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.

Multi-centre randomised controlled trial comparing arthroscopic hip surgery to physiotherapist-led care for femoroacetabular impingement (FAI) syndrome on hip cartilage metabolism: the Australian FASHIoN trial.

BACKGROUND: Arthroscopic surgery for femoroacetabular impingement syndrome (FAI) is known to lead to self-reported symptom improvement. In the context of surgical interventions with known contextual effects and no true sham comparator trials, it is important to ascertain outcomes that are less susceptible to placebo effects. The primary aim of this trial was to determine if study participants with FAI who have hip arthroscopy demonstrate greater improvements in delayed gadolinium-enhanced magnetic resonance imaging (MRI) of cartilage (dGEMRIC) index between baseline and 12 months, compared to participants who undergo physiotherapist-led management. METHODS: Multi-centre, pragmatic, two-arm superiority randomised controlled trial comparing physiotherapist-led management to hip arthroscopy for FAI. FAI participants were recruited from participating orthopaedic surgeons clinics, and randomly allocated to receive either physiotherapist-led conservative care or surgery. The surgical intervention was arthroscopic FAI surgery. The physiotherapist-led conservative management was an individualised physiotherapy program, named Personalised Hip Therapy (PHT). The primary outcome measure was change in dGEMRIC score between baseline and 12 months. Secondary outcomes included a range of patient-reported outcomes and structural measures relevant to FAI pathoanatomy and hip osteoarthritis development. Interventions were compared by intention-to-treat analysis. RESULTS: Ninety-nine participants were recruited, of mean age 33 years and 58% male. Primary outcome data were available for 53 participants (27 in surgical group, 26 in PHT). The adjusted group difference in change at 12 months in dGEMRIC was -59 ms (95%CI - 137.9 to - 19.6) (p = 0.14) favouring PHT. Hip-related quality of life (iHOT-33) showed improvements in both groups with the adjusted between-group difference at 12 months showing a statistically and clinically important improvement in arthroscopy of 14 units (95% CI 5.6 to 23.9) (p = 0.003). CONCLUSION: The primary outcome of dGEMRIC showed no statistically significant difference between PHT and arthroscopic hip surgery at 12 months of follow-up. Patients treated with surgery reported greater benefits in symptoms at 12 months compared to PHT, but these benefits are not explained by better hip cartilage metabolism. TRIAL REGISTRATION DETAILS: Australia New Zealand Clinical Trials Registry reference: ACTRN12615001177549 . Trial registered 2/11/2015.

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.

Protocol for a multi-centre randomised controlled trial comparing arthroscopic hip surgery to physiotherapy-led care for femoroacetabular impingement (FAI): the Australian FASHIoN trial.

BACKGROUND: Femoroacetabular impingement syndrome (FAI), a hip disorder affecting active young adults, is believed to be a leading cause of hip osteoarthritis (OA). Current management approaches for FAI include arthroscopic hip surgery and physiotherapy-led non-surgical care; however, there is a paucity of clinical trial evidence comparing these approaches. In particular, it is unknown whether these management approaches modify the future risk of developing hip OA. The primary objective of this randomised controlled trial is to determine if participants with FAI who undergo hip arthroscopy have greater improvements in hip cartilage health, as demonstrated by changes in delayed gadolinium-enhanced magnetic resonance imaging (MRI) of cartilage (dGEMRIC) index between baseline and 12 months, compared to those who undergo physiotherapy-led non-surgical management. METHODS: This is a pragmatic, multi-centre, two-arm superiority randomised controlled trial comparing hip arthroscopy to physiotherapy-led management for FAI. A total of 140 participants with FAI will be recruited from the clinics of participating orthopaedic surgeons, and randomly allocated to receive either surgery or physiotherapy-led non-surgical care. The surgical intervention involves arthroscopic FAI surgery from one of eight orthopaedic surgeons specialising in this field, located in three different Australian cities. The physiotherapy-led non-surgical management is an individualised physiotherapy program, named Personalised Hip Therapy (PHT), developed by a panel to represent the best non-operative care for FAI. It entails at least six individual physiotherapy sessions over 12 weeks, and up to ten sessions over six months, provided by experienced musculoskeletal physiotherapists trained to deliver the PHT program. The primary outcome measure is the change in dGEMRIC score of a ROI containing both acetabular and femoral head cartilages at the chondrolabral transitional zone of the mid-sagittal plane between baseline and 12 months. Secondary outcomes include patient-reported outcomes and several structural and biomechanical measures relevant to the pathogenesis of FAI and development of hip OA. Interventions will be compared by intention-to-treat analysis. DISCUSSION: The findings will help determine whether hip arthroscopy or an individualised physiotherapy program is superior for the management of FAI, including for the prevention of hip OA. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry reference: ACTRN12615001177549 . Trial registered 2/11/2015 (retrospectively registered).

