Good Statistical Practice-development of tailored Good Clinical Practice training for statisticians.

BACKGROUND: Statisticians are fundamental in ensuring clinical research, including clinical trials, are conducted with quality, transparency, reproducibility and integrity. Good Clinical Practice (GCP) is an international quality standard for the conduct of clinical trials research. Statisticians are required to undertake training on GCP but existing training is generic and, crucially, does not cover statistical activities. This results in statisticians undertaking training mostly unrelated to their role and variation in awareness and implementation of relevant regulatory requirements with regards to statistical conduct. The need for role-relevant training is recognised by the UK NHS Health Research Authority and the Medicines and Healthcare products Regulatory Agency (MHRA). METHODS: The Good Statistical Practice (GCP for Statisticians) project was instigated by the UK Clinical Research Collaboration (UKCRC) Registered Clinical Trials Unit (CTU) Statisticians Operational Group and funded by the National Institute for Health and Care Research (NIHR), to develop materials to enable role-specific GCP training tailored to statisticians. Review of current GCP training was undertaken by survey. Development of training materials were based on MHRA GCP. Critical review and piloting was conducted with UKCRC CTU and NIHR researchers with comment from MHRA. Final review was conducted through the UKCRC CTU Statistics group. RESULTS: The survey confirmed the need and desire for the development of dedicated GCP training for statisticians. An accessible, comprehensive, piloted training package was developed tailored to statisticians working in clinical research, particularly the clinical trials arena. The training materials cover legislation and guidance for best practice across all clinical trial processes with statistical involvement, including exercises and real-life scenarios to bridge the gap between theory and practice. Comprehensive feedback was incorporated. The training materials are freely available for national and international adoption. CONCLUSION: All research staff should have training in GCP yet the training undertaken by most academic statisticians does not cover activities related to their role. The Good Statistical Practice (GCP for Statisticians) project has developed and extensively piloted new, role-specific, comprehensive, accessible GCP training tailored to statisticians working in clinical research, particularly the clinical trials arena. This role-specific training will encourage best practice, leading to transparent and reproducible statistical activity, as required by regulatory authorities and funders.

High-dose dual-antibiotic loaded cement for hip hemiarthroplasty in the UK (WHiTE 8): a randomised controlled trial.

BACKGROUND: Hip fracture is the most common injury requiring treatment in hospital. Controversy exists regarding the use of antibiotic loaded bone cement in hip fractures treated with hemiarthroplasty. We aimed to compare the rate of deep surgical site infection in patients receiving high-dose dual-antibiotic loaded cement versus standard care single-antibiotic loaded cement. METHODS: We included people aged 60 years and older with a hip fracture attending 26 UK hospitals in this randomised superiority trial. Participants undergoing cemented hemiarthroplasty were randomly allocated in a 1:1 ratio to either a standard care single-antibiotic loaded cement or high-dose dual-antibiotic loaded cement. Participants and outcome assessors were masked to the treatment allocation. The primary outcome was deep surgical site infection at 90 days post-randomisation as defined by the US Centers for Disease Control and Prevention in an as-randomised population of consenting participants with available data at 120 days. Secondary outcomes were quality of life, mortality, antibiotic use, mobility, and residential status at day 120. The trial is registered with ISRCTN15606075. FINDINGS: Between Aug 17, 2018, and Aug 5, 2021, 4936 participants were randomly assigned to either standard care single-antibiotic loaded cement (2453 participants) or high-dose dual-antibiotic loaded cement (2483 participants). 38 (1·7%) of 2183 participants with follow-up data in the single-antibiotic loaded cement group had a deep surgical site infection by 90 days post-randomisation, as did 27 (1·2%) of 2214 participants in the high-dose dual-antibiotic loaded cement group (adjusted odds ratio 1·43; 95% CI 0·87-2·35; p=0·16). INTERPRETATION: In this trial, the use of high-dose dual-antibiotic loaded cement did not reduce the rate of deep surgical site deep infection among people aged 60 years or older receiving a hemiarthroplasty for intracapsular fracture of the hip. FUNDING: Heraeus Medical. Supported by the UK National Institute for Health and Care Research Oxford Biomedical Research Centre.

Tailored exercise management (TEMPO) versus usual care for people aged 80 years or older with hip/knee osteoarthritis: study protocol for a feasibility randomised controlled trial.

BACKGROUND: Exercise is recommended for all people with osteoarthritis. However, these recommendations are based on randomised clinical trials including people with an average age between 60 and 70 years, and these findings cannot reliably be generalised to people aged 80 years or older. Rapid loss of muscle occurs after 70 years of age, and older people are more likely to also have other health conditions that contribute to difficulties with daily activities and impact on their response to exercise. To improve care for people aged 80 or older with osteoarthritis, it is thought that a tailored exercise intervention targeting both osteoarthritis and any other health conditions they have, may be needed. The aim of this study will be to test if it is possible to conduct a randomised controlled trial (RCT) for people over 80 years of age with hip/knee osteoarthritis of a tailored exercise intervention. METHODS: A multicentre, parallel, 2-group, feasibility RCT with embedded qualitative study, conducted in ≥ 3 UK NHS physiotherapy outpatient services. Participants (n ≥ 50) with clinical knee and/or hip osteoarthritis and ≥ 1 comorbidity will be recruited by screening referrals to participating NHS physiotherapy outpatient services, via screening of general practice records and via identification of eligible individuals from a cohort study run by our research group. Participants will be randomised (computer-generated: 1:1) to receive either: a 12-week education and tailored exercise intervention (TEMPO); or usual care and written information. The primary feasibility objectives are to estimate: (1) ability to screen and recruit eligible participants; (2) retention of participants, measured by the proportion of participants who provide outcome data at 14-week follow-up. Secondary quantitative objectives are to estimate: (1) participant engagement assessed by physiotherapy session attendance and home exercise adherence; (2) sample size calculation for a definitive RCT. One-to-one semi-structured interviews will explore the experiences of trial participants and physiotherapists delivering the TEMPO programme. DISCUSSION: Progression criteria will be used to determine whether a definitive trial to evaluate the clinical and cost-effectiveness of the TEMPO programme is considered feasible with or without modifications to the intervention or trial design. TRIAL REGISTRATION: ISRCTN75983430. Registered 3/12/2021. https://www.isrctn.com/ISRCTN75983430.

