Group sequential designs for pragmatic clinical trials with early outcomes: methods and guidance for planning and implementation.

BACKGROUND: Group sequential designs are one of the most widely used methodologies for adaptive design in randomized clinical trials. In settings where early outcomes are available, they offer large gains in efficiency compared to a fixed design. However, such designs are underused and used predominantly in therapeutic areas where there is expertise and experience in implementation. One barrier to their greater use is the requirement to undertake simulation studies at the planning stage that require considerable knowledge, coding experience and additional costs. Based on some modest assumptions about the likely patterns of recruitment and the covariance structure of the outcomes, some simple analytic expressions are presented that negate the need to undertake simulations. METHODS: A model for longitudinal outcomes with an assumed approximate multivariate normal distribution and three contrasting simple recruitment models are described, based on fixed, increasing and decreasing rates. For assumed uniform and exponential correlation models, analytic expressions for the variance of the treatment effect and the effects of the early outcomes on reducing this variance at the primary outcome time-point are presented. Expressions for the minimum and maximum values show how the correlations and timing of the early outcomes affect design efficiency. RESULTS: Simulations showed how patterns of information accrual varied between correlation and recruitment models, and consequentially to some general guidance for planning a trial. Using a previously reported group sequential trial as an exemplar, it is shown how the analytic expressions given here could have been used as a quick and flexible planning tool, avoiding the need for extensive simulation studies based on individual participant data. CONCLUSIONS: The analytic expressions described can be routinely used at the planning stage of a putative trial, based on some modest assumptions about the likely number of outcomes and when they might occur and the expected recruitment patterns. Numerical simulations showed that these models behaved sensibly and allowed a range of design options to be explored in a way that would have been difficult and time-consuming if the previously described method of simulating individual trial participant data had been used.

Interventions for treating fractures of the distal femur in adults.

BACKGROUND: Fractures of the distal femur (the far end of the thigh bone just above the knee) are a considerable cause of morbidity. Various different surgical and non-surgical treatments have been used in the management of these injuries but the best treatment remains unknown. OBJECTIVES: To evaluate the benefits and harms of interventions for treating fractures of the distal femur in adults. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was October 2021. SELECTION CRITERIA: We included randomised and quasi-randomised controlled trials in adults comparing interventions for treating fractures of the distal femur. Interventions included surgical implants (retrograde intramedullary nail (RIMN), fixed-angle devices, non-locking plate fixation, locking plate, internal fixation, distal femoral replacement, mono-axial plates, poly-axial plates and condylar buttress plates) and non-surgical management. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our critical outcomes were validated patient-reported outcome measures (PROMs), direct adverse events, participant-reported quality of life (QoL) and pain scores. Our other important outcomes were adverse events indirectly related to intervention, symptomatic non-union, malunion and resource use. We used GRADE to assess certainty of evidence for each outcome. MAIN RESULTS: We included 14 studies with 753 participants: 13 studies compared different surgical interventions, and one study compared surgical with non-surgical management. Here, we report the effects for RIMN compared with locking plates. Three studies (221 participants) reported this comparison; it included the largest study population and these are the two most commonly used devices in contemporary orthopaedic trauma practice. Studies used three different tools to assess PROMs. We found very-low certainty evidence for lower Disability Rating Index scores after RIMN at short-term follow-up favouring RIMN (mean difference (MD) -21.90, 95% confidence interval (CI) -38.16 to -5.64; 1 study, 12 participants) and low-certainty evidence of little or no difference at long-term follow-up (standardised mean difference (SMD) -0.22, 95% CI -0.50 to 0.06; 2 studies, 198 participants). Re-expressing the SMD of the long-term follow-up data to Knee Society Score (KSS) used by one study found no clinical benefit of RIMN, based on a minimal clinically important difference of 9 points (MD 2.47, 95% CI -6.18 to 0.74). The effect on QoL was very uncertain at four months (MD 0.01, 95% CI -0.42 to 0.44; 1 study, 14 participants) and one year (MD 0.10, 95% CI -0.01 to 0.21; 1 study, 156 participants); this evidence was very low certainty. For direct adverse events, studies reported reoperation, loss of fixation, superficial and deep infection, haematoma formation and implant loosening. Effects for all events were imprecise with the possibility of benefit or harm for both treatments. We considered reoperation the most clinically relevant. There was very low-certainty evidence of little or no difference in reoperation between the two implants (risk ratio (RR) 1.48, 95% CI 0.55 to 4.00; 1 study, 104 participants). No studies reported pain.  For other important outcomes, we noted that people treated with RIMN may be more likely to have varus/valgus deformity (RR 2.18, 95% CI 1.09 to 4.37; 1 study, 33 participants; low-certainty evidence). However, we found no evidence of any important differences between treatments in terms of bony union, indirect adverse events, or resource use. Other comparisons of surgical interventions included in the review were: RIMN versus single fixed-angle device (3 studies, 175 participants); RIMN versus non-locking plate fixation (1 study, 18 participants); locking plate versus single fixed-angle device (2 studies, 130 participants); internal fixation versus distal femoral replacement (1 study, 23 participants); mono-axial plates versus poly-axial plates (2 studies, 67 participants); mono-axial plate versus condylar buttress plate (1 study, 78 participants). The certainty of the evidence for outcomes in these comparisons was low to very low, and most effect estimates were imprecise. AUTHORS' CONCLUSIONS: This review highlights the major limitations of the available evidence concerning current treatment interventions for fractures of the distal femur. The currently available evidence is incomplete and insufficient to inform clinical practice. Priority should be given to randomised controlled trials comparing contemporary treatments for people with fractures of the distal femur. At a minimum, these should report validated patient-reported functional and quality-of-life outcomes at one and two years, with an agreed core outcome set. All trials should be reported in full using the CONSORT guidelines.