Personalised Hip Therapy: development of a non-operative protocol to treat femoroacetabular impingement syndrome in the FASHIoN randomised controlled trial.

INTRODUCTION: Femoroacetabular impingement (FAI) syndrome is increasingly recognised as a cause of hip pain. As part of the design of a randomised controlled trial (RCT) of arthroscopic surgery for FAI syndrome, we developed a protocol for non-operative care and evaluated its feasibility. METHODS: In phase one, we developed a protocol for non-operative care for FAI in the UK National Health Service (NHS), through a process of systematic review and consensus gathering. In phase two, the protocol was tested in an internal pilot RCT for protocol adherence and adverse events. RESULTS: The final protocol, called Personalised Hip Therapy (PHT), consists of four core components led by physiotherapists: detailed patient assessment, education and advice, help with pain relief and an exercise-based programme that is individualised, supervised and progressed over time. PHT is delivered over 12-26 weeks in 6-10 physiotherapist-patient contacts, supplemented by a home exercise programme. In the pilot RCT, 42 patients were recruited and 21 randomised to PHT. Review of treatment case report forms, completed by physiotherapists, showed that 13 patients (62%) received treatment that had closely followed the PHT protocol. 13 patients reported some muscle soreness at 6 weeks, but there were no serious adverse events. CONCLUSION: PHT provides a structure for the non-operative care of FAI and offers guidance to clinicians and researchers in an evolving area with limited evidence. PHT was deliverable within the National Health Service, is safe, and now forms the comparator to arthroscopic surgery in the UK FASHIoN trial (ISRCTN64081839). TRIAL REGISTRATION NUMBER: ISRCTN 09754699.

Microvascular blood flow in normal and pathologic rotator cuffs.

BACKGROUND: Microvascular blood flow in the tendon plays an important role in the pathogenesis of rotator cuff abnormalities. There are conflicting views about the presence of a hypovascular zone in the supraspinatus tendon. Besides, no studies have looked at the pattern of blood flow around a partial-thickness tear. Our aim was to measure microvascular blood flow in normal and a range of pathologic rotator cuff tendons using laser doppler flowmetry. METHODS: A total of 120 patients having arthroscopic shoulder surgery were divided into 4 equal groups on the basis of their intraoperative diagnosis: normal rotator cuff, subacromial impingement syndrome, and partial-thickness or full-thickness rotator cuff tear. Microvascular blood flow was measured at 5 different regions of each cuff using a laser doppler probe. The values were compared to assess variability within and between individuals. RESULTS: Total blood flow was greater in the normal rotator cuff group compared with the groups with pathologic rotator cuffs, with the largest difference seen in the subacromial impingement group. Within individuals, blood flow was highest at the musculotendinous junction and lowest at the lateral insertional part of the tendon. Among groups, the blood flow was significantly lower at the anteromedial and posteromedial cuff in the groups with impingement and full-thickness tears compared with the group with normal cuff. CONCLUSION: Real-time in vivo laser doppler analysis has shown that microvascular blood flow is not uniform throughout the supraspinatus tendon. Blood flow in the pathologic supraspinatus tendon was significantly lower compared with the normal tendon.

Ultrasound dimensions of the rotator cuff in young healthy adults.

