Determining a risk-proportionate approach to the validation of statistical programming for clinical trials.

BACKGROUND: The contribution of the statistician to the design and analysis of a clinical trial is acknowledged as essential. Ability to reconstruct the statistical contribution to a trial requires rigorous and transparent documentation as evidenced by the reproducibility of results. The process of validating statistical programmes is a key requirement. While guidance relating to software development and life cycle methodologies details steps for validation by information systems developers, there is no guidance applicable to programmes written by statisticians. We aimed to develop a risk-based approach to the validation of statistical programming that would support scientific integrity and efficient resource use within clinical trials units. METHODS: The project was embedded within the Information Systems Operational Group and the Statistics Operational Group of the UK Clinical Research Collaboration Registered Clinical Trials Unit network. Members were asked to share materials relevant to validation of statistical programming. A review of the published literature, regulatory guidance and knowledge of relevant working groups was undertaken. Surveys targeting the Information Systems Operational Group and Statistics Operational Group were developed to determine current practices across the Registered Clinical Trials Unit network. A risk-based approach was drafted and used as a basis for a workshop with representation from statisticians, information systems developers and quality assurance managers (n = 15). The approach was subsequently modified and presented at a second, larger scale workshop (n = 47) to gain a wider perspective, with discussion of content and implications for delivery. The approach was revised based on the discussions and suggestions made. The workshop was attended by a member of the Medicines for Healthcare products Regulatory Agency Inspectorate who also provided comments on the revised draft. RESULTS: Types of statistical programming were identified and categorised into six areas: generation of randomisation lists; programmes to explore/understand the data; data cleaning, including complex checks; derivations including data transformations; data monitoring; or interim and final analysis. The risk-based approach considers each category of statistical programme against the impact of an error and its likelihood, whether the programming can be fully prespecified, the need for repeated use and the need for reproducibility. Approaches to the validation of programming within each category are proposed. CONCLUSION: We have developed a risk-based approach to the validation of statistical programming. It endeavours to facilitate the implementation of targeted quality assurance measures while making efficient use of limited resources.

Total Ankle Replacement Versus Arthrodesis for End-Stage Ankle Osteoarthritis: A Randomized Controlled Trial.

BACKGROUND: End-stage ankle osteoarthritis causes severe pain and disability. There are no randomized trials comparing the 2 main surgical treatments: total ankle replacement (TAR) and ankle fusion (AF). OBJECTIVE: To determine which treatment is superior in terms of clinical scores and adverse events. DESIGN: A multicenter, parallel-group, open-label randomized trial. (ISRCTN registry number: 60672307). SETTING: 17 National Health Service trusts across the United Kingdom. PATIENTS: Patients with end-stage ankle osteoarthritis, aged 50 to 85 years, and suitable for either procedure. INTERVENTION: Patients were randomly assigned to TAR or AF surgical treatment. MEASUREMENTS: The primary outcome was change in Manchester-Oxford Foot Questionnaire walking/standing (MOXFQ-W/S) domain scores between baseline and 52 weeks after surgery. No blinding was possible. RESULTS: Between 6 March 2015 and 10 January 2019, a total of 303 patients were randomly assigned; mean age was 68 years, and 71% were men. Twenty-one patients withdrew before surgery, and 281 clinical scores were analyzed. At 52 weeks, the mean MOXFQ-W/S scores improved for both groups. The adjusted difference in the change in MOXFQ-W/S scores from baseline was -5.6 (95% CI, -12.5 to 1.4), showing that TAR improved more than AF, but the difference was not considered clinically or statistically significant. The number of adverse events was similar between groups (109 vs. 104), but there were more wound healing issues in the TAR group and more thromboembolic events and nonunion in the AF group. The symptomatic nonunion rate for AF was 7%. A post hoc analysis suggested superiority of fixed-bearing TAR over AF (-11.1 [CI, -19.3 to -2.9]). LIMITATION: Only 52-week data; pragmatic design creates heterogeneity of implants and surgical techniques. CONCLUSION: Both TAR and AF improve MOXFQ-W/S and had similar clinical scores and number of harms. Total ankle replacement had greater wound healing complications and nerve injuries, whereas AF had greater thromboembolism and nonunion, with a symptomatic nonunion rate of 7%. PRIMARY FUNDING SOURCE: National Institute for Health and Care Research Heath Technology Assessment Programme.

Effectiveness of Belimumab After Rituximab in Systemic Lupus Erythematosus : A Randomized Controlled Trial.

