were quality of life, complications and resource use at 8 weeks and at 3, 6 and 9 months.

Results: Participants had a mean age of 48.7 years, were predominantly male (79%) and had ruptured their tendon during sports (70%). Over 93% of participants completed follow-up. There was no statistically significant difference in Achilles Tendon Rupture Score at 9 months post injury (-1.38, 95% confidence interval -4.9 to 2.1). There was a statistically significant difference in Achilles Tendon Rupture Score at 8 weeks post injury in favour of the functional brace group (5.53, 95% confidence interval 2.0 to 9.1), but not at 3 or 6 months post injury. Quality of life showed the same pattern, with a statistically significant difference at 8 weeks post injury but not at later time points. Complication profiles were similar in both groups. Re-rupture of the tendon occurred 17 times in the plaster cast group and 13 times in the functional brace group. There was no difference in resource use.

Conclusions: This trial provides strong evidence that early weight-bearing in a functional brace provides similar outcomes to traditional plaster casting and is safe for patients receiving non-operative treatment of Achilles tendon rupture. The probability that functional bracing is cost-effective exceeds 95% for the base-case imputed analysis, assuming a cost-effectiveness threshold of £20,000 per quality-adjusted life-year. On average, functional brace is associated with lower costs (-£103, 95% confidence interval -£290 to £84) and more quality-adjusted life-years (0.015, 95% confidence interval -0.0013 to 0.030) than plaster cast.

Limitations: Some patients declined to participate in the trial, but only a small proportion of these declined because they had a preference for one treatment or another. Overall, 58% of eligible patients agreed to participate, so the participants are broadly representative of the population under investigation.

Future Work: Although the UK Study of Tendo Achilles Rehabilitation provides guidance with regard to early management, rehabilitation following Achilles tendon rupture is prolonged and further research is required to define the optimal mode of rehabilitation after the initial cast/brace has been removed.

Trial Registration: Current Controlled Trials ISRCTN62639639.

Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in ; Vol. 24, No. 8. See the NIHR Journals Library website for further project information.
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http://dx.doi.org/10.3310/hta24080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049909PMC
February 2020

Effect of Incisional Negative Pressure Wound Therapy vs Standard Wound Dressing on Deep Surgical Site Infection After Surgery for Lower Limb Fractures Associated With Major Trauma: The WHIST Randomized Clinical Trial.

JAMA 2020 02;323(6):519-526

Oxford Trauma, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, University of Oxford, Oxford, England.

Importance: Following surgery to treat major trauma-related fractures, deep wound infection rates are high. It is not known if negative pressure wound therapy can reduce infection rates in this setting.

Objective: To assess outcomes in patients who have incisions resulting from surgery for lower limb fractures related to major trauma and were treated with either incisional negative pressure wound therapy or standard wound dressing.

Design, Setting, And Participants: A randomized clinical trial conducted at 24 trauma hospitals representing the UK Major Trauma Network that included 1548 patients aged 16 years or older who underwent surgery for a lower limb fracture caused by major trauma from July 7, 2016, through April 17, 2018, with follow-up to December 11, 2018.

Interventions: Incisional negative pressure wound therapy (n = 785), which involved a specialized dressing used to create negative pressure over the wound, vs standard wound dressing not involving negative pressure (n = 763).

Main Outcomes And Measures: The primary outcome measure was deep surgical site infection at 30 days diagnosed according to the criteria from the US Centers for Disease Control and Prevention. A preplanned secondary analysis of the primary outcome was performed at 90 days. The secondary outcomes were patient-reported disability (Disability Rating Index), health-related quality of life (EuroQol 5-level EQ-5D), surgical scar assessment (Patient and Observer Scar Assessment Scale), and chronic pain (Douleur Neuropathique Questionnaire) at 3 and 6 months, as well as other local wound healing complications at 30 days.