Getting Recovery Right After Neck Dissection (GRRAND-F): Mixed-methods feasibility study to design a pragmatic randomised controlled trial.

Objective: To determine the feasibility of a randomised controlled trial to estimate the effectiveness and cost-effectiveness of a rehabilitation intervention following neck dissection (ND) after head and neck cancer (HNC). Design: Two-arm, open, pragmatic, parallel, multicentre, randomised controlled feasibility trial. Setting: Two UK NHS hospitals. Participants: People who had HNC in whom a ND was part of their care. We excluded those with a life expectancy of six months or less, pre-existing, long-term neurological disease affecting the shoulder and cognitive impairment. Intervention: Usual care (standard care supplemented with a booklet on postoperative self-management) was received by all participants. The GRRAND intervention programme consisted of usual care plus up to six individual physiotherapy sessions including neck and shoulder range of motion and progressive resistance exercises, advice and education. Between sessions, participants were advised to complete a home exercise programme. Randomisation: 1:1 randomisation. Allocation was based on minimisation, stratified by hospital site and spinal accessory nerve sacrifice. It was not possible to mask treatment received. Main outcome measures: Primary: Participant recruitment, retention and fidelity to the study protocol and interventions from study participants and staff at six months post-randomisation (and 12 months for those reaching that time-point). Secondary: clinical measures of pain, function, physical performance, health-related quality of life, health utilisation and adverse events. Results: 36 participants were recruited and enrolled. The study achieved five of its six feasibility targets. These included consent - 70% of eligible participants were consented; intervention fidelity - 78% participants discharged completed the intervention sessions; contamination - none - no participants in the control arm received the GRRAND-F intervention and retention - 8% of participants were lost to follow-up. The only feasibility target that was not achieved was the recruitment target where only 36 of the planned 60 participants were recruited over 18 months. This was principally due to the COVID-19 pandemic which caused all research activity to be paused or reduced, with a subsequent reduction in. Conclusions: Based on the findings a full-trial can now be designed to better understand whether this proposed intervention is effective. Clinical Trial Registration: https://www.isrctn.com/ISRCTN1197999, identifier ISRCTN11979997.

Recommendations for progression criteria during external randomised pilot trial design, conduct, analysis and reporting.

BACKGROUND: External randomised pilot trials aim to assess whether a future definitive Randomised Controlled Trial (RCT) is feasible. Prespecified progression criteria help guide the interpretation of pilot trial findings to decide whether, and how, a definitive RCT should be conducted. This commentary presents a set of proposed recommendations for progression criteria to guide researchers when (i) designing, (ii) conducting, (iii) analysing and (iv) reporting external randomised pilot trials. METHODS: Recommendations were developed following a mixed methods approach. This involved (i) a methodological review of pilot trial publications, (ii) a cross-sectional study of pilot trial research funding applications, (iii) qualitative interviews with pilot trial researchers and (iv) a survey of corresponding authors of identified pilot trial publications. Initial recommendations were refined following two consultation stakeholder workshops held in July 2022. Recommendations for progression criteria for external randomised pilot trials: i. DESIGN: consider progression criteria from the earliest opportunity; map progression criteria to feasibility objectives; consider quantitative and qualitative interpretations of feasibility; provide justification; develop guidelines rather than rules; seek input from relevant stakeholders. ii. Conduct: regularly monitor pilot trial data against progression criteria. iii. ANALYSIS: avoid considering each progression criterion in isolation; engage in discussion with relevant stakeholders; consider context and other factors external to the pilot trial; consider feasibility (can we?) and progression (will we?). iv. Reporting: we propose a reporting checklist in relation to progression criteria and recommend reporting in a table format for clarity. CONCLUSION: These recommendations provide a helpful resource for researchers to consider progression criteria at different stages of external randomised pilot trials. We have produced a simple infographic tool to summarise these recommendations for researchers to refer to. Further research is needed to evaluate whether these proposed recommendations should inform future development, or update, of established guidelines for the design, conduct, analysis and reporting of external randomised pilot trials.

Economic costs, health-related quality of life outcomes and cost-utility of a physical and psychological group intervention targeted at older adults with neurogenic claudication.