BACKGROUND: B-cell depletion with rituximab is commonly used for patients with systemic lupus erythematosus (SLE) that is refractory to conventional therapy, but it yields variable responses. We hypothesized that high B-cell activating factor (BAFF) levels after rituximab can cause disease flares, thereby limiting its effectiveness. OBJECTIVE: To obtain preliminary evidence for efficacy of the anti-BAFF therapeutic belimumab after rituximab in SLE. DESIGN: Phase 2, randomized, double-blind (patients, assessors, researchers, care providers), placebo-controlled, parallel-group, superiority trial. (ISRCTN: 47873003). SETTING: England. PARTICIPANTS: Fifty-two patients who had SLE that was refractory to conventional treatment and whose physicians had recommended rituximab therapy were recruited between 2 February 2017 and 28 March 2019. INTERVENTION: Participants were treated with rituximab and 4 to 8 weeks later were randomly assigned (1:1) to receive intravenous belimumab or placebo for 52 weeks. MEASUREMENTS: The prespecified primary end point was serum IgG anti-double-stranded DNA (anti-dsDNA) antibody levels at 52 weeks. Secondary outcomes included incidence of disease flares and adverse events. RESULTS: At 52 weeks, IgG anti-dsDNA antibody levels were lower in patients treated with belimumab compared with placebo (geometric mean, 47 [95% CI, 25 to 88] vs. 103 [CI, 49 to 213] IU/mL; 70% greater reduction from baseline [CI, 46% to 84%]; P < 0.001). Belimumab reduced risk for severe flare (BILAG-2004 grade A) compared with placebo (hazard ratio, 0.27 [CI, 0.07 to 0.98]; log-rank P = 0.033), with 10 severe flares in the placebo group and 3 in the belimumab group. Belimumab did not increase incidence of serious adverse events. Belimumab significantly suppressed B-cell repopulation compared with placebo (geometric mean, 0.012 [CI, 0.006 to 0.014] vs. 0.037 [CI, 0.021 to 0.081] × 109/L) at 52 weeks in a subset of patients (n = 25) with available data. LIMITATIONS: Small sample size; biomarker primary end point. CONCLUSION: Belimumab after rituximab significantly reduced serum IgG anti-dsDNA antibody levels and reduced risk for severe flare in patients with SLE that was refractory to conventional therapy. The results suggest that this combination could be developed as a therapeutic strategy. PRIMARY FUNDING SOURCE: Versus Arthritis.

Effect of Corneal Cross-linking versus Standard Care on Keratoconus Progression in Young Patients: The KERALINK Randomized Controlled Trial.

PURPOSE: To examine the efficacy and safety of corneal cross-linking (CXL) for stabilization of progressive keratoconus. DESIGN: Observer-masked, randomized, controlled, parallel-group superiority trial. PARTICIPANTS: Sixty participants 10 to 16 years of age with progressive keratoconus, one eye of each deemed the study eye. METHODS: The study eye was randomized to either CXL plus standard care or standard care alone, with spectacle or contact lens correction as necessary for vision. MAIN OUTCOME MEASURES: The primary outcome was steep keratometry (K2) in the study eye as a measure of the steepness of the cornea at 18 months. Secondary outcomes included keratoconus progression defined as a 1.5-diopter (D) increase in K2, visual acuity, keratoconus apex corneal thickness, and quality of life. RESULTS: Of 60 participants, 30 were randomized to CXL and standard care groups. Of these, 30 patients in the CXL group and 28 patients in the standard care group were analyzed. Mean K2 in the study eye 18 months after randomization was 49.7 D (standard deviation [SD], 3.8 D) in the CXL group and 53.4 D (SD, 5.8 D) in the standard care group. The adjusted mean difference in K2 in the study eye was -3.0 D (95% confidence interval [CI], -4.9 to -1.1 D; P = 0.002), favoring CXL. Adjusted differences between groups in uncorrected and corrected vision favored eyes receiving CXL: -0.31 logarithm of the minimum angle of resolution (logMAR; 95% CI, -0.50 to -0.11 logMAR; P = 0.002) and -0.51 logMAR (95% CI, -1.37 to 0.35 logMAR; P = 0.002). Keratoconus progression in the study eye occurred in 2 patients (7%) randomized to CXL compared with 12 patients (43%) randomized to standard care. The unadjusted odds ratio suggests that on average, patients in the CXL arm had 90% (odds ratio, 0.1; 95% CI, 0.02-0.48; P = 0.004) lower odds of experiencing progression compared with those receiving standard care. CONCLUSIONS: CXL arrests progression of keratoconus in the majority of young patients. CXL should be considered as a first-line treatment in progressive disease. If the arrest of keratoconus progression induced by CXL is sustained in longer follow-up, particular benefit may be derived from avoiding a later requirement for contact lens wear or corneal transplantation.

Risk Factors for Visual Field Deterioration in the United Kingdom Glaucoma Treatment Study.

PURPOSE: The United Kingdom Glaucoma Treatment Study (UKGTS) investigated the visual field (VF)-preserving effect of medical treatment in open-angle glaucoma (OAG). The objective of this analysis was to identify risk factors associated with VF deterioration. DESIGN: Randomized, double-masked, placebo-controlled multicenter trial. PARTICIPANTS: Five hundred sixteen participants with previously untreated OAG were recruited prospectively in 10 United Kingdom centers. METHODS: Eligibility criteria were modeled on those for the Early Manifest Glaucoma Trial. Study participants were randomized to either latanoprost 0.005% or placebo eye drops. The observation period was 2 years and involved, among other procedures, VF testing and intraocular pressure (IOP) measurement at 11 scheduled visits, with clustering of tests at baseline, 18 months, and 24 months. Guided progression analysis pattern deviation maps were used to determine VF deterioration. Cox regression was used to compute the hazard ratios (HRs) and respective 95% confidence intervals (CIs) while accounting for the correlation within sites. Model selection was guided by backward stepwise selection conducted on the model containing all variables that were significant at the 0.2 level in the univariate analysis. Follow-up variables that showed collinearity with baseline values were not retained in the final model. MAIN OUTCOME MEASURE: Time to VF deterioration. RESULTS: Treatment with latanoprost reduced the HR, for VF deterioration by 58% (HR, 0.42; 95% CI, 0.27-0.67; P = 0.001). Factors associated with deterioration were bilateral disease (HR, 1.59 for yes vs. no; 95% CI, 1.02-2.50; P = 0.041), higher baseline IOP (HR, 1.07 per mmHg; 95% CI, 1.02-1.12; P = 0.008), and disc hemorrhage at visit 1 (HR, 2.08; 95% CI, 1.07-4.04; P = 0.030). Smoking (current or previous) was associated with a reduced HR, for VF deterioration (HR, 0.59; 95% CI, 0.37-0.93; P = 0.023). No other evaluated factors were found to be statistically significant in the multivariable analysis. CONCLUSIONS: In the UKGTS, treatment with latanoprost halved VF deterioration risk. Bilateral disease, higher IOP, and disc hemorrhage were confirmed as risk factors for deterioration; smoking history seemed to be protective against VF deterioration.