Results: Among 1548 participants who were randomized (mean [SD] age, 49.8 [20.3] years; 561 [36%] were aged ≤40 years; 583 [38%] women; and 881 [57%] had multiple injuries), 1519 (98%) had data available for the primary outcome. At 30 days, deep surgical site infection occurred in 5.84% (45 of 770 patients) of the incisional negative pressure wound therapy group and in 6.68% (50 of 749 patients) of the standard wound dressing group (odds ratio, 0.87 [95% CI, 0.57 to 1.33]; absolute risk difference, -0.77% [95% CI, -3.19% to 1.66%]; P = .52). There was no significant difference in the deep surgical site infection rate at 90 days (11.4% [72 of 629 patients] in the incisional negative pressure wound therapy group vs 13.2% [78 of 590 patients] in the standard wound dressing group; odds ratio, 0.84 [95% CI, 0.59 to 1.19]; absolute risk difference, -1.76% [95% CI, -5.41% to 1.90%]; P = .32). For the 5 prespecified secondary outcomes reported, there were no significant differences at any time point.

Conclusions And Relevance: Among patients who underwent surgery for major trauma-related lower limb fractures, use of incisional negative pressure wound therapy, compared with standard wound dressing, resulted in no significant difference in the rate of deep surgical site infection. The findings do not support the use of incisional negative pressure wound therapy in this setting, although the event rate at 30 days was lower than expected.

Trial Registration: isrctn.org Identifier: ISRCTN12702354.
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http://dx.doi.org/10.1001/jama.2020.0059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042841PMC
February 2020

Plaster cast versus functional brace for non-surgical treatment of Achilles tendon rupture (UKSTAR): a multicentre randomised controlled trial and economic evaluation.

Lancet 2020 02;395(10222):441-448

Warwick Clinical Trials Unit, University of Warwick, Coventry, UK.

Background: Patients with Achilles tendon rupture who have non-operative treatment have traditionally been treated with immobilisation of the tendon in plaster casts for several weeks. Functional bracing is an alternative non-operative treatment that allows earlier mobilisation, but evidence on its effectiveness and safety is scarce. The aim of the UKSTAR trial was to compare functional and quality-of-life outcomes and resource use in patients treated non-operatively with plaster cast versus functional brace.

Methods: UKSTAR was a pragmatic, superiority, multicentre, randomised controlled trial done at 39 hospitals in the UK. Patients (aged ≥16 years) who were being treated non-operatively for a primary Achilles tendon rupture at the participating centres were potentially eligible. The exclusion criteria were presenting more than 14 days after injury, previous rupture of the same Achilles tendon, or being unable to complete the questionnaires. Eligible participants were randomly assigned (1:1) to receive a plaster cast or functional brace using a centralised web-based system. Because the interventions were clearly visible, neither patients nor clinicians could be masked. Participants wore the intervention for 8 weeks. The primary outcome was patient-reported Achilles tendon rupture score (ATRS) at 9 months, analysed in the modified intention-to-treat population (all patients in the groups to which they were allocated, excluding participants who withdrew or died before providing any outcome data). The main safety outcome was the incidence of tendon re-rupture. Resource use was recorded from a health and personal social care perspective. The trial is registered with ISRCTN, ISRCTN62639639.

Findings: Between Aug 15, 2016, and May 31, 2018, 1451 patients were screened, of whom 540 participants (mean age 48·7 years, 79% male) were randomly allocated to receive plaster cast (n=266) or functional brace (n=274). 527 (98%) of 540 were included in the modified intention-to-treat population, and 13 (2%) were excluded because they withdrew or died before providing any outcome data. There was no difference in ATRS at 9 months post injury (cast group n=244, mean ATRS 74∙4 [SD 19∙8]; functional brace group n=259, ATRS 72∙8 [20∙4]; adjusted mean difference -1∙38 [95% CI -4∙9 to 2∙1], p=0·44). There was no difference in the rate of re-rupture of the tendon (17 [6%] of 266 in the plaster cast group vs 13 [5%] of 274 in the functional brace group, p=0·40). The mean total health and personal social care cost was £1181 for the plaster cast group and £1078 for the functional bract group (mean between-group difference -£103 [95% CI -289 to 84]).