Group sequential designs in pragmatic trials: feasibility and assessment of utility using data from a number of recent surgical RCTs.

BACKGROUND: Assessing the long term effects of many surgical interventions tested in pragmatic RCTs may require extended periods of participant follow-up to assess effectiveness and use patient-reported outcomes that require large sample sizes. Consequently the RCTs are often perceived as being expensive and time-consuming, particularly if the results show the test intervention is not effective. Adaptive, and particularly group sequential, designs have great potential to improve the efficiency and cost of testing new and existing surgical interventions. As a means to assess the potential utility of group sequential designs, we re-analyse data from a number of recent high-profile RCTs and assess whether using such a design would have caused the trial to stop early. METHODS: Many pragmatic RCTs monitor participants at a number of occasions (e.g. at 6, 12 and 24 months after surgery) during follow-up as a means to assess recovery and also to keep participants engaged with the trial process. Conventionally one of the outcomes is selected as the primary (final) outcome, for clinical reasons, with others designated as either early or late outcomes. In such settings, novel group sequential designs that use data from not only the final outcome but also from early outcomes at interim analyses can be used to inform stopping decisions. We describe data from seven recent surgical RCTs (WAT, DRAFFT, WOLLF, FASHION, CSAW, FIXDT, TOPKAT), and outline possible group sequential designs that could plausibly have been proposed at the design stage. We then simulate how these group sequential designs could have proceeded, by using the observed data and dates to replicate how information could have accumulated and decisions been made for each RCT. RESULTS: The results of the simulated group sequential designs showed that for two of the RCTs it was highly likely that they would have stopped for futility at interim analyses, potentially saving considerable time (15 and 23 months) and costs and avoiding patients being exposed to interventions that were either ineffective or no better than standard care. We discuss the characteristics of RCTs that are important in order to use the methodology we describe, particularly the value of early outcomes and the window of opportunity when early stopping decisions can be made and how it is related to the length of recruitment period and follow-up. CONCLUSIONS: The results for five of the RCTs tested showed that group sequential designs using early outcome data would have been feasible and likely to provide designs that were at least as efficient, and possibly more efficient, than the original fixed sample size designs. In general, the amount of information provided by the early outcomes was surprisingly large, due to the strength of correlations with the primary outcome. This suggests that the methods described here are likely to provide benefits more generally across the range of surgical trials and more widely in other application areas where trial designs, outcomes and follow-up patterns are structured and behave similarly.

Five-year outcomes for patients sustaining severe fractures of the lower limb : mid-term results from the Wound management for Open Lower Limb Fracture (WOLLF) trial.

AIMS: The aim of this study was to report the outcomes of patients with severe open fractures of the lower limb in the five years after they took part in the Wound management for Open Lower Limb Fracture (WOLLF) trial. METHODS: The WOLLF trial compared standard dressings to negative pressure wound therapy (NPWT) applied at the end of the first surgical wound debridement, and patients were followed-up for 12 months. At 12 months, 170 of the original 460 participants agreed to take part in this medium-term follow-up study. Patients reported their Disability Rating Index (DRI) (0 to 100, where 100 is total disability) and health-related quality of life (HRQoL) using the EuroQol five-dimension three-level health questionnaire (EQ-5D-3L) annually by self-reported questionnaire. Further surgical interventions related to the open fracture were also recorded. RESULTS: There was no evidence of a difference in patient-reported disability, HRQoL, or the need for further surgery between patients treated with NPWT versus standard dressings at five years. Considering the combined results for all participants, there was a small but statistically significant change in DRI scores over time (1.6 units per year; p = 0.005), but no evidence that EQ-5D-3L scores changed significantly during years two to five (p = 0.551). CONCLUSION: This study shows that the high levels of disability and reduced HRQoL reported by patients 12 months after severe open fractures of the lower limb persist in the medium term, with little evidence of improvement between years two and five. Cite this article: Bone Joint J 2022;104-B(5):633-639.

Baseline quality of life in people with hip fracture: results from the multicentre WHiTE cohort study.