Femtosecond Laser-Assisted Cataract Surgery Versus Phacoemulsification Cataract Surgery (FACT): A Randomized Noninferiority Trial.

PURPOSE: To report the 3-month results of a randomized trial (Femtosecond Laser-Assisted Cataract Trial [FACT]) comparing femtosecond laser-assisted cataract surgery (FLACS) with standard phacoemulsification cataract surgery (PCS). DESIGN: Multicenter, randomized controlled trial funded by the UK National Institute of Health Research (HTA 13/04/46/). PARTICIPANTS: Seven hundred eighty-five patients with age-related cataract. METHODS: This trial took place in 3 hospitals in the UK National Health Service (NHS). Randomization (1:1) was stratified by site, surgeon, and 1 or both eyes eligible using a secure web-based system. Postoperative assessments were masked to the allocated intervention. The primary outcome was unaided distance visual acuity (UDVA) in the study eye at 3 months. Secondary outcomes included corrected distance visual acuity, complications, and patient-reported outcomes measures. The noninferiority margin was 0.1 logarithm of the minimum angle of resolution (logMAR). ISRCTN.com registry, number ISRCTN77602616. MAIN OUTCOME MEASURES: We enrolled 785 participants between May 2015 and September 2017 and randomly assigned 392 to FLACS and 393 to PCS. At 3 months postoperatively, mean UDVA difference between treatment arms was -0.01 logMAR (-0.05 to 0.03), and mean corrected distance visual acuity difference was -0.01 logMAR (95% confidence interval [CI], -0.05 to 0.02). Seventy-one percent of both FLACS and PCS cases were within ±0.5 diopters (D) of the refractive target, and 93% of FLACS and 92% of PCS cases were within ±1.0 D. There were 2 posterior capsule tears in the PCS arm and none in the FLACS arm. There were no significant differences between arms for any secondary outcome. CONCLUSIONS: Femtosecond laser-assisted cataract surgery is not inferior to conventional PCS surgery 3 months after surgery. Both methods are as good in terms of vision, patient-reported health, and safety outcomes at 3 months. Longer-term outcomes of the clinical effectiveness and cost-effectiveness are awaited.

Human papillomavirus infection: protocol for a randomised controlled trial of imiquimod cream (5%) versus podophyllotoxin cream (0.15%), in combination with quadrivalent human papillomavirus or control vaccination in the treatment and prevention of recurrence of anogenital warts (HIPvac trial).

BACKGROUND: Anogenital warts are the second most common sexually transmitted infection diagnosed in sexual health services in England. About 90% of genital warts are caused by human papillomavirus (HPV) types 6 or 11, and half of episodes diagnosed are recurrences. The best and most cost-effective treatment for patients with anogenital warts is unknown. The commonly used treatments are self-administered topical agents, podophyllotoxin (0.15% cream) or imiquimod (5% cream), or cryotherapy with liquid nitrogen. Quadrivalent HPV (qHPV) vaccination is effective in preventing infection, and disease, but whether it has any therapeutic effect is not known. METHODS AND DESIGN: To investigate the efficacy of clearance and prevention of recurrence of external anogenital warts by topical treatments, podophyllotoxin 0.15% cream or imiquimod 5% cream, in combination with a three-dose regimen of qHPV or control vaccination. 500 adult patients presenting with external anogenital warts with either a first or subsequent episode of anogenital warts will be entered into this randomised, controlled partially blinded 2 × 2 factorial trial. DISCUSSION: The trial is expected to provide the first high-quality evidence of the comparative efficacy and cost-effectiveness of the two topical treatments in current use, as well as investigate the potential benefit of HPV vaccination, in the management of anogenital warts. TRIAL REGISTRATION: The trial was registered prior to starting recruitment under the following reference numbers: International Standard Randomized Controlled Trial Number (ISRCTN) Registry - ISRCTN32729817 (registered 25 July 2014); European Union Clinical Trials Register (EudraCT) - 2013-002951-14 (registered 26 June 2013).

Optimizing treatment with tumour necrosis factor inhibitors in rheumatoid arthritis-a proof of principle and exploratory trial: is dose tapering practical in good responders?

Objectives: RA patients receiving TNF inhibitors (TNFi) usually maintain their initial doses. The aim of the Optimizing Treatment with Tumour Necrosis Factor Inhibitors in Rheumatoid Arthritis trial was to evaluate whether tapering TNFi doses causes loss of clinical response. Methods: We enrolled RA patients receiving etanercept or adalimumab and a DMARD with DAS28 under 3.2 for over 3 months. Initially (months 0-6) patients were randomized to control (constant TNFi) or two experimental groups (tapering TNFi by 33 or 66%). Subsequently (months 6-12) control subjects were randomized to taper TNFi by 33 or 66%. Disease flares (DAS28 increasing ⩾0.6 with at least one additional swollen joint) were the primary outcome. Results: Two hundred and forty-four patients were screened, 103 randomized and 97 treated. In months 0-6 there were 8/50 (16%) flares in controls, 3/26 (12%) with 33% tapering and 6/21 (29%) with 66% tapering. Multivariate Cox analysis showed time to flare was unchanged with 33% tapering but was reduced with 66% tapering compared with controls (adjusted hazard ratio 2.81, 95% CI: 0.99, 7.94; P = 0.051). Analysing all tapered patients after controls were re-randomized (months 6-12) showed differences between groups: there were 6/48 (13%) flares with 33% tapering and 14/39 (36%) with 66% tapering. Multivariate Cox analysis showed 66% tapering reduced time to flare (adjusted hazard ratio 3.47, 95% CI: 1.26, 9.58; P = 0.016). Conclusion: Tapering TNFi by 33% has no impact on disease flares and appears practical in patients in sustained remission and low disease activity states. Trail registration: EudraCT, https://www.clinicaltrialsregister.eu, 2010-020738-24; ISRCTN registry, https://www.isrctn.com, 28955701.

