Jamie R. Stokes

Background: Patients with symptoms of pain and restricted function related to knee osteoarthritis are typically offered a knee replacement. However, a proportion remain dissatisfied with their outcomes, and the failure risk is disproportionately higher in the young. Knee joint distraction may be an intervention to postpone the time to knee replacement in this patient population. Objective and main outcome measure: The primary objective of the Knee Arthroplasty versus Joint Distraction Study for Osteoarthritis (KARDS) was to evaluate the effectiveness of knee joint distraction compared to knee replacement based on patient-reported pain 12 months post surgery using the Knee Injury and Osteoarthritis Outcomes Score pain score as the primary outcome. Design and methods: KARDS was an open-label, two-arm individually randomised controlled non-inferiority trial with an embedded 12-month internal pilot phase and process evaluation to evaluate recruitment feasibility. A hybrid expertise design was used to account for surgeon expertise and potential lack of individual equipoise. The trial was closed to recruitment early following cessation of elective orthopaedic surgery secondary to COVID-19 pandemic. Descriptive statistics are reported. Setting: United Kingdom National Health Service Trusts. Participants: Adult patients aged < 65 years with symptoms severe enough to warrant knee replacement, in the opinion of the treating clinician. Interventions: Participants were randomised to receive either knee joint distraction (static distraction of 5 mm, using external fixator for 6 weeks) or knee replacement. Results: Twenty-four participants were randomised from a single centre between March 2021 and October 2022 with minimum 3-month safety follow-up post surgery. Eleven participants were randomised to knee joint distraction and 13 to knee replacement. Seventeen patients were male (71%), median age 60 (47–65) years. One patient withdrew due to being medically unfit for surgery and two received a different treatment than which they were randomised (one crossover from each arm). The median Knee Injury and Osteoarthritis Outcomes Score pain score in the knee joint distraction group improved from 38.9 (22–50) at baseline to 55.6 (0–100) at 12 months, corresponding scores in the knee replacement improved from 30.6 (6–36) to 75.0 (50–100). Adverse events were more common with knee joint distraction, pin site infection being the commonest complications ( n = 4, 58%). As part of process evaluation, we conducted semistructured qualitative interviews with staff in secondary care and with study participants. Data were analysed using thematic content analysis. One overarching theme emerged: ‘An unexpected journey’, which encapsulates staff and participants’ experiences. Conclusion: Reduced research capacity and the suspension of elective surgery following the COVID-19 pandemic caused significant recruitment barriers. Despite early termination, KARDS demonstrated that patients were willing to be recruited to a trial investigating a novel treatment for knee osteoarthritis and the trial was feasible and implementable. The limited results indicated that the technique is safe with no safety concerns. Clinical and cost-effectiveness of knee joint distraction remains uncertain. The embedded KARDS process evaluation has provided helpful insights. Limitations: Reduced research capacity at sites and suspension of elective surgery services within the United Kingdom following COVID-19 caused significant recruitment barriers to KARDS. All the recruited patients in both arms of the study were White. Future work: As a commissioned piece of research with delivery significantly impacted by the National Health Service environment post-COVID and the impact on National Health Service surgical services, the research question remains highly relevant. Any future research in this field can be helped by the pilot data published here along with the lessons learnt. Funding: This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number 17/122/06.