AIMS: To assess the variation in pre-fracture quality of life (QoL) within the UK hip fracture population, and quantify the nature and strength of associations between QoL and other routinely collected patient characteristics and treatment choices. METHODS: The World Hip Trauma Evaluation (WHiTE) study, an observational cohort study of UK hip fracture patients, collects a range of routine data and a health-related QoL score (EuroQol five-dimension questionnaire (EQ-5D)). Pre-fracture QoL data are summarized and statistical models fitted to understand associations between QoL, patient characteristics, fracture types, and operations. RESULTS: Fitting a multiple linear regression model indicated that 36.5% of the variance in pre-fracture EQ-5D scores was explained by routinely collected patient characteristics: sex (0.14%), age (0.17%), American Society of Anesthesiologists (ASA) score (0.73%), Abbreviated Mental Test Score (AMTS; 1.3%), pre-fracture mobility (11.2%), and EQ-5D respondent (participant, relative, or carer; 23.0%). There was considerable variation in pre-fracture EQ-5D scores between operations within fracture types. Participants with trochanteric fractures reported statistically significant but not clinically relevant lower pre-fracture QoL than those with intracapsular fractures. Participants with intracapsular fractures treated with internal fixation or total hip arthroplasty (THA) reported better QoL than those treated with hemiarthroplasty with the overall fittest group receiving THA. CONCLUSION: Pre-fracture QoL varies considerably between hip fracture patients; it is generally higher in younger than older patients, patients with better mobility, and those patients who live more independently. Pre-fracture QoL is significantly associated with a range of patient characteristics (e.g. age, mobility, residency). These data explain ~35% of the variation in QoL.Cite this article: Bone Joint Res 2020;9(8):468-476.

The PAT randomized clinical trial.

AIMS: A pragmatic, single-centre, double-blind randomized clinical trial was conducted in a NHS teaching hospital to evaluate whether there is a difference in functional knee scores, quality-of-life outcome assessments, and complications at one-year after intervention between total knee arthroplasty (TKA) and patellofemoral arthroplasty (PFA) in patients with severe isolated patellofemoral arthritis. METHODS: This parallel, two-arm, superiority trial was powered at 80%, and involved 64 patients with severe isolated patellofemoral arthritis. The primary outcome measure was the functional section of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score at 12 months. Secondary outcomes were the full 24-item WOMAC, Oxford Knee Score (OKS), American Knee Society Score (AKSS), EuroQol five dimension (EQ-5D) quality-of-life score, the University of California, Los Angeles (UCLA) Physical Activity Rating Scale, and complication rates collected at three, six, and 12 months. For longer-term follow-up, OKS, EQ-5D, and self-reported satisfaction score were collected at 24 and 60 months. RESULTS: Among 64 patients who were randomized, five patients did not receive the allocated intervention, three withdrew, and one declined the intervention. There were no statistically significant differences in the patients' WOMAC function score at 12 months (adjusted mean difference, -1.2 (95% confidence interval -9.19 to 6.80); p = 0.765). There were no clinically significant differences in the secondary outcomes. Complication rates were comparable (superficial surgical site infections, four in the PFA group versus five in the TKA group). There were no statistically significant differences in the patients' OKS score at 24 and 60 months or self-reported satisfaction score or pain-free years. CONCLUSION: Among patients with severe isolated patellofemoral arthritis, this study found similar functional outcome at 12 months and mid-term in the use of PFA compared with TKA. Cite this article: Bone Joint J 2020;102-B(3):310-318.

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

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 Health Technology Assessment; Vol. 24, No. 8. See the NIHR Journals Library website for further project information.

WHAT DID THE TRIAL FIND?: Patients recovered steadily after their injury but were still not back to normal at 9 months. The average Achilles Tendon Rupture Score rose from 38 out of 100 at 8 weeks to 73 out of 100 at 9 months. Patents who had the functional brace reported that their recovery was a little better at 8 weeks than did the patients having the plaster cast, but there was no evidence of a difference after that. There were 17 cases of re-rupture of the Achilles tendon in the plaster cast group and 13 cases in the functional brace group. There was no evidence of a difference in costs. In conclusion, this study provides strong evidence that early weight-bearing in a functional brace provides similar outcomes to traditional plaster casting and is safe for patients having treatment for Achilles tendon rupture.

Achilles tendon rupture affects > 11,000 people each year in the UK, leading to prolonged periods away from work, sports and social activities. Traditionally, after a ruptured tendon, the foot and ankle are 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 it affects later recovery. This study aimed to compare traditional plaster casting with functional bracing for adult patients with Achilles tendon rupture. The participants reported their own recovery using the Achilles Tendon Rupture Score, which consists of 10 questions about symptoms and physical activity (in which a score of 100 is the best possible outcome). We also recorded quality of life, complications, including re-rupture of the tendon, and costs from both the NHS and the patients' perspective. A total of 540 patients, treated at 39 hospitals, agreed to take part and were assigned by chance to either plaster cast or functional brace. Patients reported their recovery at 8 weeks and at 3, 6 and 9 months.

Interpreting and reporting fracture classification and operation type in hip fracture: implications for research studies and routine national audits.