Guidelines for the Content of Statistical Analysis Plans in Clinical Trials.

Importance: While guidance on statistical principles for clinical trials exists, there is an absence of guidance covering the required content of statistical analysis plans (SAPs) to support transparency and reproducibility. Objective: To develop recommendations for a minimum set of items that should be addressed in SAPs for clinical trials, developed with input from statisticians, previous guideline authors, journal editors, regulators, and funders. Design: Funders and regulators (n = 39) of randomized trials were contacted and the literature was searched to identify existing guidance; a survey of current practice was conducted across the network of UK Clinical Research Collaboration-registered trial units (n = 46, 1 unit had 2 responders) and a Delphi survey (n = 73 invited participants) was conducted to establish consensus on SAPs. The Delphi survey was sent to statisticians in trial units who completed the survey of current practice (n = 46), CONSORT (Consolidated Standards of Reporting Trials) and SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guideline authors (n = 16), pharmaceutical industry statisticians (n = 3), journal editors (n = 9), and regulators (n = 2) (3 participants were included in 2 groups each), culminating in a consensus meeting attended by experts (N = 12) with representatives from each group. The guidance subsequently underwent critical review by statisticians from the surveyed trial units and members of the expert panel of the consensus meeting (N = 51), followed by piloting of the guidance document in the SAPs of 5 trials. Findings: No existing guidance was identified. The registered trials unit survey (46 responses) highlighted diversity in current practice and confirmed support for developing guidance. The Delphi survey (54 of 73, 74% participants completing both rounds) reached consensus on 42% (n = 46) of 110 items. The expert panel (N = 12) agreed that 63 items should be included in the guidance, with an additional 17 items identified as important but may be referenced elsewhere. Following critical review and piloting, some overlapping items were combined, leaving 55 items. Conclusions and Relevance: Recommendations are provided for a minimum set of items that should be addressed and included in SAPs for clinical trials. Trial registration, protocols, and statistical analysis plans are critically important in ensuring appropriate reporting of clinical trials.

Restrictive versus liberal blood transfusion for acute upper gastrointestinal bleeding (TRIGGER): a pragmatic, open-label, cluster randomised feasibility trial.

BACKGROUND: Transfusion thresholds for acute upper gastrointestinal bleeding are controversial. So far, only three small, underpowered studies and one single-centre trial have been done. Findings from the single-centre trial showed reduced mortality with restrictive red blood cell (RBC) transfusion. We aimed to assess whether a multicentre, cluster randomised trial is a feasible method to substantiate or refute this finding. METHODS: In this pragmatic, open-label, cluster randomised feasibility trial, done in six university hospitals in the UK, we enrolled all patients aged 18 years or older with new presentations of acute upper gastrointestinal bleeding, irrespective of comorbidity, except for exsanguinating haemorrhage. We randomly assigned hospitals (1:1) with a computer-generated randomisation sequence (random permuted block size of 6, without stratification or matching) to either a restrictive (transfusion when haemoglobin concentration fell below 80 g/L) or liberal (transfusion when haemoglobin concentration fell below 100 g/L) RBC transfusion policy. Neither patients nor investigators were masked to treatment allocation. Feasibility outcomes were recruitment rate, protocol adherence, haemoglobin concentration, RBC exposure, selection bias, and information to guide design and economic evaluation of the phase 3 trial. Main exploratory clinical outcomes were further bleeding and mortality at day 28. We did analyses on all enrolled patients for whom an outcome was available. This trial is registered, ISRCTN85757829 and NCT02105532. FINDINGS: Between Sept 3, 2012, and March 1, 2013, we enrolled 936 patients across six hospitals (403 patients in three hospitals with a restrictive policy and 533 patients in three hospitals with a liberal policy). Recruitment rate was significantly higher for the liberal than for the restrictive policy (62% vs 55%; p=0·04). Despite some baseline imbalances, Rockall and Blatchford risk scores were identical between policies. Protocol adherence was 96% (SD 10) in the restrictive policy vs 83% (25) in the liberal policy (difference 14%; 95% CI 7-21; p=0·005). Mean last recorded haemoglobin concentration was 116 (SD 24) g/L for patients on the restrictive policy and 118 (20) g/L for those on the liberal policy (difference -2·0 [95% CI -12·0 to 7·0]; p=0·50). Fewer patients received RBCs on the restrictive policy than on the liberal policy (restrictive policy 133 [33%] vs liberal policy 247 [46%]; difference -12% [95% CI -35 to 11]; p=0·23), with fewer RBC units transfused (mean 1·2 [SD 2·1] vs 1·9 [2·8]; difference -0·7 [-1·6 to 0·3]; p=0·12), although these differences were not significant. We noted no significant difference in clinical outcomes. INTERPRETATION: A cluster randomised design led to rapid recruitment, high protocol adherence, separation in degree of anaemia between groups, and non-significant reduction in RBC transfusion in the restrictive policy. A large cluster randomised trial to assess the effectiveness of transfusion strategies for acute upper gastrointestinal bleeding is both feasible and essential before clinical practice guidelines change to recommend restrictive transfusion for all patients with acute upper gastrointestinal bleeding. FUNDING: NHS Blood and Transplant Research and Development.