BACKGROUND: Emerging evidence suggests that structured and progressive exercise underpinned by a cognitive behavioural approach can improve functional outcomes in patients with neurogenic claudication (NC). However, evidence surrounding its economic benefits is lacking. OBJECTIVES: To estimate the economic costs, health-related quality of life outcomes and cost-effectiveness of a physical and psychological group intervention (BOOST programme) versus best practice advice (BPA) in older adults with NC. METHODS: An economic evaluation was conducted based on data from a pragmatic, multicentre, superiority, randomised controlled trial. The base-case economic evaluation took the form of an intention-to-treat analysis conducted from a UK National Health Service (NHS) and personal social services (PSS) perspective and separately from a societal perspective. Costs (£ 2018-2019 prices) were collected prospectively over a 12 month follow-up period. A bivariate regression of costs and quality-adjusted life-years (QALYs), with multiple imputation of missing data, was conducted to estimate the incremental cost per QALY gained and the incremental net monetary benefit (INMB) of the BOOST programme in comparison to BPA. Sensitivity and pre-specified subgroup analyses explored uncertainty and heterogeneity in cost-effectiveness estimates. RESULTS: Participants (N = 435) were randomised to the BOOST programme (n = 292) or BPA (n = 143). Mean (standard error [SE]) NHS and PSS costs over 12 months were £1,974 (£118) in the BOOST arm versus £1,827 (£169) in the BPA arm (p = 0.474). Mean (SE) QALY estimates were 0.620 (0.009) versus 0.599 (0.006), respectively (p = 0.093). The probability that the BOOST programme is cost-effective ranged between 67 and 83% (NHS and PSS perspective) and 79-89% (societal perspective) at cost-effectiveness thresholds between £15,000 and £30,000 per QALY gained. INMBs ranged between £145 and £464 at similar cost-effectiveness thresholds. The cost-effectiveness results remained robust to sensitivity analyses. CONCLUSIONS: The BOOST programme resulted in modest QALY gains over the 12 month follow-up period. Future studies with longer intervention and follow-up periods are needed to address uncertainty around the health-related quality of life impacts and cost-effectiveness of such programmes. Trial registration This study has been registered in the International Standard Randomised Controlled Trial Number registry, reference number ISRCTN12698674. Registered on 10 November 2015.

Determining external randomised pilot trial feasibility in preparation for a definitive trial: a web-based survey of corresponding authors of external pilot trial publications.

BACKGROUND: External randomised pilot trials aim to determine whether a future definitive randomised controlled trial (RCT) should be conducted, and if so, how. However, not every pilot trial that suggests that a definitive trial will be feasible will progress to a definitive study. In this study, we surveyed corresponding authors of external randomised pilot trial publications to assess pilot trial outcomes in terms of feasibility and progression. METHODS: Web-based surveys were sent to corresponding authors of external randomised pilot trial publications, open for four weeks between January and February 2022. Four surveys were produced depending on whether the corresponding author had published a trial protocol or results publication, and whether progression criteria were reported. Surveys asked whether a future RCT was considered feasible, whether progression criteria were met (if applicable), what other factors informed the assessment of pilot trial feasibility, and whether the pilot trial has progressed to further research. Data was analysed using descriptive statistics and conventional content analysis. RESULTS: 98 of 276 corresponding authors completed the survey (average response rate of 36% across all surveys). Of these, 89 respondents indicated that their trial had completed. Ninety per cent of respondents who were corresponding authors of completed pilot trials stated that their pilot trial was either feasible (42/89, 47%) or feasible with changes to the trial design (38/89, 43%), yet only 66% (59/89) reported the intention to conduct a future definitive trial. Availability of funding for a future definitive trial and changing priorities of the Chief Investigator were the most common barriers to progression identified. Qualitative research findings was the most frequent factor considered both by corresponding authors who reported and who did not report progression criteria when determining trial feasibility. CONCLUSIONS: Just under one quarter (21/89, 24%) of respondents who considered their external randomised pilot trial to be feasible, or feasible with changes, did not intend to conduct a definitive trial highlighting research inefficiency and waste. TRIAL REGISTRATION: Open Science Framework osf.io/d28hr [20 December 2021].

Assessing a 12-month course of oral alendronate for adults with avascular necrosis of the hip: MANTIS RCT with internal pilot.

BACKGROUND: People with avascular necrosis of the hip have very limited treatment options currently available to stop the progression of this disease; this often results in the need for a hip replacement. There is some weak evidence that a class of drugs called bisphosphonates may delay the course of the disease, and this trial was commissioned and set up to provide robust evidence regarding the use of bisphosphonates in adults aged ≥ 18 years with this condition. OBJECTIVES: The aim of the Managing Avascular Necrosis Treatments: an Interventional Study ( MANTIS ) trial was to evaluate the clinical effectiveness and cost-effectiveness of a 12-month course of alendronate in the treatment of avascular necrosis. DESIGN: This was a 66-month, definitive, multisite, two-arm, parallel-group, placebo-controlled, double-blind, randomised controlled trial, with an internal pilot phase. SETTING: Eight secondary care NHS hospitals across the UK. PARTICIPANTS: Planned trial size - 280 adult patients with avascular necrosis. INTERVENTION: Participants in the intervention group received 70 mg of alendronate (an oral bisphosphonate) weekly for 12 months. MAIN OUTCOMES: The main outcomes were Oxford Hip Score at 12 months (short-term outcome) and the time to decision that a hip replacement is required at 36 months (long-term outcome). RESULTS: Twenty-one patients were recruited and randomised to receive either the intervention drug, alendronate, or a placebo-matched tablet. LIMITATIONS: This trial was principally limited by low disease prevalence. Other limitations included the late disease stage at which participants were identified and the rapid progression of the disease. FUTURE WORK: This trial was limited by a low recruitment rate. Avascular necrosis of the hip should be treated as a rare disease. Future trials would need to recruit many more sites and recruit over a longer time period, and, for this reason, a registry may provide a more effective means of collecting data pertaining to this disease. CONCLUSIONS: The MANTIS trial was terminated at the end of the pilot phase, because it did not meet its go/no-go criteria. The main issue was a poor recruitment rate, owing to a lower than expected disease prevalence and difficulties in identifying the condition at a sufficiently early stage. Those patients who were identified and screened either were too advanced in their disease progression or were already taking medication. We would not recommend that a short-term interventional study is conducted on this condition until its prevalence, geographic foci and natural history and better understood. The difficulty of acquiring this understanding is likely to be a barrier in most health-care markets. One means of developing this understanding would be the introduction of a database/registry for patients suffering from avascular necrosis of the hip. TRIAL REGISTRATION: The trial is registered as ISRCTN14015902. FUNDING: This project was funded by the National Institute for Health and Care Research ( NIHR ) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 43. See the NIHR Journals Library website for further project information.