AIMS: This study explores data quality in operation type and fracture classification recorded as part of a large research study and a national audit with an independent review. PATIENTS AND METHODS: At 17 centres, an expert surgeon reviewed a randomly selected subset of cases from their centre with regard to fracture classification using the AO system and type of operation performed. Agreement for these variables was then compared with the data collected during conduct of the World Hip Trauma Evaluation (WHiTE) cohort study. Both types of surgery and fracture classification were collapsed to identify the level of detail of reporting that achieved meaningful agreement. In the National Hip Fracture Database (NHFD), the types of operation and fracture classification were explored to identify the proportion of "highly improbable" combinations. RESULTS: The records were reviewed for 903 cases. Agreement for the subtypes of extracapsular fracture was poor; most centres achieved no better than "fair" agreement. When the classification was collapsed to a single option for "extracapsular" fracture, only four centres failed to have at least "moderate" agreement. There was only "moderate" agreement for the subtypes of intracapsular fracture, which improved to "substantial" when collapsed to "intracapsular". Subtrochanteric fracture types were well reported with "substantial" agreement. There was near "perfect" agreement for internal fixation procedures. "Perfect" or "substantial" agreement was achieved when the type of arthroplasty surgery was reported at the level of "hemiarthroplasty" and "total hip replacement". When reviewing data submitted to the NHFD, a minimum of 5.2% of cases contained "highly improbable" procedures for the stated fracture classification. CONCLUSION: The complexity of collecting fracture classification data at a national scale compromises the accuracy with which detailed classification systems can be reported. Data around type of surgery performed show similar tendencies. Data capture, reporting, and interpretation in future studies must take this into account. Cite this article: Bone Joint J 2019;101-B:1292-1299.

Effect of Negative Pressure Wound Therapy vs Standard Wound Management on 12-Month Disability Among Adults With Severe Open Fracture of the Lower Limb: The WOLLF Randomized Clinical Trial.

Importance: Open fractures of the lower limb occur when a broken bone penetrates the skin. There can be major complications from these fractures, which can be life-changing. Objectives: To assess the disability, rate of deep infection, and quality of life in patients with severe open fracture of the lower limb treated with negative pressure wound therapy (NPWT) vs standard wound management after the first surgical debridement of the wound. Design, Setting, and Participants: Multicenter randomized trial performed in the UK Major Trauma Network, recruiting 460 patients aged 16 years or older with a severe open fracture of the lower limb from July 2012 through December 2015. Final outcome data were collected through November 2016. Exclusions were presentation more than 72 hours after injury and inability to complete questionnaires. Interventions: NPWT (n = 226) in which an open-cell solid foam or gauze was placed over the surface of the wound and connected to a suction pump, creating a partial vacuum over the dressing, vs standard dressings not involving application of negative pressure (n = 234). Main Outcomes and Measures: Disability Rating Index score (range, 0 [no disability] to 100 [completely disabled]) at 12 months was the primary outcome measure, with a minimal clinically important difference of 8 points. Secondary outcomes were complications including deep infection and quality of life (score ranged from 1 [best possible] to -0.59 [worst possible]; minimal clinically important difference, 0.08) collected at 3, 6, 9, and 12 months. Results: Among 460 patients who were randomized (mean age, 45.3 years; 74% men), 88% (374/427) of available study participants completed the trial. There were no statistically significant differences in the patients' Disability Rating Index score at 12 months (mean score, 45.5 in the NPWT group vs 42.4 in the standard dressing group; mean difference, -3.9 [95% CI, -8.9 to 1.2]; P = .13), in the number of deep surgical site infections (16 [7.1%] in the NPWT group vs 19 [8.1%] in the standard dressing group; difference, 1.0% [95% CI, -4.2% to 6.3%]; P = .64), or in quality of life between groups (difference in EuroQol 5-dimensions questionnaire, 0.02 [95% CI, -0.05 to 0.08]; Short Form-12 Physical Component Score, 0.5 [95% CI, -3.1 to 4.1] and Mental Health Component Score, -0.4 [95% CI, -2.2 to 1.4]). Conclusions and Relevance: Among patients with severe open fracture of the lower limb, use of NPWT compared with standard wound dressing did not improve self-rated disability at 12 months. The findings do not support this treatment for severe open fractures. Trial Registration: isrctn.org Identifier: ISRCTN33756652.

Hip arthroscopy versus best conservative care for the treatment of femoroacetabular impingement syndrome (UK FASHIoN): a multicentre randomised controlled trial.