Second-line agents in myositis: 1-year factorial trial of additional immunosuppression in patients who have partially responded to steroids.

OBJECTIVE: Ciclosporin and MTX are used in idiopathic inflammatory myopathies (DM and PM) when patients incompletely respond to glucocorticoids. Their effectiveness is unproved in randomized controlled trials (RCTs). We evaluated their benefits in a placebo-controlled factorial RCT. METHODS: A 56-week multicentre factorial-design double-blind placebo-controlled RCT compared steroids alone, MTX (15-25 mg weekly) plus steroids, ciclosporin (1-5 mg/kg/day) plus steroids and all three treatments. It enrolled adults with myositis (by Bohan and Peter criteria) with active disease receiving corticosteroids. RESULTS: A total of 359 patients were screened and 58 randomized. Of the latter, 37 patients completed 12 months of treatment, 7 were lost to follow-up and 14 discontinued treatment. Patients completing 12 months of treatment showed significant improvement (P < 0.001 on paired t-tests) in manual muscle testing (14% change), walking time (22% change) and function (9% change). Intention to treat and completer analyses indicated that ciclosporin monotherapy, MTX monotherapy and ciclosporin/MTX combination therapy showed no significant treatment effects in comparison with placebo. CONCLUSION: Neither MTX nor ciclosporin (by themselves or in combination) improved clinical features in myositis patients who had incompletely responded to glucocorticoids. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number Register; http://www.controlled-trials.com/; ISRCTN40085050.

A re-randomisation design for clinical trials.

BACKGROUND: Recruitment to clinical trials is often problematic, with many trials failing to recruit to their target sample size. As a result, patient care may be based on suboptimal evidence from underpowered trials or non-randomised studies. METHODS: For many conditions patients will require treatment on several occasions, for example, to treat symptoms of an underlying chronic condition (such as migraines, where treatment is required each time a new episode occurs), or until they achieve treatment success (such as fertility, where patients undergo treatment on multiple occasions until they become pregnant). We describe a re-randomisation design for these scenarios, which allows each patient to be independently randomised on multiple occasions. We discuss the circumstances in which this design can be used. RESULTS: The re-randomisation design will give asymptotically unbiased estimates of treatment effect and correct type I error rates under the following conditions: (a) patients are only re-randomised after the follow-up period from their previous randomisation is complete; (b) randomisations for the same patient are performed independently; and (c) the treatment effect is constant across all randomisations. Provided the analysis accounts for correlation between observations from the same patient, this design will typically have higher power than a parallel group trial with an equivalent number of observations. CONCLUSIONS: If used appropriately, the re-randomisation design can increase the recruitment rate for clinical trials while still providing an unbiased estimate of treatment effect and correct type I error rates. In many situations, it can increase the power compared to a parallel group design with an equivalent number of observations.

Quantitative Maximum Shear-Wave Stiffness of Breast Masses as a Predictor of Histopathologic Severity.

OBJECTIVE: The objective of our study was to compare quantitative maximum breast mass stiffness on shear-wave elastography (SWE) with histopathologic outcome. SUBJECTS AND METHODS: From September 2008 through September 2010, at 16 centers in the United States and Europe, 1647 women with a sonographically visible breast mass consented to undergo quantitative SWE in this prospective protocol; 1562 masses in 1562 women had an acceptable reference standard. The quantitative maximum stiffness (termed "Emax") on three acquisitions was recorded for each mass with the range set from 0 (very soft) to 180 kPa (very stiff). The median Emax and interquartile ranges (IQRs) were determined as a function of histopathologic diagnosis and were compared using the Mann-Whitney U test. We considered the impact of mass size on maximum stiffness by performing the same comparisons for masses 9 mm or smaller and those larger than 9 mm in diameter. RESULTS: The median patient age was 50 years (mean, 51.8 years; SD, 14.5 years; range, 21-94 years), and the median lesion diameter was 12 mm (mean, 14 mm; SD, 7.9 mm; range, 1-53 mm). The median Emax of the 1562 masses (32.1% malignant) was 71 kPa (mean, 90 kPa; SD, 65 kPa; IQR, 31-170 kPa). Of 502 malignancies, 23 (4.6%) ductal carcinoma in situ (DCIS) masses had a median Emax of 126 kPa (IQR, 71-180 kPa) and were less stiff than 468 invasive carcinomas (median Emax, 180 kPa [IQR, 138-180 kPa]; p = 0.002). Benign lesions were much softer than malignancies (median Emax, 43 kPa [IQR, 24-83 kPa] vs 180 kPa [IQR, 129-180 kPa]; p < 0.0001). Usual benign lesions were soft, including 62 cases of fibrocystic change (median Emax, 32 kPa; IQR, 24-94 kPa), 51 cases of fibrosis (median Emax, 36 kPa; IQR, 22-102 kPa), and 301 fibroadenomas (median Emax, 45 kPa; IQR, 30-79 kPa). Eight lipomas (median Emax, 14 kPa; IQR, 8-15 kPa), 154 cysts (median Emax, 29 kPa; IQR, 10-58 kPa), and seven lymph nodes (median Emax, 17 kPa; IQR, 9-40 kPa) were softer than usual benign lesions (p < 0.0001 for lipomas and cysts; p = 0.007 for lymph nodes). Risk lesions were slightly stiffer than usual benign lesions (p = 0.002) but tended to be softer than DCIS (p = 0.14). Fat necrosis and abscesses were relatively stiff. Conclusions were similar for both small and large masses. CONCLUSION: Despite overlap in Emax values, maximum stiffness measured by SWE is a highly effective predictor of the histopathologic severity of sonographically depicted breast masses.