Background: Anterior cruciate ligament injury of the knee is common and leads to decreased activity and risk of secondary osteoarthritis of the knee. Management of patients with a non-acute anterior cruciate ligament injury can be non-surgical (rehabilitation) or surgical (reconstruction). However, insufficient evidence exists to guide treatment. Objective(s): To determine in patients with non-acute anterior cruciate ligament injury and symptoms of instability whether a strategy of surgical management (reconstruction) without prior rehabilitation was more clinically and cost-effective than non-surgical management (rehabilitation). Design: A pragmatic, multicentre, superiority, randomised controlled trial with two-arm parallel groups and 1:1 allocation. Due to the nature of the interventions, no blinding could be carried out. Setting: Twenty-nine NHS orthopaedic units in the United Kingdom. Participants: Participants with a symptomatic (instability) non-acute anterior cruciate ligament-injured knee. Interventions: Patients in the surgical management arm underwent surgical anterior cruciate ligament reconstruction as soon as possible and without any further rehabilitation. Patients in the rehabilitation arm attended physiotherapy sessions and only were listed for reconstructive surgery on continued instability following rehabilitation. Surgery following initial rehabilitation was an expected outcome for many patients and within protocol. Main outcome measures: The primary outcome was the Knee Injury and Osteoarthritis Outcome Score 4 at 18 months post randomisation. Secondary outcomes included return to sport/activity, intervention-related complications, patient satisfaction, expectations of activity, generic health quality of life, knee-specific quality of life and resource usage. Results: Three hundred and sixteen participants were recruited between February 2017 and April 2020 with 156 randomised to surgical management and 160 to rehabilitation. Forty-one per cent (n = 65) of those allocated to rehabilitation underwent subsequent reconstruction within 18 months with 38% (n = 61) completing rehabilitation and not undergoing surgery. Seventy-two per cent (n = 113) of those allocated to surgery underwent reconstruction within 18 months. Follow-up at the primary outcome time point was 78% (n = 248; surgical, n = 128; rehabilitation, n = 120). Both groups improved over time. Adjusted mean Knee Injury and Osteoarthritis Outcome Score 4 scores at 18 months had increased to 73.0 in the surgical arm and to 64.6 in the rehabilitation arm. The adjusted mean difference was 7.9 (95% confidence interval 2.5 to 13.2; p = 0.005) in favour of surgical management. The per-protocol analyses supported the intention-to-treat results, with all treatment effects favouring surgical management at a level reaching statistical significance. There was a significant difference in Tegner Activity Score at 18 months. Sixty-eight per cent (n = 65) of surgery patients did not reach their expected activity level compared to 73% (n = 63) in the rehabilitation arm. There were no differences between groups in surgical complications (n = 1 surgery, n = 2 rehab) or clinical events (n = 11 surgery, n = 12 rehab). Of surgery patients, 82.9% were satisfied compared to 68.1% of rehabilitation patients. Health economic analysis found that surgical management led to improved health-related quality of life compared to non-surgical management (0.052 quality-adjusted life-years, p = 0.177), but with higher NHS healthcare costs (£1107, p < 0.001). The incremental cost-effectiveness ratio for the surgical management programme versus rehabilitation was £19,346 per quality-adjusted life-year gained. Using £20,000–30,000 per quality-adjusted life-year thresholds, surgical management is cost-effective in the UK setting with a probability of being the most cost-effective option at 51% and 72%, respectively. Limitations: Not all surgical patients underwent reconstruction, but this did not affect trial interpretation. The adherence to physiotherapy was patchy, but the trial was designed as pragmatic. Conclusions: Surgical management (reconstruction) for non-acute anterior cruciate ligament-injured patients was superior to non-surgical management (rehabilitation). Although physiotherapy can still provide benefit, later-presenting non-acute anterior cruciate ligament-injured patients benefit more from surgical reconstruction without delaying for a prior period of rehabilitation. Future work: Confirmatory studies and those to explore the influence of fidelity and compliance will be useful. Trial registration: This trial is registered as Current Controlled Trials ISRCTN10110685; ClinicalTrials.gov Identifier: NCT02980367. Funding: This award was funded by the National Institute of Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 14/140/63) and is published in full in Health Technology Assessment; Vol. 28, No. 27. See the NIHR Funding and Awards website for further award information.

Surgery for nail bed injuries in children is common. One of the key surgical decisions is whether to replace the nail plate following nail bed repair. The aim of this RCT was to assess the clinical effectiveness and cost-effectiveness of nail bed repair with fingernail replacement/substitution compared with repair without fingernail replacement. A two-arm 1 : 1 parallel-group open multicentre superiority RCT was performed across 20 secondary-care hospitals in the UK. The co-primary outcomes were surgical-site infection at around 7 days after surgery and cosmetic appearance summary score at a minimum of 4 months. Some 451 children presenting with a suspected nail bed injury were recruited between July 2018 and July 2019; 224 were allocated to the nail-discarded arm, and 227 to the nail-replaced arm. There was no difference in the number of surgical-site infections at around 7 days between the two interventions or in cosmetic appearance. The mean total healthcare cost over the 4 months after surgery was €84 (95 per cent c.i. 34 to 140) lower for the nail-discarded arm than the nail-replaced arm (P < 0.001). After nail bed repair, discarding the fingernail was associated with similar rates of infection and cosmesis ratings as replacement of the finger nail, but was cost saving. Registration number: ISRCTN44551796 (http://www.controlled-trials.com).

Background: To assess the quality of reporting of RCT protocols approved by UK research ethics committees before and after the publication of the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guideline. Methods: We had access to RCT study protocols that received ethical approval in the UK in 2012 (n=103) and 2016 (n=108). From those, we assessed the adherence to the 33 SPIRIT items (i.e. a total of 64 components of the 33 SPIRIT items). We descriptively analysed the adherence to SPIRIT guidelines as proportion of adequately reported items (median and interquartile range [IQR]) and stratified the results by year of approval and sponsor. Results: The proportion of reported SPIRIT items increased from a median of 64.9% (IQR, 57.6–69.2%) in 2012 to a median of 72.5% (IQR, 65.3–78.3%) in 2016. Industry-sponsored RCTs reported more SPIRIT items in 2012 (median 67.4%; IQR, 64.1–69.4%) compared to non-industry-sponsored trials (median 59.8%; IQR, 46.5–67.7%). This gap between industry- and non-industry-sponsored trials increased in 2016 (industry-sponsored: median 75.6%; IQR, 71.2–79.0% vs non-industry-sponsored: median 65.3%; IQR, 51.6–76.3%). Conclusions: The adherence to SPIRIT guidelines has improved in the UK from 2012 to 2016 but remains on a modest level, especially for non-industry-sponsored RCTs.