BACKGROUND: Femoroacetabular impingement syndrome is an important cause of hip pain in young adults. It can be treated by arthroscopic hip surgery, including reshaping the hip, or with physiotherapist-led conservative care. We aimed to compare the clinical effectiveness of hip arthroscopy with best conservative care. METHODS: UK FASHIoN is a pragmatic, multicentre, assessor-blinded randomised controlled trial, done at 23 National Health Service hospitals in the UK. We enrolled patients with femoroacetabular impingement syndrome who presented at these hospitals. Eligible patients were at least 16 years old, had hip pain with radiographic features of cam or pincer morphology but no osteoarthritis, and were believed to be likely to benefit from hip arthroscopy. Patients with bilateral femoroacetabular impingement syndrome were eligible; only the most symptomatic hip was randomly assigned to treatment and followed-up. Participants were randomly allocated (1:1) to receive hip arthroscopy or personalised hip therapy (an individualised, supervised, and progressive physiotherapist-led programme of conservative care). Randomisation was stratified by impingement type and recruiting centre and was done by research staff at each hospital, using a central telephone randomisation service. Patients and treating clinicians were not masked to treatment allocation, but researchers who collected the outcome assessments and analysed the results were masked. The primary outcome was hip-related quality of life, as measured by the patient-reported International Hip Outcome Tool (iHOT-33) 12 months after randomisation, and analysed in all eligible participants who were allocated to treatment (the intention-to-treat population). This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN64081839, and is closed to recruitment. FINDINGS: Between July 20, 2012, and July 15, 2016, we identified 648 eligible patients and recruited 348 participants: 171 participants were allocated to receive hip arthroscopy and 177 to receive personalised hip therapy. Three further patients were excluded from the trial after randomisation because they did not meet the eligibility criteria. Follow-up at the primary outcome assessment was 92% (319 of 348 participants). At 12 months after randomisation, mean iHOT-33 scores had improved from 39·2 (SD 20·9) to 58·8 (27·2) for participants in the hip arthroscopy group, and from 35·6 (18·2) to 49·7 (25·5) in the personalised hip therapy group. In the primary analysis, the mean difference in iHOT-33 scores, adjusted for impingement type, sex, baseline iHOT-33 score, and centre, was 6·8 (95% CI 1·7-12·0) in favour of hip arthroscopy (p=0·0093). This estimate of treatment effect exceeded the minimum clinically important difference (6·1 points). There were 147 patient-reported adverse events (in 100 [72%] of 138 patients) in the hip arthroscopy group) versus 102 events (in 88 [60%] of 146 patients) in the personalised hip therapy group, with muscle soreness being the most common of these (58 [42%] vs 69 [47%]). There were seven serious adverse events reported by participating hospitals. Five (83%) of six serious adverse events in the hip arthroscopy group were related to treatment, and the one in the personalised hip therapy group was not. There were no treatment-related deaths, but one patient in the hip arthroscopy group developed a hip joint infection after surgery. INTERPRETATION: Hip arthroscopy and personalised hip therapy both improved hip-related quality of life for patients with femoroacetabular impingement syndrome. Hip arthroscopy led to a greater improvement than did personalised hip therapy, and this difference was clinically significant. Further follow-up will reveal whether the clinical benefits of hip arthroscopy are maintained and whether it is cost effective in the long term. FUNDING: The Health Technology Assessment Programme of the National Institute of Health Research.

Intramedullary nail fixation versus locking plate fixation for adults with a fracture of the distal tibia: the UK FixDT RCT.

BACKGROUND: The best treatment for fractures of the distal tibia remains controversial. Most of these fractures require surgical fixation, but the outcomes are unpredictable and complications are common. OBJECTIVES: To assess disability, quality of life, complications and resource use in patients treated with intramedullary (IM) nail fixation versus locking plate fixation in the 12 months following a fracture of the distal tibia. DESIGN: This was a multicentre randomised trial. SETTING: The trial was conducted in 28 UK acute trauma centres from April 2013 to final follow-up in February 2017. PARTICIPANTS: In total, 321 adult patients were recruited. Participants were excluded if they had open fractures, fractures involving the ankle joint, contraindication to nailing or inability to complete questionnaires. INTERVENTIONS: IM nail fixation (n = 161), in which a metal rod is inserted into the hollow centre of the tibia, versus locking plate fixation (n = 160), in which a plate is attached to the surface of the tibia with fixed-angle screws. MAIN OUTCOME MEASURES: The primary outcome measure was the Disability Rating Index (DRI) score, which ranges from 0 points (no disability) to 100 points (complete disability), at 6 months with a minimum clinically important difference of 8 points. The DRI score was also collected at 3 and 12 months. The secondary outcomes were the Olerud-Molander Ankle Score (OMAS), quality of life as measured using EuroQol-5 Dimensions (EQ-5D), complications such as infection, and further surgery. Resource use was collected to inform the health economic evaluation. RESULTS: Participants had a mean age of 45 years (standard deviation 16.2 years), were predominantly male (61%, 197/321) and had experienced traumatic injury after a fall (69%, 223/321). There was no statistically significant difference in DRI score at 6 months [IM nail fixation group, mean 29.8 points, 95% confidence interval (CI) 26.1 to 33.7 points; locking plate group, mean 33.8 points, 95% CI 29.7 to 37.9 points; adjusted difference, 4.0 points, 95% CI -1.0 to 9.0 points; p = 0.11]. There was a statistically significant difference in DRI score at 3 months in favour of IM nail fixation (IM nail fixation group, mean 44.2 points, 95% CI 40.8 to 47.6 points; locking plate group, mean 52.6 points, 95% CI 49.3 to 55.9 points; adjusted difference 8.8 points, 95% CI 4.3 to 13.2 points; p < 0.001), but not at 12 months (IM nail fixation group, mean 23.1 points, 95% CI 18.9 to 27.2 points; locking plate group, 24.0 points, 95% CI 19.7 to 28.3 points; adjusted difference 1.9 points, 95% CI -3.2 to 6.9 points; p = 0.47). Secondary outcomes showed the same pattern, including a statistically significant difference in mean OMAS and EQ-5D scores at 3 and 6 months in favour of IM nail fixation. There were no statistically significant differences in complications, including the number of postoperative infections (13% in the locking plate group and 9% in the IM nail fixation group). Further surgery was more common in the locking plate group (12% in locking plate group and 8% in IM nail fixation group at 12 months). The economic evaluation showed that IM nail fixation provided a slightly higher quality of life in the 12 months after injury and at lower cost and, therefore, it was cost-effective compared with locking plate fixation. The probability of cost-effectiveness for IM nail fixation exceeded 90%, regardless of the value of the cost-effectiveness threshold. LIMITATIONS: As wound dressings after surgery are clearly visible, it was not possible to blind the patients to their treatment allocation. This evidence does not apply to intra-articular (pilon) fractures of the distal tibia. CONCLUSIONS: Among adults with an acute fracture of the distal tibia who were randomised to IM nail fixation or locking plate fixation, there were similar disability ratings at 6 months. However, recovery across all outcomes was faster in the IM nail fixation group and costs were lower. FUTURE WORK: The potential benefit of IM nail fixation in several other fractures requires investigation. Research is also required into the role of adjuvant treatment and different rehabilitation strategies to accelerate recovery following a fracture of the tibia and other long-bone fractures in the lower limb. The patients in this trial will remain in longer-term follow-up. TRIAL REGISTRATION: Current Controlled Trials ISRCTN99771224 and UKCRN 13761. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 25. See the NIHR Journals Library website for further project information.

