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.

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 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.

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.

Optimal timing of anticoagulation after acute ischemic stroke with atrial fibrillation (OPTIMAS): Protocol for a randomized controlled trial.

RATIONALE: Atrial fibrillation causes one-fifth of ischemic strokes, with a high risk of early recurrence. Although long-term anticoagulation is highly effective for stroke prevention in atrial fibrillation, initiation after stroke is usually delayed by concerns over intracranial hemorrhage risk. Direct oral anticoagulants offer a significantly lower risk of intracranial hemorrhage than other anticoagulants, potentially allowing earlier anticoagulation and prevention of recurrence, but the safety and efficacy of this approach has not been established. AIM: Optimal timing of anticoagulation after acute ischemic stroke with atrial fibrillation (OPTIMAS) will investigate whether early treatment with a direct oral anticoagulant, within four days of stroke onset, is as effective or better than delayed initiation, 7 to 14 days from onset, in atrial fibrillation patients with acute ischemic stroke. METHODS AND DESIGN: OPTIMAS is a multicenter randomized controlled trial with blinded outcome adjudication. Participants with acute ischemic stroke and atrial fibrillation eligible for anticoagulation with a direct oral anticoagulant are randomized 1:1 to early or delayed initiation. As of December 2021, 88 centers in the United Kingdom have opened. STUDY OUTCOMES: The primary outcome is a composite of recurrent stroke (ischemic stroke or symptomatic intracranial hemorrhage) and systemic arterial embolism within 90 days. Secondary outcomes include major bleeding, functional status, anticoagulant adherence, quality of life, health and social care resource use, and length of hospital stay. SAMPLE SIZE TARGET: A total of 3478 participants assuming event rates of 11.5% in the control arm and 8% in the intervention arm, 90% power and 5% alpha. We will follow a non-inferiority gatekeeper analysis approach with a non-inferiority margin of 2 percentage points. DISCUSSION: OPTIMAS aims to provide high-quality evidence on the safety and efficacy of early direct oral anticoagulant initiation after atrial fibrillation-associated ischemic stroke.Trial registrations: ISRCTN: 17896007; ClinicalTrials.gov: NCT03759938.

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.

M.I.C.E-Mental Health Intervention for Children with Epilepsy: a randomised controlled, multi-centre clinical trial evaluating the clinical and cost-effectiveness of MATCH-ADTC in addition to usual care compared to usual care alone for children and young people with common mental health disorders and epilepsy-study protocol.

BACKGROUND: Mental health disorders in the context of long-term conditions in children and young people are currently overlooked and undertreated. Evidence-based psychological treatments for common childhood mental health disorders (anxiety, depression and disruptive behaviour disorders) have not been systematically evaluated in young people with epilepsy despite their high prevalence in this population. The aim of this multi-site randomised controlled trial is to determine the clinical and cost-effectiveness of adding a modular psychological intervention to usual care for the mental health disorders in comparison to assessment-enhanced usual care alone. METHODS: In total, 334 participants aged 3-18 years attending epilepsy services will be screened for mental health disorders with the Strengths and Difficulties Questionnaire (SDQ) and the diagnostic Development and Wellbeing Assessment (DAWBA). Those identified as having a mental health disorder and consenting to the trial will be randomised to either receive up to 22 sessions of the modular psychological intervention (MATCH-ADTC) delivered over the telephone over 6 months by non-mental health professionals in addition to usual care or to assessment-enhanced usual care alone. Outcomes will be measured at baseline, 6 months and 12 months post-randomisation. It is hypothesised that MATCH-ADTC plus usual care will be superior to assessment-enhanced usual care in improving emotional and behavioural symptoms. The primary outcome is the SDQ reported by parents at 6 months. Secondary outcomes include parent-reported mental health measures such as the Revised Children's Anxiety and Depression Scale, quality of life measures such as the Paediatric Quality of Life Inventory and physical health measures such as the Hague Seizure Severity Scale. Outcome assessors will be blinded to group assignment. Qualitative process evaluations and a health economic evaluation will also be completed. DISCUSSION: This trial aims to determine whether a systematic and integrated approach to the identification and treatment of mental health disorders in children and young people with epilepsy is clinically and cost-effective. The findings will contribute to policies and practice with regard to addressing mental health needs in children and young people with other long-term conditions. TRIAL REGISTRATION: ISRCTN ISRCTN57823197 . Registered on 25 February 2019.

Femtosecond laser-assisted cataract surgery compared with phacoemulsification: the FACT non-inferiority RCT.