WHAT WAS THE QUESTION?: The Managing Avascular Necrosis Treatments: an Interventional Study ( MANTIS ) trial was designed to compare ways of treating patients with avascular necrosis who are seeking to slow down the deterioration of their condition. Alendronate is a drug routinely available across the NHS in both tablet and injection form, and doctors and scientists believe that it might prevent ongoing hip deterioration and result in fewer patients requiring a total hip replacement. WHAT DID WE DO?: This trial attempted to compare alendronate taken as a tablet with an identical-looking tablet that did not contain any of the drug (a placebo) to find out if alendronate reduced the number of patients requiring a hip replacement and having pain (compared with patients who did not get alendronate). WHAT DID WE FIND?: Patients were willing to participate in the trial but we were able to recruit only a small number to the study. The main reason for this was difficulty in identifying potentially suitable patients and approaching them at the right point in their medical care. This was more challenging than anticipated, particularly because the NHS sites and professionals that patients with this condition seek out are extremely variable in the UK. It was also difficult to locate and identify patients with the condition at an early enough stage, and before they had already started taking the drug. WHAT DOES THIS MEAN?: More information on patients with this rare condition, such as NHS referral pathways, and an understanding of how the condition progresses may help to improve our understanding of this patient group. This information could also help us determine whether or not there is scope to carry out the study in a different way that might enable these patients to be more easily identified.

Inclusion of progression criteria in external randomised pilot trials: a cross-sectional study of funding applications submitted to the NIHR Research for Patient Benefit Programme.

BACKGROUND: External randomised pilot trials aim to assess whether a future definitive randomised controlled trial (RCT) is feasible. Pre-specified progression criteria help guide the interpretation of pilot trial findings to decide whether, and how, a definitive trial should be conducted. We aimed to examine how researchers report and plan to assess progression criteria in external pilot trial funding applications submitted to the NIHR Research for Patient Benefit Programme. METHODS: We conducted a cross-sectional study of progression criteria inclusion in Stage 1 (outline) and corresponding Stage 2 (full) funding applications for external randomised external pilot trials submitted to NIHR RfPB between July 2017 and July 2019. RESULTS: Of the 100 Stage 1 outline applications assessed, 95 were eligible for inclusion (of these, 52 were invited to Stage 2 full application; 43 were rejected) and 49/52 were eligible for inclusion at Stage 2 full application (of these, 35 were awarded funding; 14 were rejected). Over half of applications assessed at Stage 1 (48/95, 51%), and 73% of those assessed at Stage 2 (36/49) included progression criteria in their research plans. Progression criteria were most often reported in a stop-go format, often with additional specified factors that should be considered when determining feasibility (Stage 1 33/48, 69%; Stage 2 21/36, 58%). Recruitment and retention were the most frequent indicators of feasibility to inform progression criteria. One-third of applications provided some justification or rationale for their targets (Stage 1 16/48, 33%; Stage 2 12/36, 33%). Funding committee feedback mentioned progression criteria in over 20% of applications (Stage 1 22/95, 23%; Stage 2 11/49, 22%) to either request the addition of progression criteria or provide justification for the criteria stipulated. CONCLUSIONS: Our findings indicate that researchers do not always include progression criteria in external randomised pilot trial applications submitted to research funders. This can result in a lack of transparency in the assessment of randomised pilot trial feasibility. TRIAL REGISTRATION: Open Science Framework osf.io/89ap7, registered 29th June 2021.

Progressive exercise versus best practice advice for adults aged 50 years or over after ankle fracture: the AFTER pilot randomised controlled trial.

OBJECTIVE: The aim of the Ankle Fracture Treatment: Enhancing Rehabilitation (AFTER) study, a multicentre external pilot parallel-group randomised controlled trial (RCT), was to assess feasibility of a definitive trial comparing rehabilitation approaches after ankle fracture. SETTING: Five UK National Health Service hospitals. PARTICIPANTS: Participants were aged 50 years and over with an ankle fracture requiring immobilisation for at least 4 weeks. INTERVENTIONS: Participants were allocated 1:1 via a central web-based randomisation system to: (1) best practice advice (one session of physiotherapy, up to two optional additional advice sessions) or (2) progressive exercise (up to six sessions of physiotherapy). PRIMARY OUTCOME MEASURES: Feasibility: (1) participation rate, (2) intervention adherence and (3) retention. RESULTS: Sixty-one of 112 (54%) eligible participants participated, exceeding progression criteria for participation of 25%. Recruitment progression criteria was 1.5 participants per site per month and 1.4 was observed. At least one intervention session was delivered for 28/30 (93%) of best practice advice and 28/31 (90%) of progressive exercise participants, exceeding the 85% progression criteria. For those providing follow-up data, the proportion of participants reporting performance of home exercises in the best practice advice and the progressive exercise groups at 3 months was 20/23 (87%) and 21/25 (84%), respectively. Mean time from injury to starting physiotherapy was 74.1 days (95% CI 53.9 to 94.1 days) for the best practice advice and 72.7 days (95% CI 54.7 to 88.9) for the progressive exercise group. Follow-up rate (6-month Olerud and Molander Ankle Score) was 28/30 (93%) for the best practice advice group and 26/31 (84%) in the progressive exercise group with an overall follow-up rate of 89%. CONCLUSIONS: This pilot RCT demonstrated that a definitive trial would be feasible. The main issues to address for a definitive trial are intervention modifications to enable earlier provision of rehabilitation and ensuring similar rates of follow-up in each group. TRIAL REGISTRATION NUMBER: ISRCTN16612336.