BACKGROUND: No studies have looked at the rotator cuff dimensions in the young healthy population using ultrasonography. Our aim is to define the ultrasound dimensions of the rotator cuff in the healthy young adult population and explore correlations with other patient characteristics. METHODS: Thirty male and 30 female healthy volunteers (aged 18-40 years), with no shoulder problems, underwent ultrasound assessment of both shoulders by a musculoskeletal radiologist. The dimensions of the rotator cuff, deltoid, and biceps were measured in a standardized manner. RESULTS: A total of 120 shoulders were scanned. The mean maximum width of the supraspinatus footprint was 14.9 mm in men and 13.5 mm in women (P < .001). The mean thickness of the supraspinatus tendon was 4.9 mm in women and 5.6 mm in men. The mean thickness of the subscapularis was 4.4 in men and 3.8 mm in women and for the infraspinatus was 4.9 mm in men and 4.4 mm in women. There was no correlation between height, weight, biceps, or deltoid thickness with any tendon measurements. Apart from supraspinatus tendon thickness, the difference between dominant and nondominant shoulders in the same sex was not significant for any other tendon dimensions. CONCLUSION: This study has defined the dimensions of the rotator cuff in the young healthy adult, which has not been previously published. This is important for the documentation of normal ultrasound anatomy of the rotator cuff and also demonstrates that the asymptomatic contralateral shoulder can and should be used to estimate the expected dimensions.

Anterior knee pain patients without structural knee abnormalities and normal lower limb skeletal alignment have a higher prevalence of cam-femoroacetabular impingement syndrome than the general population.

OBJECTIVES: This study aimed to ascertain the prevalence of cam femoroacetabular impingement syndrome (cam-FAIS) in anterior knee pain (AKP) patients devoid of both structural patellofemoral joint abnormalities and lower limb skeletal malalignment. A secondary objective was to examine pain and disability differences between AKP patients with and without cam-FAIS. METHODS: A total of 209 AKP patients were screened for eligibility. Inclusion criteria were normal imaging studies and normal lower limb alignment, and exclusion criteria were previous knee surgery and knee and/or hip osteoarthritis. Of those, 49 (23.4%) were eligible and this number matched a previous power analysis to detect statistically significant differences in prevalence of cam-FAIS in a population of AKP patients. The first step in the study sequence was to ask the patient whether they had groin pain. If so, the impingement test was done. Then, the femoral cam morphology defined by an alpha angle greater than or equal to 55° in a 45° Dunn axial view of the hip was ruled out. Additionally, patients completed Kujala and International Knee Documentation Committee (IKDC) functional knee scores for disability assessment. General population control group was obtained from literature. RESULTS: The study included 9 males and 40 females, with an average age of 36 (20-50, ±SD 8.03) years. Groin pain and positive impingement test were found in 26/49 patients (53%). An alpha angle ≥55° was observed in 35/49 patients (71%). A combination of groin pain, positive impingement test and an alpha angle ≥55° was seen in 18/49 patients (37%). The AKP patients with groin pain, a positive impingement test and an alpha angle ≥55° exhibited statistically similar pain and disability levels as AKP patients without cam-FAIS. CONCLUSION: The results of this study suggest that AKP patients without structural abnormalities in the patellofemoral joint and without lower limbs malalignment have a statistically significantly higher prevalence of cam-FAIS than the general population. Moreover, AKP patients with cam-FAIS have a statistically similar degree of pain and disability than AKP patients without it. STUDY DESIGN: Cross-sectional study. LEVEL OF EVIDENCE: IV.

Ankle fracture internal fixation performed by cadaveric simulation-trained versus standard-trained orthopaedic trainees: a preliminary, multicentre randomized controlled trial.

Aims: Ankle fracture fixation is commonly performed by junior trainees. Simulation training using cadavers may shorten the learning curve and result in a technically superior surgical performance. Methods: We undertook a preliminary, pragmatic, single-blinded, multicentre, randomized controlled trial of cadaveric simulation versus standard training. Primary outcome was fracture reduction on postoperative radiographs. Results: Overall, 139 ankle fractures were fixed by 28 postgraduate year three to five trainee surgeons (mean age 29.4 years; 71% males) during ten months' follow-up. Under the intention-to-treat principle, a technically superior fixation was performed by the cadaveric-trained group compared to the standard-trained group, as measured on the first postoperative radiograph against predefined acceptability thresholds. The cadaveric-trained group used a lower intraoperative dose of radiation than the standard-trained group (mean difference 0.011 Gym2, 95% confidence interval 0.003 to 0.019; p = 0.009). There was no difference in procedure time. Conclusion: Trainees randomized to cadaveric training performed better ankle fracture fixations and irradiated patients less during surgery compared to standard-trained trainees. This effect, which was previously unknown, is likely to be a consequence of the intervention. Further study is required.