Background: Rupture of the anterior cruciate ligament (ACL) is a common injury, primarily affecting young, active individuals. Despite surgical intervention being the more common treatment for patients suffering ACL ruptures, current management is based on limited and generally low-quality evidence. We describe a statistical analysis plan (SAP) for the ACL SNNAP randomised controlled trial, which aims to investigate the necessity of surgical management in patients with ACL injuries. Methods/design: ACL SNNAP is a pragmatic, multi-centre, superiority, parallel-group randomised controlled trial in participants with a symptomatic non-acute ACL deficient knee. Participants are allocated in a 1:1 ratio to either non-surgical management (rehabilitation) or surgical management (reconstruction) with the aim of assessing the efficacy and cost-effectiveness. The primary outcome of the study is the Knee Injury and Osteoarthritis Outcome Score (KOOS4) at 18 months post-randomisation. The KOOS4 score at 18 months will be evaluated using a linear regression model adjusting for recruitment centre and baseline KOOS4 scores, allowing for intra-centre correlation. A secondary analysis of the primary outcome will be carried out using an area under the curve (AUC) approach using treatment estimates obtained from a mixed model using baseline, 6 months, 12 months, and 18 months post-randomisation outcome data. Secondary outcomes will be measured at 18 months and will include return to activity/level of sport participation, intervention-related complications, the EQ-5D-5L questionnaire, all 5 individual subscales of the KOOS questionnaire, the ACL-QOL score, expectations of return to activity and cost-effectiveness of the interventions. Missing primary outcome data will be investigated through a sensitivity analysis. Full details of the planned methods for the statistical analysis of clinical outcomes are presented in this paper. The study protocol for the ACL SNNAP trial has been published previously. Discussion: The methods of analysis for the ACL SNNAP trial have been described here to minimise the risk of data-driven results and reporting bias. Any deviations from the analysis methods described in this paper will be described in full and justified in the publications of the trial results. Trial registration: ISRCTN ISRCTN10110685. Registered on 16 November 2016

Background: Up to three quarters of surgical patients receive inadequate pain relief, with 40% of patients reporting severe pain following knee replacement, which may indicate the current pain relief strategies using opiate-based analgesia cannot achieve patient satisfaction. Liposomal bupivacaine is liposome-encapsulated bupivacaine which has been reported to be effective for up to 72 h. The study of Peri-Articular Anaesthetic for Replacement of the Knee (SPAARK) trial has been designed to assess the effectiveness of peri-articular liposomal bupivacaine and bupivacaine hydrochloride compared with peri-articular bupivacaine hydrochloride alone in the management of post-operative pain following knee replacement. Methods/design: The SPAARK trial is a multi-centre, patient-blinded, randomised controlled trial. The co-primary outcomes are post-operative recovery assessed by global QoR-40 scores at 72 h and cumulative pain VAS score from 6 to 72 h following surgery. Longer-term measures of the co-primary outcomes are collected at 6 weeks and 6 and 12 months post randomisation, together with secondary outcomes, i.e. the Oxford Knee Score, and the American Knee Society Score. Cumulative opiate use and fitness for discharge are measured up to 72 h post-surgery. The analysis approaches for the primary and secondary outcomes are described here, as are the descriptive statistics which will be reported. The full SPAARK protocol has already been published. Results: The co-primary outcomes will be analysed using multivariate linear regression adjusting for stratification factors and other important prognostic variables, including baseline scores in the case of the QoR-40. The adjusted mean difference between the two groups together with 97.5% confidence intervals will be reported for each of the primary outcomes. Other continuous variables will be assessed using the same method. Binary outcomes will be assessed using chi-squared tests. Discussion: The paper provides details of the planned statistical analyses for the SPAARK trial and aims 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: ISRCTN54191675. Registered on 13 November 2017.