Hormone replacement therapy (conjugated oestrogens plus bazedoxifene) for post-menopausal women with symptomatic hand osteoarthritis: primary report from the HOPE-e randomised, placebo-controlled, feasibility study.

Background: Symptomatic hand osteoarthritis is more common in women than in men, and its incidence increases around the age of menopause, implicating oestrogen deficiency. No randomised controlled trials of hormone replacement therapy (HRT) have been done in people with hand osteoarthritis. We aimed to determine the feasibility and acceptability of a form of HRT (conjugated oestrogens plus bazedoxifene) in post-menopausal women with painful hand osteoarthritis. Methods: The HOPE-e feasibility study was a randomised, double-blind, placebo-controlled trial, for which we recruited women aged 40-65 years, for whom 1-10 years had passed after their final menstrual period, with definite hand osteoarthritis and at least two painful hand joints. Participants were recruited across three primary or secondary care sites and from the community and were randomly assigned (1:1) to receive conjugated oestrogens plus bazedoxifene or placebo, orally once every day for 24 weeks, before weaning for 4 weeks until the end of the study. The primary feasibility outcomes were rates of identification, recruitment, randomisation, retention, and compliance of eligible participants, and the likelihood of unmasking. The secondary objective was to generate proof-of-concept quantitative and qualitative data on the acceptability of proposed clinical outcomes for a full trial and adverse events. We used an intention-to-treat analysis, and criteria for progression to a full trial were pre-defined as recruitment of at least 30 participants across all sites in 18 months; a dropout rate of less than or equal to 30% of randomised individuals; and acceptability to the majority of participants, including acceptable rates of adverse events. Due to the COVID-19 pandemic, the recruitment window was reduced to 12-15 months. A proportionately reduced minimum sample size of 22 was judged to be sufficient to test feasibility. This trial was registered at ISRCTN, ISRCTN12196200. Findings: From May 9, 2019 to Dec 31, 2020, 434 enquiries or referrals were received. We did 96 telephone pre-screens; of the 35 eligible participants, seven were excluded as ineligible at the telephone or face-to-face screening and 28 (80% [95% CI 63-92]) were randomly assigned. Of the 406 who were not randomly assigned, 250 (62%) were ineligible (with contraindicated medications accounting for 50 [20%] of these), 101 (25%) did not respond to further enquiries, and 55 (14%) chose not to proceed (with the most common reason being not wanting to take a hormone-based drug). All 28 randomised participants completed all follow-up assessments with high compliance and outcome measure completeness. All three adverse event-related treatment withdrawals were in the placebo group. No serious adverse events were reported. Participants and investigators were successfully masked (participant Bang's blinding index placebo group 0·50 [95% CI 0·25-0·75]). The trial met the prespecified criteria for progression to a full trial. Interpretation: This first-ever feasibility study of a randomised controlled trial of HRT for post-menopausal women with painful hand osteoarthritis met its progression criteria, although it was not powered to detect a clinical effect. This outcome indicates that a full trial of an HRT in this population is feasible and acceptable and identifies potential refinements with regard to the design of such a trial. Funding: Research for Patient Benefit programme, National Institute for Health Research.

Platelet-rich plasma injection for acute Achilles tendon rupture : two-year follow-up of the PATH-2 randomized, placebo-controlled, superiority trial.

AIMS: To determine whether platelet-rich plasma (PRP) injection improves outcomes two years after acute Achilles tendon rupture. METHODS: A randomized multicentre two-arm parallel-group, participant- and assessor-blinded superiority trial was undertaken. Recruitment commenced on 28 July 2015 and two-year follow-up was completed in 21 October 2019. Participants were 230 adults aged 18 years and over, with acute Achilles tendon rupture managed with non-surgical treatment from 19 UK hospitals. Exclusions were insertion or musculotendinous junction injuries, major leg injury or deformity, diabetes, platelet or haematological disorder, medication with systemic corticosteroids, anticoagulation therapy treatment, and other contraindicating conditions. Participants were randomized via a central online system 1:1 to PRP or placebo injection. The main outcome measure was Achilles Tendon Rupture Score (ATRS) at two years via postal questionnaire. Other outcomes were pain, recovery goal attainment, and quality of life. Analysis was by intention-to-treat. RESULTS: A total of 230 participants were randomized, 114 to PRP and 116 to placebo. Two-year questionnaires were sent to 216 participants who completed a six-month questionnaire. Overall, 182/216 participants (84%) completed the two-year questionnaire. Participants were aged a mean of 46 years (SD 13.0) and 25% were female (57/230). The majority of participants received the allocated intervention (219/229, 96%). Mean ATRS scores at two years were 82.2 (SD 18.3) in the PRP group (n = 85) and 83.8 (SD 16.0) in the placebo group (n = 92). There was no evidence of a difference in the ATRS at two years (adjusted mean difference -0.752, 95% confidence interval -5.523 to 4.020; p = 0.757) or in other secondary outcomes, and there were no re-ruptures between 24 weeks and two years. CONCLUSION: PRP injection did not improve patient-reported function or quality of life two years after acute Achilles tendon rupture compared with placebo. The evidence from this study indicates that PRP offers no patient benefit in the longer term for patients with acute Achilles tendon rupture.Cite this article: Bone Joint J 2022;104-B(11):1256-1265.