Interpretation: Traditional plaster casting was not found to be superior to early weight-bearing in a functional brace, as measured by ATRS, in the management of patients treated non-surgically for Achilles tendon rupture. Clinicians may consider the use of early weight-bearing in a functional brace as a safe and cost-effective alternative to plaster casting.

Funding: UK National Institute for Health Research Health Technology Assessment Programme.
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http://dx.doi.org/10.1016/S0140-6736(19)32942-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016510PMC
February 2020

Woodcast versus standard casting material for the immobilization of nonoperatively treated distal radial fractures.

Bone Joint J 2020 Jan;102-B(1):48-54

Oxford Trauma, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS), University of Oxford, Oxford, UK.

Aims: Distal radial fractures are the most common fracture sustained by the adult population. Most can be treated using cast immobilization without the need for surgery. The aim of this study was to assess the feasibility of a definitive trial comparing the commonly used fibreglass cast immobilization with an alternative product called Woodcast. Woodcast is a biodegradable casting material with theoretical benefits in terms of patient comfort as well as benefits to the environment.

Methods: This was a multicentre, two-arm, open-label, parallel-group randomized controlled feasibility trial. Patients with a fracture of the distal radius aged 16 years and over were recruited from four centres in the UK and randomized (1:1) to receive a Woodcast or fibreglass cast. Data were collected on participant recruitment and retention, clinical efficacy, safety, and patient acceptability.

Results: Over an eight-month period, 883 patients were screened, 271 were found to be eligible, and 120 were randomized. Patient-reported outcome measures were available for 116 (97%) of participants at five weeks and 99 (83%) at three months. Clinical outcomes and patient acceptability were similar between the two interventions and no serious adverse events were reported in either intervention arm.

Conclusion: Both interventions were deemed efficacious and safe in the cohort studied. This study showed that a definitive study comparing Woodcast and fibreglass was feasible in terms of patient recruitment and retention. Cite this article: 2020;102-B(1):48-54.
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http://dx.doi.org/10.1302/0301-620X.102B1.BJJ-2019-0243.R2DOI Listing
January 2020

Study of Peri-Articular Anaesthetic for Replacement of the Knee (SPAARK): study protocol for a patient-blinded, randomised controlled superiority trial of liposomal bupivacaine.

Trials 2019 Dec 16;20(1):732. Epub 2019 Dec 16.

Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK.

Background: Optimising the management of peri-operative pain and recovery following knee replacement has been identified as a patient priority. Current pain relief strategies use opiate-based analgesia; however, up to 50% of patients experience significant side effects. Local anaesthetic incisional infiltration is one alternative. The length of the duration of action is a major limiting factor of current local anaesthetic techniques. Liposomal bupivacaine has been reported to be effective for up to 72 h. This randomised controlled trial will evaluate the clinical and cost effectiveness of liposomal bupivacaine.

Methods: SPAARK is a patient-blinded, multi-centre, active comparator, superiority, two-arm, parallel-group randomised controlled trial. Five hundred patients undergoing knee replacement will be recruited and randomised to liposomal bupivacaine plus bupivacaine hydrochloride or bupivacaine hydrochloride alone. The co-primary outcomes are the Quality of Recovery 40 measured at 72 h post-surgery and also cumulative pain measured daily using a 0-10 visual analogue scale for the first 3 days following surgery. Secondary outcomes include cumulative opioid consumption, fitness for discharge, functional outcomes assessed using the Oxford Knee Score and American Knee Society Score, the EuroQol five dimensions instrument and complications. A cost utility analysis is also planned.

Discussion: The clinical effectiveness and cost effectiveness of liposomal bupivacaine have yet to be evaluated in the National Health Service, making this trial appropriate and timely.