SPIRIT 2013 Statement: defining standard protocol items for clinical trials.

The protocol of a clinical trial serves as the foundation for study planning, conduct, reporting, and appraisal. However, trial protocols and existing protocol guidelines vary greatly in content and quality. This article describes the systematic development and scope of SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) 2013, a guideline for the minimum content of a clinical trial protocol. The 33-item SPIRIT checklist applies to protocols for all clinical trials and focuses on content rather than format. The checklist recommends a full description of what is planned; it does not prescribe how to design or conduct a trial. By providing guidance for key content, the SPIRIT recommendations aim to facilitate the drafting of high-quality protocols. Adherence to SPIRIT would also enhance the transparency and completeness of trial protocols for the benefit of investigators, trial participants, patients, sponsors, funders, research ethics committees or institutional review boards, peer reviewers, journals, trial registries, policymakers, regulators, and other key stakeholders.

SPIRIT 2013 statement: defining standard protocol items for clinical trials.

The protocol of a clinical trial serves as the foundation for study planning, conduct, reporting, and appraisal. However, trial protocols and existing protocol guidelines vary greatly in content and quality. This article describes the systematic development and scope of SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) 2013, a guideline for the minimum content of a clinical trial protocol.The 33-item SPIRIT checklist applies to protocols for all clinical trials and focuses on content rather than format. The checklist recommends a full description of what is planned; it does not prescribe how to design or conduct a trial. By providing guidance for key content, the SPIRIT recommendations aim to facilitate the drafting of high-quality protocols. Adherence to SPIRIT would also enhance the transparency and completeness of trial protocols for the benefit of investigators, trial participants, patients, sponsors, funders, research ethics committees or institutional review boards, peer reviewers, journals, trial registries, policymakers, regulators, and other key stakeholders.

Cost-Utility Analysis of Total Ankle Replacement Compared with Ankle Arthrodesis for Patients Aged 50-85 Years with End-Stage Ankle Osteoarthritis: The TARVA Study.

BACKGROUND: Patients with end-stage ankle osteoarthritis suffer from reduced mobility and quality of life and the main surgical treatments are total ankle replacement (TAR) and ankle fusion (AF). OBJECTIVES: Our aim was to calculate the mean incremental cost per quality-adjusted life-year (QALY) of TAR compared with AF in patients with end-stage ankle osteoarthritis, over 52 weeks and over the patients' lifetime. METHOD: We conducted a cost-utility analysis of 282 participants from 17 UK centres recruited to a randomised controlled trial (TARVA). QALYs were calculated using index values from EQ-5D-5L. Resource use information was collected from case report forms and self-completed questionnaires. Primary analysis was within-trial analysis from the National Health Service (NHS) and Personal Social Services (PSS) perspective, while secondary analyses were within-trial analysis from wider perspective and long-term economic modelling. Adjustments were made for baseline resource use and index values. RESULTS: Total cost at 52 weeks was higher in the TAR group compared with the AF group, from the NHS and PSS perspective (mean adjusted difference £2539, 95% confidence interval [CI] £1142, £3897). The difference became very small from the wider perspective (£155, 95% CI -  £1947, £2331). There was no significant difference between TAR and AF in terms of QALYs (mean adjusted difference 0.02, 95% CI -  0.015, 0.05) at 52 weeks post-operation. The incremental cost-effectiveness ratio (ICER) was £131,999 per QALY gained 52 weeks post-operation. Long-term economic modelling resulted in an ICER of £4200 per QALY gained, and there is a 69% probability of TAR being cost effective at a cost-effectiveness threshold of £20,000 per QALY gained. CONCLUSION: TAR does not appear to be cost effective over AF 52 weeks post-operation. A decision model suggests that TAR can be cost effective over the patients' lifetime but there is a need for longer-term prospectively collected data. Clinical trial registration ISRCTN60672307 and ClinicalTrials.gov NCT02128555.

Rehabilitation following surgery for lumbar spinal stenosis.