Radiological malunion after ankle fractures in older adults : definitions and new thresholds derived from clinical outcome data from the AIM trial.

AIMS: The rationale for exacting restoration of skeletal anatomy after unstable ankle fracture is to improve outcomes by reducing complications from malunion; however, current definitions of malunion lack confirmatory clinical evidence. METHODS: Radiological (absolute radiological measurements aided by computer software) and clinical (clinical interpretation of radiographs) definitions of malunion were compared within the Ankle Injury Management (AIM) trial cohort, including people aged ≥ 60 years with an unstable ankle fracture. Linear regressions were used to explore the relationship between radiological malunion (RM) at six months and changes in function at three years. Function was assessed with the Olerud-Molander Ankle Score (OMAS), with a minimal clinically important difference set as six points, as per the AIM trial. Piecewise linear models were used to investigate new radiological thresholds which better explain symptom impact on ankle function. RESULTS: Previously described measures of RM and surgeon opinion of clinically significant malunion (CSM) were shown to be related but with important differences. CSM was more strongly related to outcome (-13.9 points on the OMAS; 95% confidence interval (CI) -21.9 to -5.4) than RM (-5.5 points; 95% CI -9.8 to -1.2). Existing malunion thresholds for talar tilt and tibiofibular clear space were shown to be slightly conservative; new thresholds which better explain function were identified (talar tilt > 2.4°; tibiofibular clear space > 6 mm). Based on this new definition the presence of RM had an impact on function, which was statistically significant, but the clinical significance was uncertain (-9.1 points; 95% CI -13.8 to -4.4). In subsequent analysis, RM of a posterior malleolar fracture was shown to have a statistically significant impact on OMAS change scores, but the clinical significance was uncertain (-11.6 points; 95% CI -21.9 to -0.6). CONCLUSION: These results provide clinical evidence which supports the previously accepted definitions. Further research to investigate more conservative clinical thresholds for malunion is indicated.Cite this article: Bone Jt Open 2022;3(10):841-849.

Anti-tumour necrosis factor therapy for early-stage Dupuytren's disease (RIDD): a phase 2b, randomised, double-blind, placebo-controlled trial.

Background: Dupuytren's disease is a common fibrotic condition that causes the fingers to flex irreversibly into the palm. Treatments for late-stage disease all have limitations, and there is no approved treatment for early-stage disease. We identified tumour necrosis factor as a therapeutic target in Dupuytren's disease, and in a dose ranging trial found 40 mg adalimumab in 0·4 mL to be most efficacious. Here we aimed to assess the effects of intranodular injection of adalimumab in early-stage disease. Methods: In this phase 2b, randomised, double-blind, placebo-controlled trial adults with early-stage Dupuytren's disease and an established clinically distinct nodule with a clear history of progression in the preceding 6 months were recruited from two clinical centres in the UK and were randomly assigned 1:1 to receive four injections of adalimumab or saline every 3 months. Participants and assessors were masked. The primary outcome was nodule hardness measured with a durometer at 12 months. Data were analysed by linear mixed effects regression models in the intention-to-treat population with multiple imputation for missing primary outcome data. The trial is registered at the ISRCTN registry, ISRCTN 27786905 and is complete. Findings: Between Feb 17, 2017, and Jan 11, 2019, 284 participants were screened in the UK and 140 were enrolled. 47 (34%) participants were female and 93 (66%) were male. Mean age of participants was 59·7 years (SD 10·0). Primary outcome data were available from 113 participants. Nodule hardness was lower (-4·6 AU [95% CI -7·1 to -2·2], p=0·0002) in the adalimumab compared with the saline group at 12 months. There were no related serious adverse events; the most common adverse events were minor injection site reactions. Interpretation: Intranodular injections of adalimumab in participants with early-stage Dupuytren's disease resulted in softening and reduction in size of the nodules. Longer follow-up would be required to assess the effect of tumour necrosis factor inhibition on disease progression, extension deficit and hand function.

Immobilisation of torus fractures of the wrist in children (FORCE): a randomised controlled equivalence trial in the UK.