Unit of analysis issues in laboratory-based research.

Many studies in the biomedical research literature report analyses that fail to recognise important data dependencies from multilevel or complex experimental designs. Statistical inferences resulting from such analyses are unlikely to be valid and are often potentially highly misleading. Failure to recognise this as a problem is often referred to in the statistical literature as a unit of analysis (UoA) issue. Here, by analysing two example datasets in a simulation study, we demonstrate the impact of UoA issues on study efficiency and estimation bias, and highlight where errors in analysis can occur. We also provide code (written in R) as a resource to help researchers undertake their own statistical analyses.

Effect of Locking Plate Fixation vs Intramedullary Nail Fixation on 6-Month Disability Among Adults With Displaced Fracture of the Distal Tibia: The UK FixDT Randomized Clinical Trial.

Importance: The best treatment for fractures of the distal tibia remains controversial. Most such fractures require surgical fixation but outcomes are unpredictable and complications are common. Objective: To assess disability, quality of life, and complications in patients with displaced tibial fracture treated with intramedullary nail fixation vs locking plate fixation. Design, Setting, and Participants: A multicenter randomized trial recruiting 321 patients 16 years or older with an acute, displaced, extra-articular fracture of the distal tibia from April 2013 through April 2016 with final follow-up in February 2017. Exclusion criteria included open fractures, fractures involving the ankle joint, contraindication to nailing, or inability to complete questionnaires. Interventions: Intramedullary nail fixation (nail group; n = 161), a metal rod inserted into the hollow center of the tibia, vs locking plate fixation (plate group; n = 160), a plate attached to the surface of the tibia with fixed-angle screws. Main Outcomes and Measures: Disability Rating Index (DRI; score range, 0 [no disability] to 100 [complete disability]) at 6 months was the primary outcome measure, with a minimal clinically important difference of 8 points. DRI measurement was also collected at 3 and 12 months. Secondary outcomes were the Olerud-Molander Ankle Score (OMAS), quality of life, and complications (such as infection and further surgery). Results: Among 321 randomized patients (mean age, 45 years [SD, 16.2]; men, 197 [61%]; had experienced traumatic injury after a fall, 223 [69%]), 258 completed the study. There was no statistically significant difference in the DRI score at 6 months between groups (mean score, 29.8 in the nail group vs 33.8 in the plate group; adjusted difference, 4.0 [95% CI, -1.0 to 9.0], P = .11). There was a statistically significant difference in the DRI score at 3 months in favor of nail fixation (mean score, 44.2 in the nail group and 52.6 in the plate group; adjusted difference, 8.8 [95% CI, 4.3 to 13.2], P < .001), but not at 12 months (mean score, 23.1 in the nail group and 24.0 in the plate group; adjusted difference, 1.9 [95% CI, -3.2 to 6.9], P = .47). Secondary outcomes showed the same pattern, including a statistically significant difference in mean OMAS at 3 and 6 months in favor of nail fixation. There were no statistically significant differences in complications, including the number of postoperative infections (9% in the nail group vs 13% in the plate group). Further surgery was more common in the plate group at 12 months (8% in nail group vs 12% in plate group). Conclusions and Relevance: Among patients 16 years or older with an acute, displaced, extra-articular fracture of the distal tibia, neither nail fixation nor locking plate fixation resulted in superior disability status at 6 months. Other factors may need to be considered in deciding the optimal approach. Trial Registration: clinicaltrials.gov Identifier: ISRCTN99771224.