BACKGROUND: Lumbar spinal stenosis is a common cause of back pain that can also give rise to pain in the buttock, thigh or leg, particularly when walking. Several possible treatments are available, of which surgery appears to be best at restoring function and reducing pain. Surgical outcome is not ideal, and a sizeable proportion of patients do not regain good function. No accepted evidence-based approach to postoperative care is known-a fact thathas prompted this review. OBJECTIVES: To determine whether active rehabilitation programmes following primary surgery for lumbar spinal stenosis have an impact on functional outcomes and whether such programmes are superior to 'usual postoperative care'. SEARCH METHODS: We searched the following databases from their first issues to March 2013: CENTRAL (The Cochrane Library, most recent issue), the Cochrane Back Review Group Trials Register, MEDLINE, EMBASE, CINAHL and PEDro. SELECTION CRITERIA: We considered randomised controlled trials (RCTs) that compared the effectiveness of active rehabilitation versus usual care in adults (> 18 years of age) with confirmed lumbar spinal stenosis who had undergone spinal decompressive surgery (with or without fusion) for the first time. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data from the included trials by using a predeveloped form. We contacted authors of original trials to request additional unpublished data as required. We recorded baseline characteristics of participants, interventions, comparisons, follow-up and outcome measures to enable assessment of clinical homogeneity. Clinical relevance was independently assessed by using the five questions recommended by the Cochrane Back Review Group (CBRG), and risk of bias within studies was determined by using CBRG criteria.We pooled individual study results in a meta-analysis when appropriate. For continuous outcomes, we calculated the mean difference (MD) when the same measurement scales were used in all studies and the standardised mean difference (SMD) when different measurement scales were used. Whenreported means and standard deviations of the outcomes showed that outcome data were skewed, we log-transformed data for all studies in the comparison and performed a meta-analysis on the log-scale. Results of analyses performed on the log-scale were converted back to the original scale. We used a fixed-effect inverse variance model to measure treatment effect when no substantial evidence of statistical heterogeneity was found. When we detected substantial statistical heterogeneity, we used a random-effects inverse variance model.The primary outcome measure was functional status as measured by a back-specific functional scale. Secondary outcomes included measures of leg pain, low back pain and global improvement/general health. We considered statistical significance and clinical relevance of outcomes. We used the GRADE approach to assess the overall quality of evidence for each outcome on the basis of five criteria, for which evidence was ranked from high to very low quality, depending on the number of criteria met. MAIN RESULTS: Our searches yielded 1,726 results, and a total of three studies (N = 373 participants) were included in the review and meta-analysis. All studies were deemed to have low risk of bias; no study had unacceptably high dropout rates. Also, no unacceptably unbalanced dropout rates, unacceptably low adherence rates or non-adherence to the protocol or clearly significant unbalanced baseline differences were noted for the primary outcome. Outcomes in the short term (within six months postoperative)Evidence of moderate quality from three RCTs (N = 340) shows that active rehabilitation is more effective than usual care for functional status (log SMD -0.22, 95% confidence interval (CI) -0.44 to 0.00, corresponding to an average percentage improvement (reduction in standardised functional score) of 20%, 95% CI 0% to 36%) and for reported low back pain (log MD -0.18, 95% CI-0.35 to -0.02, corresponding to an average percentage improvement (reduction in VAS score) of 16%, 95% CI 2% to 30%). In contrast, evidence of low quality suggests that rehabilitation is no more effective than usual care for leg pain (log MD -0.17, 95% CI -0.52 to 0.19, corresponding to an average percentage improvement (reduction in VAS score) of 16%, 95% CI 21% worsening to 41% improvement). Low-quality evidence from two RCTs (N = 238) indicates that rehabilitation has no additional benefit on general health status as compared to usual care (MD 1.30, 95% CI -4.45 to 7.06). Outcomes in the long term (at 12 months postoperative)Evidence of moderate quality from three RCTs (N = 373) shows that rehabilitation is more effective than usual care for functional status (log SMD -0.26, 95% CI -0.46 to -0.05, corresponding to an average percentage improvement (reduction in standardised functional score) of 23%, 95% CI 5% to 37%), for reported low back pain (log MD -0.20, 95% CI -0.36 to -0.05, corresponding to an average percentage improvement (reduction in VAS score) of 18%, 95% CI 5% to 30%]. Evidence of moderate quality (N = 373) and for leg pain (log MD -0.24, 95% CI -0.47 to -0.01, corresponding to an average percentage improvement (reduction in VAS score) of 21%, 95% CI 1% to 37%). In contrast, evidence of low quality from two studies (N = 273) suggests that rehabilitation is no more effective than usual care with respect to improvement in general health (MD -0.48, 95% CI -6.41 to 5.4).None of the included papers reported any relevant adverse events. AUTHORS' CONCLUSIONS: Evidence suggests that active rehabilitation is more effective than usual care in improving both short- and long-term (back-related) functional status. Similar findings were noted for secondary outcomes, including short-term improvement in low back pain and long-term improvement in both low back pain and leg pain, although limited impact was observed in relation to improvements in general health status. The clinical relevance of these effects is medium to small. Our evaluation is limited by the small number of relevant studies identified, and further research is required.

An exploration of patients' expectation of and satisfaction with surgical outcome.

PURPOSE: The majority of studies of surgical outcome focus on measures of function and pain. Increasingly, however, the desire to include domains such as patients' satisfaction and expectations had led to the development of simple measures and their inclusion into clinical studies. The purpose of this study was to determine patients' pre-operative expectations of and post-operative satisfaction with the outcome of their spinal surgery. METHODS: As part of the FASTER randomised controlled trial, patients were asked pre-operatively to quantify their expected improvement in pain and health status at 6 weeks, 6 and 12 months following surgery using 100 mm visual analogue scales (VAS), and to indicate their confidence in achieving this result and also the importance of this recovery to them. Patients were then asked to rate their satisfaction with the improvement achieved at each post-operative review using 100 mm VAS. RESULTS: Although differences between patients' expectation and achievement were minimal 6 weeks post-operatively, there was a clear discrepancy at 6 months and 1 year, with patient expectations far exceeding achievement. There were significant correlations between failure to achieve expectations and the importance patients attached to this recovery at each post-operative assessment, but not with their confidence in achieving this result. Satisfaction levels remained high despite expectations not being met, with discectomy patients being more satisfied than decompression patients. CONCLUSIONS: Patients' pre-operative expectations of surgical outcome exceed their long-term achievement. The more importance the patient attached to a good outcome, the larger is the discrepancy between expectation and achievement. Despite this, satisfaction levels remained high. The impact of unrealistic expectations on outcome remains unclear.