BACKGROUND: The most common fractures in children are torus (buckle) fractures of the wrist. Controversy exists over treatment, which ranges from splint immobilisation and discharge to cast immobilisation, follow-up, and repeat imaging. This study compared pain and function in affected children offered a soft bandage and immediate discharge with those receiving rigid immobilisation and follow-up as per treating centre protocol. METHODS: In this randomised controlled equivalence trial we included 965 children (aged 4-15 years) with a distal radius torus fracture from 23 hospitals in the UK. Children were randomly allocated in a 1:1 ratio to the offer of bandage group or rigid immobilisation group using bespoke web-based randomisation software. Treating clinicians, participants, and their families could not be masked to treatment allocation. Exclusion criteria included multiple injuries, diagnosis at more than 36 h after injury, and inability to complete follow-up. The primary outcome was pain at 3-days post-randomisation measured using Wong-Baker FACES Pain Rating Scale. We performed a modified intention-to-treat and per protocol analysis. The trial was registered with ISRCTN registry, ISRCTN13955395. FINDINGS: Between Jan 16, 2019, and July 13, 2020, 965 children were randomly allocated to a group, 489 to the offer of a bandage group and 476 to the rigid immobilisation group, 379 (39%) were girls and 586 (61%) were boys. Primary outcome data was collected for 908 (94%) of participants, all of whom were included in the modified intention-to-treat analysis. Pain was equivalent at 3 days with 3·21 points (SD 2·08) in the offer of bandage group versus 3·14 points (2·11) in the rigid immobilisation group. With reference to a prespecified equivalence margin of 1·0, the adjusted difference in the intention-to-treat population was -0·10 (95% CI -0·37 to 0·17) and-0·06 (95% CI -0·34 to 0·21) in the per-protocol population. INTERPRETATION: This trial found equivalence in pain at 3 days in children with a torus fracture of the distal radius assigned to the offer of a bandage group or the rigid immobilisation group, with no between-group differences in pain or function during the 6 weeks of follow-up. FUNDING: UK National Institute for Health and Care Research.

Offer of a bandage versus rigid immobilisation in 4- to 15-year-olds with distal radius torus fractures: the FORCE equivalence RCT.

BACKGROUND: Torus (buckle) fractures of the wrist are the most common fractures in children involving the distal radius and/or ulna. It is unclear if children require rigid immobilisation and follow-up or would recover equally as well by being discharged without any immobilisation or a bandage. Given the large number of these injuries, identifying the optimal treatment strategy could have important effects on the child, the number of days of school absence and NHS costs. OBJECTIVES: To establish whether or not treating children with a distal radius torus fracture with the offer of a soft bandage and immediate discharge (i.e. offer of a bandage) provides the same recovery, in terms of pain, function, complications, acceptability, school absence and resource use, as treatment with rigid immobilisation and follow-up as per usual practice (i.e. rigid immobilisation). DESIGN: A pragmatic, multicentre, randomised controlled equivalence trial. SETTING: Twenty-three UK emergency departments. PARTICIPANTS: A total of 965 children (aged 4-15 years) with a distal radius torus fracture were randomised from January 2019 to July 2020 using a secure, centralised, online-encrypted randomisation service. Exclusion criteria included presentation > 36 hours after injury, multiple injuries and an inability to complete follow-up. INTERVENTIONS: A bandage was offered to 489 participants and applied to 458, and rigid immobilisation was carried out in 476 participants. Participants and clinicians were not blinded to the treatment allocation. MAIN OUTCOME MEASURES: The pain at 3 days post randomisation was measured using the Wong-Baker FACES Pain Rating Scale. Secondary outcomes were the patient-reported outcomes measurement system upper extremity limb score for children, health-related quality of life, complications, school absence, analgesia use and resource use collected up to 6 weeks post randomisation. RESULTS: A total of 94% of participants provided primary outcome data. At 3 days, the primary outcome of pain was equivalent in both groups. With reference to the prespecified equivalence margin of 1.0, the adjusted difference in the intention-to-treat population was -0.10 (95% confidence interval -0.37 to 0.17) and the per-protocol population was -0.06 (95% confidence interval -0.34 to 0.21). There was equivalence of pain in both age subgroups (i.e. 4-7 years and 8-15 years). There was no difference in the rate of complications, with five complications (1.0%) in the offer of a bandage group and three complications (0.6%) in the rigid immobilisation group. There were no differences between treatment groups in functional recovery, quality of life or school absence at any point during the follow-up. Analgesia use was marginally higher at day 1 in the offer of a bandage group than it was in the rigid immobilisation group (83% vs. 78% of participants), but there was no difference at other time points. The offer of a bandage significantly reduced the cost of treatment and had a high probability of cost-effectiveness at a willingness-to-pay threshold of £30,000 per quality-adjusted life-year. LIMITATIONS: Families had a strong pre-existing preference for the rigid immobilisation treatment. Given this, and the inability to blind families to the treatment allocation, observer bias was a concern. However, there was clear evidence of equivalence. CONCLUSIONS: The study findings support the offer of a bandage in children with a distal radius torus fracture. FUTURE WORK: A clinical decision tool to determine which children require radiography is an important next step to prevent overtreatment of minor wrist fractures. There is also a need to rationalise interventions for other common childhood injuries (e.g. 'toddler's fractures' of the tibia). TRIAL REGISTRATION: This trial is registered as ISRCTN13955395 and UKCRN Portfolio 39678. FUNDING: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 33. See the NIHR Journals Library website for further project information.

BACKGROUND: Torus fractures (also called buckle fractures) of the wrist are the most common type of broken bone in children, affecting 60,000 children in the UK per year. They are the mildest form of broken bone, in which the bone crushes (or buckles). Despite these fractures being so common, there is no 'standard treatment'. The traditional treatment is to use a plaster cast and arrange outpatient follow-up. Recent medical research has suggested that wearing a bandage, or even having no treatment, might result in similar healing. In this study, we looked into whether or not a bandage (which was optional to wear) and no further follow-up resulted in the same recovery as a hard splint and usual follow-up. A total of 965 children aged 4­15 years from 23 emergency departments in the UK took part in the study. Children were evenly divided between the bandage and hard splint groups in a process called randomisation. Prior to the study, families told us that managing pain after injury was the most important issue to them. We asked children and their families to tell us about pain, recovery using the arm, quality of life, complications encountered and school absences. We also looked at the financial costs to families and the NHS. WHAT DID THE TRIAL FIND?: The two treatments resulted in the same outcomes. The majority of those offered a bandage chose to wear it immediately. There was no difference at all in the levels of pain between those treated with a hard splint and usual outpatient follow-up and those offered a bandage and discharge (i.e. no further follow up) from hospital the same day. Similarly, there was no difference in the recovery using the arm, quality of life, complications encountered or school absences. There was a very slight increase in pain killer use in the bandage group at day 1, but not at any other time point. Overall, the cost of the offer of a bandage was slightly lower for families and the NHS. In conclusion, the findings of this study support offering a bandage to be used at the discretion of families to treat children with a torus fracture of the wrist.