Cast versus functional brace in the rehabilitation of patients treated non-operatively for a rupture of the Achilles tendon: protocol for the UK study of tendo achilles rehabilitation (UK STAR) multi-centre randomised trial.

INTRODUCTION: Achilles tendon rupture affects over 11 000 people yearly in the UK, and the incidence is increasing. Controversy remains with regard to the best rehabilitation strategy for these patients. In operatively treated patients, functional bracing provides better outcomes compared with plaster casts. However, the role of functional bracing in non-operatively managed patients is unclear. This is the protocol for a multicentre randomised trial of plaster cast immobilisation versus functional bracing for patients with a non-operatively managed Achilles tendon rupture. METHODS AND ANALYSIS: All adults presenting with a primary rupture of the Achilles tendon will be screened. Non-operatively treated patients will be eligible to take part in the trial. Broad eligibility criteria will ensure that the results of the study can be generalised to the wider patient population. Randomisation will be on a 1:1 basis. Both rehabilitation strategies are widely used within the National Health Service. Standardised protocols will be followed, and details of plaster material and brace will be as per the site's usual practice.A minimum of 330 patients will be randomised to obtain 90% power to detect a difference of 8 points in Achilles Tendon Total Rupture Score at 9 months. Quality of life and resource use will be collected at 3, 6 and 9 months. The differences between treatment groups will be assessed on an intention-to-treat basis. The results of the trial-based economic evaluation will be expressed in terms of incremental cost per quality-adjusted life-year gained. ETHICS AND DISSEMINATION: The National Research Ethic Committee approved this study on 18 March 2016 (16/SC/0109).The National Institute for Health Research Health Technology Assessment monograph and a manuscript to a peer-reviewed journal will be submitted on completion of the trial (summer 2019). The results of this trial will substantially inform clinical practice on the clinical and cost-effectiveness of the treatment of this injury. This study has been registered on the International Standard Randomised Controlled Trial Number registry with reference no ISRCTN62639639.

Protocol for a randomised controlled trial of standard wound management versus negative pressure wound therapy in the treatment of adult patients with an open fracture of the lower limb: UK Wound management of Lower Limb Fractures (UK WOLLF).

INTRODUCTION: Patients who sustain open lower limb fractures have reported infection risks as high as 27%. The type of dressing applied after initial debridement could potentially affect this risk. In this trial, standard dressings will be compared with a new emerging treatment, negative pressure wound therapy, for patients with open lower limb fractures. METHODS AND ANALYSIS: All adult patients presenting with an open lower limb fracture, with a Gustilo and Anderson (G&A) grade 2/3, will be considered for inclusion. 460 consented patients will provide 90% power to detect a difference of eight points in the Disability Rating Index (DRI) score at 12 months, at the 5% level. A randomisation sequence, stratified by trial centre and G&A grade, will be produced and administered by a secure web-based service. A qualitative substudy will assess patients' experience of giving consent for the trial, and acceptability of trial procedures to patients and staff. Patients will have clinical follow-up in a fracture clinic up to a minimum of 12 months as per standard National Health Service (NHS) practice. Functional and quality of life outcome data will be collected using the DRI, SF12 and EQ-5D questionnaires at 3, 6, 9 and 12 months postoperatively. In addition, information will be requested with regards to resource use and any late complications or surgical interventions related to their injury. The main analysis will investigate differences in the DRI score at 1 year after injury, between the two treatment groups on an intention-to-treat basis. Tests will be two sided and considered to provide evidence for a significant difference if p values are less than 0.05. ETHICS AND DISSEMINATION: Ethical approval was given by NRES Committee West Midlands-Coventry & Warwickshire on 6/2/2012 (ref: 12/WM/0001). The results of the trial will be disseminated via peer-reviewed publications and presentations at relevant conferences. TRIAL REGISTRATION NUMBER: ISRCTN33756652.

UK DRAFFT: a randomised controlled trial of percutaneous fixation with Kirschner wires versus volar locking-plate fixation in the treatment of adult patients with a dorsally displaced fracture of the distal radius.

BACKGROUND: In high-income countries, 6% of all women will have sustained a fracture of the wrist (distal radius) by the age of 80 years and 9% by the age of 90 years. Advances in orthopaedic surgery have improved the outcome for patients: many such fractures can be treated in a plaster cast alone, but others require surgical fixation to hold the bone in place while they heal. The existing evidence suggests that modern locking-plate fixation provides improved functional outcomes, but costs more than traditional wire fixation. METHODS: In this multicentre trial, we randomly assigned 461 adult patients having surgery for an acute dorsally displaced fracture of the distal radius to either percutaneous Kirschner-wire fixation or locking-plate fixation. The primary outcome measure was the Patient-Rated Wrist Evaluation© (PRWE) questionnaire at 12 months after the fracture. In this surgical trial, neither the patients nor the surgeons could be blind to the intervention. We also collected information on complications and combined costs and quality-adjusted life-years (QALYs) to assess cost-effectiveness. RESULTS: The baseline characteristics of the two groups were well balanced and over 90% of patients completed follow-up. Both groups of patients recovered wrist function by 12 months. There was no clinically relevant difference in the PRWE questionnaire score at 3 months, 6 months or 12 months [difference at 12 months: -1.3; 95% confidence interval (CI) -4.5 to 1.8; p=0.398]. There was no difference in the number of complications in each group and small differences in QALY gains (0.008; 95% CI -0.001 to 0.018); Kirschner-wire fixation represents a cost-saving intervention (-£727; 95% CI -£588 to -£865), particularly in younger patients. CONCLUSIONS: Contrary to the existing literature, and against the increasing use of locking-plate fixation, this trial shows that there is no difference between Kirschner wires and volar locking plates for patients with dorsally displaced fractures of the distal radius. A Kirschner-wire fixation is less expensive and quicker to perform. TRIAL REGISTRATION: Current Controlled Trials ISRCTN31379280. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 17. See the NIHR Journals Library website for further project information.