Trial Registration: ISRCTN registry, ISRCTN54191675. Registered on 14 November 2017.
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http://dx.doi.org/10.1186/s13063-019-3826-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6915937PMC
December 2019

Ten-year Mortality, Disease Progression, and Treatment-related Side Effects in Men with Localised Prostate Cancer from the ProtecT Randomised Controlled Trial According to Treatment Received.

Eur Urol 2020 03 24;77(3):320-330. Epub 2019 Nov 24.

Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK.

Background: The ProtecT trial reported intention-to-treat analysis of men with localised prostate cancer (PCa) randomly allocated to active monitoring (AM), radical prostatectomy, and external beam radiotherapy.

Objective: To determine report outcomes according to treatment received in men in randomised and treatment choice cohorts.

Design, Setting, And Participants: This study focuses on secondary care. Men with clinically localised prostate cancer at one of nine UK centres were invited to participate in the treatment trial comparing AM, radical prostatectomy, and radiotherapy.

Intervention: Two cohorts included 1643 men who agreed to be randomised; 997 declined randomisation and chose treatment.

Outcome Measurements And Statistical Analysis: Health-related quality of life impacts on urinary, bowel, and sexual function were assessed using patient-reported outcome measures. Analysis was carried out based on treatment received for each cohort and on pooled estimates using meta-analysis. Differences were estimated with adjustment for known prognostic factors using propensity scores.

Results And Limitations: According to treatment received, more men receiving AM died of PCa (AM 1.85%, surgery 0.67%, radiotherapy 0.73%), whilst this difference remained consistent with chance in the randomised cohort (p=0.08); stronger evidence was found in the exploratory analyses (randomised plus choice cohort) when AM was compared with the combined radical treatment group (p=0.003). There was also strong evidence that metastasis (AM 5.6%, surgery 2.4%, radiotherapy 2.7%) and disease progression (AM 20.35%, surgery 5.87%, radiotherapy 6.62%) were more common in the AM group. Compared with AM, there were higher risks of sexual dysfunction (95% at 6mo) and urinary incontinence (55% at 6mo) after surgery, and of sexual dysfunction (88% at 6mo) and bowel dysfunction (5% at 6mo) after radiotherapy. The key limitations are the potential for bias when comparing groups defined by treatment received and outdating of the interventions being evaluated during the lengthy follow-up required in trials of screen-detected PCa.

Conclusions: Analyses according to treatment received showed increased rates of disease-related events and lower rates of patient-reported harms in men managed by AM compared with men managed by radical treatment, and stronger evidence of greater PCa mortality in the AM group.

Patient Summary: More than 90 out of every 100 men with localised prostate cancer do not die of prostate cancer within 10yr, irrespective of whether treatment is by means of monitoring, surgery, or radiotherapy. Side effects on sexual and bladder function are much better after active monitoring, but the risks of spreading of prostate cancer are more common.
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http://dx.doi.org/10.1016/j.eururo.2019.10.030DOI Listing
March 2020

Platelet rich plasma injection for acute Achilles tendon rupture: PATH-2 randomised, placebo controlled, superiority trial.

BMJ 2019 11 20;367:l6132. Epub 2019 Nov 20.

Kadoorie Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.

Objective: To determine whether an injection of platelet rich plasma improves outcomes after acute Achilles tendon rupture.

Design: Randomised, placebo controlled, two arm, parallel group, participant and assessor masked, superiority trial.

Setting: Secondary care trauma units across 19 hospitals in the United Kingdom's health service.

Participants: Recruitment commenced in July 2015 and follow-up was completed in March 2018. 230 adults aged 18 years and over were included, with acute Achilles tendon rupture presenting within 12 days of injury and managed with non-surgical treatment. Exclusions were injury at the insertion or musculotendinous junction, major leg injury or deformity, diabetes mellitus, platelet or haematological disorder, systemic corticosteroids, anticoagulation treatment, and other contraindicating conditions.