Efficacy of Liposomal Bupivacaine and Bupivacaine Hydrochloride vs Bupivacaine Hydrochloride Alone as a Periarticular Anesthetic for Patients Undergoing Knee Replacement: A Randomized Clinical Trial.

Importance: More than half of patients who undergo knee replacement surgery report substantial acute postoperative pain. Objective: To evaluate the efficacy and cost-effectiveness of periarticular liposomal bupivacaine for recovery and pain management after knee replacement. Design, Setting, and Participants: This multicenter, patient-blinded, pragmatic, randomized clinical superiority trial involved 533 participants at 11 institutions within the National Health Service in England. Adults undergoing primary unilateral knee replacement for symptomatic end-stage osteoarthritis were enrolled between March 29, 2018, and February 29, 2020, and followed up for 1 year after surgery. Follow-up was completed March 1, 2021. A per-protocol analysis for each coprimary outcome was performed in addition to the main intention-to-treat analysis. Interventions: Two hundred sixty-six milligrams of liposomal bupivacaine admixed with 100 mg of bupivacaine hydrochloride compared with 100 mg of bupivacaine hydrochloride alone (control) administered by periarticular injection at the time of surgery. Main Outcome and Measures: The coprimary outcomes were Quality of Recovery 40 (QoR-40) score at 72 hours and pain visual analog scale (VAS) score area under the curve (AUC) from 6 to 72 hours. Secondary outcomes included QoR-40 and mean pain VAS at days 0 (evening of surgery), 1, 2, and 3; cumulative opioid consumption for 72 hours; functional outcomes and quality of life at 6 weeks, 6 months, and 1 year; and cost-effectiveness for 1 year. Adverse events and serious adverse events up to 12 months after randomization were also assessed. Results: Among the 533 participants included in the analysis, the mean (SD) age was 69.0 (9.7) years; 287 patients were women (53.8%) and 246 were men (46.2%). Baseline characteristics were balanced between study groups. There was no difference between the liposomal bupivacaine and control groups in QoR-40 score at 72 hours (adjusted mean difference, 0.54 [97.5% CI, -2.05 to 3.13]; P = .64) or the pain VAS score AUC at 6 to 72 hours (-21.5 [97.5% CI, -46.8 to 3.8]; P = .06). Analyses of pain VAS and QoR-40 scores demonstrated only 1 statistically significant difference, with the liposomal bupivacaine arm having lower pain scores the evening of surgery (adjusted difference -0.54 [97.5% CI, -1.07 to -0.02]; P = .02). No difference in cumulative opioid consumption and functional outcomes was detected. Liposomal bupivacaine was not cost-effective compared with the control treatment. No difference in adverse or serious adverse events was found between the liposomal bupivacaine and control groups. Conclusions and Relevance: This study found no difference in postoperative recovery or pain associated with the use of periarticular liposomal bupivacaine compared with bupivacaine hydrochloride alone in patients who underwent knee replacement surgery. Trial Registration: isrctn.com Identifier: ISRCTN54191675.

The Clinical Effectiveness of a Physiotherapy Delivered Physical and Psychological Group Intervention for Older Adults With Neurogenic Claudication: The BOOST Randomized Controlled Trial.

BACKGROUND: Neurogenic claudication (NC) is a debilitating spinal condition affecting older adults' mobility and quality of life. METHODS: A randomized controlled trial of 438 participants evaluated the effectiveness of a physical and psychological group intervention (BOOST program) compared to physiotherapy assessment and tailored advice (best practice advice [BPA]) for older adults with NC. Participants were identified from spinal clinics (community and secondary care) and general practice records and randomized 2:1 to the BOOST program or BPA. The primary outcome was the Oswestry Disability Index (ODI) at 12 months. Data were also collected at 6 months. Other outcomes included ODI walking item, 6-minute walk test (6MWT), and falls. The primary analysis was intention-to-treat. RESULTS: The average age of participants was 74.9 years (standard deviation [SD] 6.0) and 57% (246/435) were female. There was no significant difference in ODI scores between treatment groups at 12 months (adjusted mean difference [MD]: -1.4 [95% confidence intervals (CI) -4.03, 1.17]), but, at 6 months, ODI scores favored the BOOST program (adjusted MD: -3.7 [95% CI -6.27, -1.06]). At 12 months, the BOOST program resulted in greater improvements in walking capacity (6MWT MD: 21.7m [95% CI 5.96, 37.38]) and ODI walking item (MD: -0.2 [95% CI -0.45, -0.01]) and reduced falls risk (odds ratio: 0.6 [95% CI 0.40, 0.98]) compared to BPA. No serious adverse events were related to either treatment. CONCLUSIONS: The BOOST program substantially improved mobility for older adults with NC. Future iterations of the program will consider ways to improve long-term pain-related disability. Clinical Trials Registration Number: ISRCTN12698674.