Total ankle replacement versus ankle arthrodesis for patients aged 50-85 years with end-stage ankle osteoarthritis: the TARVA RCT.

Background: We aimed to compare the clinical effectiveness, cost-effectiveness and complication rates of total ankle replacement with those of arthrodesis (i.e. ankle fusion) in the treatment of end-stage ankle osteoarthritis. Methods: This was a pragmatic, multicentre, parallel-group, non-blinded randomised controlled trial. Patients with end-stage ankle osteoarthritis who were aged 50-85 years and were suitable for both procedures were recruited from 17 UK hospitals and randomised using minimisation. The primary outcome was the change in the Manchester-Oxford Foot Questionnaire walking/standing domain scores between the preoperative baseline and 52 weeks post surgery. Results: Between March 2015 and January 2019, 303 participants were randomised using a minimisation algorithm: 152 to total ankle replacement and 151 to ankle fusion. At 52 weeks, the mean (standard deviation) Manchester-Oxford Foot Questionnaire walking/standing domain score was 31.4 (30.4) in the total ankle replacement arm (n = 136) and 36.8 (30.6) in the ankle fusion arm (n = 140); the adjusted difference in the change was -5.6 (95% confidence interval -12.5 to 1.4; p = 0.12) in the intention-to-treat analysis. By week 52, one patient in the total ankle replacement arm required revision. Rates of wound-healing issues (13.4% vs. 5.7%) and nerve injuries (4.2% vs. < 1%) were higher and the rate of thromboembolic events was lower (2.9% vs. 4.9%) in the total ankle replacement arm than in the ankle fusion arm. The bone non-union rate (based on plain radiographs) in the ankle fusion arm was 12.1%, but only 7.1% of patients had symptoms. A post hoc analysis of fixed-bearing total ankle replacement showed a statistically significant improvement over ankle fusion in Manchester-Oxford Foot Questionnaire walking/standing domain score (-11.1, 95% confidence interval -19.3 to -2.9; p = 0.008). We estimate a 69% likelihood that total ankle replacement is cost-effective compared with ankle fusion at the National Institute for Health and Care Excellence's cost-effectiveness threshold of £20,000 per quality-adjusted life-year gained over the patient's lifetime. Limitations: This initial report contains only 52-week data, which must therefore be interpreted with caution. In addition, the pragmatic nature of the study means that there was heterogeneity between surgical implants and techniques. The trial was run across 17 NHS centres to ensure that decision-making streams reflected the standard of care in the NHS as closely as possible. Conclusions: Both total ankle replacement and ankle fusion improved patients' quality of life at 1 year, and both appear to be safe. When total ankle replacement was compared with ankle fusion overall, we were unable to show a statistically significant difference between the two arms in terms of our primary outcome measure. The total ankle replacement versus ankle arthrodesis (TARVA) trial is inconclusive in terms of superiority of total ankle replacement, as the 95% confidence interval for the adjusted treatment effect includes both a difference of zero and the minimal important difference of 12, but it can rule out the superiority of ankle fusion. A post hoc analysis comparing fixed-bearing total ankle replacement with ankle fusion showed a statistically significant improvement of total ankle replacement over ankle fusion in Manchester-Oxford Foot Questionnaire walking/standing domain score. Total ankle replacement appears to be cost-effective compared with ankle fusion at the National Institute for Health and Care Excellence's cost-effectiveness threshold of £20,000 per quality-adjusted life-year gained over a patient's lifetime based on long-term economic modelling. Future work: We recommend long-term follow-up of this important cohort, in particular radiological and clinical progress. We also recommend studies to explore the sensitivity of clinical scores to detect clinically important differences between arms when both have already achieved a significant improvement from baseline. Trial registration: This trial is registered as ISRCTN60672307 and ClinicalTrials.gov NCT02128555. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 5. See the NIHR Journals Library website for further project information.

Each year, over 29,000 patients with ankle osteoarthritis seek a specialist opinion, of whom 4000 undergo NHS surgical treatment. The main surgical treatments for severe ankle osteoarthritis are total ankle replacement or arthrodesis (i.e. ankle fusion). Both are known to be good treatments to relieve pain, and each has its advantages. Total ankle replacement is a more popular patient choice than ankle fusion. When deciding whether to undergo ankle replacement or fusion, patients consult various sources, but the majority of them rely on the advice of their surgeon to make a final decision. To the best of our knowledge, there has never been a high-quality randomised clinical trial comparing these two treatments and there are no published guidelines on the most suitable management. In this study, 303 patients were randomised to a type of ankle surgery: 138 in the total ankle replacement arm and 144 in the ankle fusion arm received surgery. We found that both total ankle replacement and ankle fusion improved patients' walking ability, but we did not find a statistically significant difference between the treatment arms based on our primary outcome measure at 1 year. When we considered the type of total ankle replacement implant, we found that the implant most commonly used in the NHS (a fixed-bearing two-component implant) had better outcomes at 1 year than ankle fusion. Both total ankle replacement and ankle fusion appear to be safe. However, there were more wound-healing issues and nerve injuries in the total ankle replacement arm than in the ankle fusion arm. Twelve per cent of patients experienced bone non-union in the ankle fusion arm, but only 7.1% experienced symptoms. We estimate that there is a 69% chance that total ankle replacement would be cost-effective compared with ankle fusion at the National Institute for Health and Care Excellence's cost-effectiveness threshold of £20,000 per quality-adjusted life-year gained over a patient's lifetime. This study provides the NHS with important information that could help to obtain the best possible outcome for patients with severe ankle arthritis.