Interventions: Participants were randomised 1:1 to platelet rich plasma (n=114) or placebo (dry needle; n=116) injection. All participants received standard rehabilitation care (ankle immobilisation followed by physiotherapy).

Main Outcomes And Measures: Primary outcome was muscle tendon function at 24 weeks, measured objectively with the limb symmetry index (injured/uninjured×100) in maximal work done during the heel rise endurance test (an instrumented measure of repeated single leg heel rises until fatigue). Secondary outcomes included patient reported function (Achilles tendon rupture score), quality of life (short form 12 version 2®), pain (visual analogue scale), goal attainment (patient specific functional scale), and adverse events. A central laboratory analysed the quality and content of platelet rich plasma. Analyses were by modified intention to treat.

Results: Participants were 46 years old on average, and 57 (25%) of 230 were female. At 24 weeks, 202 (88%) participants completed the heel rise endurance test and 216 (94%) the patient reported outcomes. The platelet rich plasma was of good quality, with expected growth factor content. No difference was detected in muscle tendon function between participants receiving platelet rich plasma injections and those receiving placebo injections (limb symmetry index, mean 34.7% (standard deviation 17.7%) 38.5% (22.8%); adjusted mean difference -3.9% (95% confidence interval -10.5% to 2.7%)) or in any secondary outcomes or adverse event rates. Complier average causal effect analyses gave similar findings.

Conclusions: There is no evidence to indicate that injections of platelet rich plasma can improve objective muscle tendon function, patient reported function, or quality of life after acute Achilles tendon rupture compared with placebo, or that they offer any patient benefit.

Trial Registration: ISRCTN54992179.
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http://dx.doi.org/10.1136/bmj.l6132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6863552PMC
November 2019

Progressive functional exercise versus best practice advice for adults aged 50 years or over after ankle fracture: protocol for a pilot randomised controlled trial in the UK - the Ankle Fracture Treatment: Enhancing Rehabilitation (AFTER) study.

BMJ Open 2019 11 2;9(11):e030877. Epub 2019 Nov 2.

Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.

Introduction: Ankle fractures result in significant morbidity in adults, with prognosis worsening with increasing age. Previous trials have not found evidence supporting supervised physiotherapy sessions, but these studies have not focused on older adults or tailored the exercise interventions to the complex needs of this patient group. The Ankle Fracture Treatment: Enhancing Rehabilitation study is a pilot randomised controlled trial to assess feasibility of a later definitive trial comparing best-practice advice with progressive functional exercise for adults aged 50 years and over after ankle fracture.The main objectives are to assess: (i) patient engagement with the trial, measured by the participation rate of those eligible; (ii) establish whether the interventions are acceptable to participants and therapists, assessed by intervention adherence levels, participant interviews and a therapist focus group; (iii) participant retention in the trial, measured by the proportion of participants providing outcome data at 6 months; (iv) acceptability of measuring outcomes at 3 and 6 month follow-up.

Methods And Analysis: A multicentre pilot randomised controlled trial with an embedded qualitative study. At least 48 patients aged 50 years and over with an ankle fracture requiring surgical management, or non-operative management by immobilisation for at least 4 weeks, will be recruited from a minimum of three National Health Service hospitals in the UK. Participants will be allocated 1:1 via a central web-based randomisation system to: (i) best-practice advice (one session of face-to-face self-management advice delivered by a physiotherapist and up to two optional additional sessions) or (ii) progressive functional exercise (up to six sessions of individual face-to-face physiotherapy). An embedded qualitative study will include one-to-one interviews with up to 20 participants and a therapist focus group.

Ethics And Dissemination: Hampshire B Research Ethics Committee (18/SC/0281) gave approval on 2 July 2018.

Trial Registration Number: ISRCTN16612336.
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http://dx.doi.org/10.1136/bmjopen-2019-030877DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6830709PMC
November 2019
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