Percutaneous fixation with Kirschner wires versus volar locking plate fixation in adults with dorsally displaced fracture of distal radius: randomised controlled trial.

OBJECTIVES: To compare the clinical effectiveness of Kirschner wire fixation with locking plate fixation for patients with a dorsally displaced fracture of the distal radius. DESIGN: A multicentre two arm parallel group assessor blind randomised controlled trial with 1:1 treatment allocation. SETTING: 18 trauma centres in the United Kingdom. PARTICIPANTS: 461 adults with a dorsally displaced fracture of the distal radius within 3 cm of the radiocarpal joint that required surgical fixation. Patients were excluded if the surgeon thought that the surface of the wrist joint was so badly displaced it required open reduction. INTERVENTIONS: Kirschner wire fixation: wires are passed through the skin over the dorsal aspect of the distal radius and into the bone to hold the fracture in the correct anatomical position. Locking plate fixation: a locking plate is applied through an incision over the volar (palm) aspect of the wrist and secured to the bone with fixed angle locking screws. PRIMARY OUTCOME MEASURE: validated patient rated wrist evaluation (PRWE). This rates wrist function in two (equally weighted) sections concerning the patient's experience of pain and disability to give a score out of 100. SECONDARY OUTCOMES: disabilities of arm, shoulder, and hand (DASH) score, the EuroQol (EQ-5D), and complications related to the surgery. RESULTS: The baseline characteristics of the two groups were well balanced, and over 90% of patients completed follow-up. The wrist function of both groups of patients improved by 12 months. There was no clinically relevant difference in the patient rated wrist score at three, six, or 12 months (difference in favour of the plate group was -1.3, 95% confidence interval -4.5 to 1.8; P=0.40). Nor was there a clinically relevant difference in health related quality of life or the number of complications in each group. CONCLUSIONS: Contrary to the existing literature, and against the rapidly increasing use of locking plate fixation, this trial found no difference in functional outcome in patients with dorsally displaced fractures of the distal radius treated with Kirschner wires or volar locking plates. Kirschner wire fixation, however, is cheaper and quicker to perform. TRIAL REGISTRATION: Current Controlled Trials ISCRTN 31379280. UKCRN 8956.

Proportional-odds models for repeated composite and long ordinal outcome scales.

In many medical studies, researchers widely use composite or long ordinal scores, that is, scores that have a large number of categories and a natural ordering often resulting from the sum of a number of short ordinal scores, to assess function or quality of life. Typically, we analyse these using unjustified assumptions of normality for the outcome measure, which are unlikely to be even approximately true. Scores of this type are better analysed using methods reserved for more conventional (short) ordinal scores, such as the proportional-odds model. We can avoid the need for a large number of cut-point parameters that define the divisions between the score categories for long ordinal scores in the proportional-odds model by the inclusion of orthogonal polynomial contrasts. We introduce the repeated measures proportional-odds logistic regression model and describe for long ordinal outcomes modifications to the generalized estimating equation methodology used for parameter estimation. We introduce data from a trial assessing two surgical interventions, briefly describe and re-analyse these using the new model and compare inferences from the new analysis with previously published results for the primary outcome measure (hip function at 12 months postoperatively). We use a simulation study to illustrate how this model also has more general application for conventional short ordinal scores, to select amongst competing models of varying complexity for the cut-point parameters.

An evaluation of the quality of statistical design and analysis of published medical research: results from a systematic survey of general orthopaedic journals.

BACKGROUND: The application of statistics in reported research in trauma and orthopaedic surgery has become ever more important and complex. Despite the extensive use of statistical analysis, it is still a subject which is often not conceptually well understood, resulting in clear methodological flaws and inadequate reporting in many papers. METHODS: A detailed statistical survey sampled 100 representative orthopaedic papers using a validated questionnaire that assessed the quality of the trial design and statistical analysis methods. RESULTS: The survey found evidence of failings in study design, statistical methodology and presentation of the results. Overall, in 17% (95% confidence interval; 10-26%) of the studies investigated the conclusions were not clearly justified by the results, in 39% (30-49%) of studies a different analysis should have been undertaken and in 17% (10-26%) a different analysis could have made a difference to the overall conclusions. CONCLUSION: It is only by an improved dialogue between statistician, clinician, reviewer and journal editor that the failings in design methodology and analysis highlighted by this survey can be addressed.