Background: Nail bed trauma is one of the most common surgically treated paediatric hand injuries in the UK. Despite surgeons generally expressing a preference to replace the nail plate after repairing the nail bed, there is limited evidence to support this practice. We describe a statistical and health economic analysis plan (SHEAP) for the Nail bed INJury Analysis (NINJA) randomised controlled trial.Methods/design: NINJA is a multicentre, pragmatic, superiority, parallel group randomised controlled trial of the treatment of nail bed injury in participants 16 years old or younger. The study aims to evaluate the efficacy and cost-effectiveness of replacing the nail plate compared to discarding it following the repair of a nail bed injury. Surgical site infection at 7–10 days post-randomisation and cosmetic appearance of the nail are the co-primary outcomes for NINJA. Surgical site infection at 7–10 days post-randomisation will be evaluated using a logistic regression model adjusting for site as the sole stratification factor and allowing for intra-site correlation. Cosmetic appearance will be assessed via the newly developed Oxford Finger Nail Appearance Score and will be evaluated by use of a Mann-WhitneyUtest. An ordinal logistic regression model will also be used to assess the Oxford Finger Nail Appearance Score, adjusting for site and allowing for intra-site correlation. Secondary outcomes are measured at 7–10 days and 4 months and include the EQ-5D-Y questionnaire, pain at first dressing change, cost-effectiveness, late surgical site infection, and participant/parent satisfaction with nail healing. Missing primary outcome data will be summarised by treatment arm and investigated through a sensitivity analysis. Full details of the planned methods of analysis and descriptive statistics are described in this paper. The NINJA study protocol has been published previously.Discussion: The planned analysis strategy for the NINJA trial has been set out here to reduce the risk of reporting bias and data-driven analysis. Any deviations from the SHEAP described in this paper will be detailed and justified fully in the final report of the trial.Trial registration: ISRCTN,ISRCTN44551796. Registered on 23 April 2018.

Background: Randomised controlled trials (RCTs) need to be reported so that their results can be unambiguously and robustly interpreted. Binary outcomes yield unique challenges, as different analytical approaches may produce relative, absolute, or no treatment effects, and results may be particularly sensitive to the assumptions made about missing data. This review of recently published RCTs aimed to identify the methods used to analyse binary primary outcomes, how missing data were handled, and how the results were reported. Methods: Systematic review of reports of RCTs published in January 2019 that included a binary primary outcome measure. We identified potentially eligible English language papers on PubMed, without restricting by journal or medical research area. Papers reporting the results from individually randomised, parallel-group RCTs were included. Results: Two hundred reports of RCTs were included in this review. We found that 64% of the 200 reports used a chi-squared-style test as their primary analytical method. Fifty-five per cent (95% confidence interval 48% to 62%) reported at least one treatment effect measure, and 38% presented only a p value without any treatment effect measure. Missing data were not always adequately described and were most commonly handled using available case analysis (69%) in the 140 studies that reported missing data. Imputation and best/worst-case scenarios were used in 21% of studies. Twelve per cent of articles reported an appropriate sensitivity analysis for missing data. Conclusions: The statistical analysis and reporting of treatment effects in reports of randomised trials with a binary primary endpoint requires substantial improvement. Only around half of the studied reports presented a treatment effect measure, hindering the understanding and dissemination of the findings. We also found that published trials often did not clearly describe missing data or sensitivity analyses for these missing data. Practice for secondary endpoints or observational studies may differ.

Introduction Trauma to the nail bed is the most common surgically treated paediatric hand injury. The majority of surgeons replace the nail plate after repairing the nail bed despite a lack of evidence to do so. Replacing the nail plate may be associated with increased postoperative infection. We will investigate the impact of replacing or discarding the nail plate on infection, cosmetic appearance, pain and subsequent healthcare use. The Nail bed INJury Analysis trial (NINJA) aims to answer the question of whether the nail plate should be replaced or discarded after surgical nail bed repair in children. Methods and analysis A two-arm parallel group open multicentre randomised control trial of replacing the nail plate or not, as part of a nail bed repair, will be undertaken in children presenting within 48 hours of a nail bed injury requiring surgical repair. The coprimary outcomes are: cosmetic appearance summary score at a minimum of 4 months and surgical site infection at around 7 days following surgery. Secondary outcomes are EuroQol EQ-5D-(Y); the pain intensity experienced at first dressing change; child/parent satisfaction with nail healing and healthcare resource use. We will recruit a minimum of 416 patients (208 in each group) over 3 years. Children and their parents/carers will be reviewed in clinic around 7 days after their operation and will be assessed for surgical site infection or other problems. The children, or depending on age, their parents/carers, will also be asked to complete a questionnaire and send in photos of their fingernail at a minimum of 4 months postsurgery to assess cosmetic appearance. Ethics and dissemination The South Central Research Ethics Committee approved this study on 4 June 2019 (18/SC/0024). A manuscript to a peer-reviewed journal will be submitted on completion of the trial as per National Institute for Health Research publication policy. The results of this trial will substantially inform clinical practice and provide evidence on whether the practice of replacing the nail plate should continue at the time of nail bed repair. Trial registration number ISRCTN44551796.