BACKGROUND: Cataract surgery is one of the most common operations. Femtosecond laser-assisted cataract surgery (FLACS) is a technique that automates a number of operative steps. OBJECTIVES: To compare FLACS with phacoemulsification cataract surgery (PCS). DESIGN: Multicentre, outcome-masked, randomised controlled non-inferiority trial. SETTING: Three collaborating NHS hospitals. PARTICIPANTS: A total of 785 patients with age-related cataract in one or both eyes were randomised between May 2015 and September 2017. INTERVENTION: FLACS (n = 392 participants) or PCS (n = 393 participants). MAIN OUTCOME MEASURES: The primary outcome was uncorrected distance visual acuity in the study eye after 3 months, expressed as the logarithm of the minimum angle of resolution (logMAR): 0.00 logMAR (or 6/6 if expressed in Snellen) is normal (good visual acuity). Secondary outcomes included corrected distance visual acuity, refractive outcomes (within 0.5 dioptre and 1.0 dioptre of target), safety and patient-reported outcome measures at 3 and 12 months, and resource use. All trial follow-ups were performed by optometrists who were masked to the trial intervention. RESULTS: A total of 353 (90%) participants allocated to the FLACS arm and 317 (81%) participants allocated to the PCS arm attended follow-up at 3 months. The mean uncorrected distance visual acuity was similar in both treatment arms [0.13 logMAR, standard deviation 0.23 logMAR, for FLACS, vs. 0.14 logMAR, standard deviation 0.27 logMAR, for PCS, with a difference of -0.01 logMAR (95% confidence interval -0.05 to 0.03 logMAR; p = 0.63)]. The mean corrected distance visual acuity values were again similar in both treatment arms (-0.01 logMAR, standard deviation 0.19 logMAR FLACS vs. 0.01 logMAR, standard deviation 0.21 logMAR PCS; p = 0.34). There were two posterior capsule tears in the PCS arm. There were no significant differences between the treatment arms for any secondary outcome at 3 months. At 12 months, the mean uncorrected distance visual acuity was 0.14 logMAR (standard deviation 0.22 logMAR) for FLACS and 0.17 logMAR (standard deviation 0.25 logMAR) for PCS, with a difference between the treatment arms of -0.03 logMAR (95% confidence interval -0.06 to 0.01 logMAR; p = 0.17). The mean corrected distance visual acuity was 0.003 logMAR (standard deviation 0.18 logMAR) for FLACS and 0.03 logMAR (standard deviation 0.23 logMAR) for PCS, with a difference of -0.03 logMAR (95% confidence interval -0.06 to 0.01 logMAR; p = 0.11). There were no significant differences between the arms for any other outcomes, with the exception of the mean binocular corrected distance visual acuity with a difference of -0.02 logMAR (95% confidence interval -0.05 to 0.00 logMAR) (p = 0.036), which favoured FLACS. There were no significant differences between the arms for any health, social care or societal costs. For the economic evaluation, the mean cost difference was £167.62 per patient higher for FLACS (95% of iterations between -£14.12 and £341.67) than for PCS. The mean QALY difference (FLACS minus PCS) was 0.001 (95% of iterations between -0.011 and 0.015), which equates to an incremental cost-effectiveness ratio (cost difference divided by QALY difference) of £167,620. LIMITATIONS: Although the measurement of outcomes was carried out by optometrists who were masked to the treatment arm, the participants were not masked. CONCLUSIONS: The evidence suggests that FLACS is not inferior to PCS in terms of vision after 3 months' follow-up, and there were no significant differences in patient-reported health and safety outcomes after 12 months' follow-up. In addition, the statistically significant difference in binocular corrected distance visual acuity was not clinically significant. FLACS is not cost-effective. FUTURE WORK: To explore the possible differences in vision in patients without ocular co-pathology. TRIAL REGISTRATION: Current Controlled Trials ISRCTN77602616. 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. 25, No. 6. See the NIHR Journals Library website for further project information. Moorfields Eye Charity (grant references GR000233 and GR000449 for the endothelial cell counter and femtosecond laser used).

Cataract is a condition in which the natural lens inside the eye becomes cloudy, leading to loss of vision. In cataract surgery, the cloudy lens is replaced by a clear, artificial one. The standard surgical method (phacoemulsification) is carried out manually by the surgeon using ultrasound. Part of the procedure can now be automated using a computer-controlled laser. This is called femtosecond laser-assisted cataract surgery (FLACS). The potential advantages of FLACS include greater precision reproducibility, but this new technique is more expensive than the standard surgery. We performed a randomised controlled trial comparing the two techniques. We assessed vision, surgical complications, patient-related quality of life and cost-effectiveness at 3 and 12 months. We found that the outcomes were almost identical for eyesight, quality of life and complications. Overall, the evidence suggests that the new technique is not worth the additional costs.

Use of direct oral anticoagulants in patients with thrombotic antiphospholipid syndrome: Guidance from the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis.

Clarity and guidance is required with regard to the use of direct oral anticoagulants in antiphospholipid syndrome (APS) patients, within the confines of the recent European Medicines Agency recommendations, discrepant recommendations in other international guidelines and the limited evidence base. To address this, the Lupus Anticoagulant/Antiphospholipid Antibodies Scientific and Standardization Committee (SSC) chair and co-chairs together with SSC Control of Anticoagulation members propose guidance for healthcare professionals to help them manage APS patients. Uncertainty in this field will be addressed. This guidance will also serve as a call and focus for research.

Imiquimod versus podophyllotoxin, with and without human papillomavirus vaccine, for anogenital warts: the HIPvac factorial RCT.

BACKGROUND: The comparative efficacy, and cost-effectiveness, of imiquimod or podophyllotoxin cream, either alone or in combination with the quadrivalent HPV vaccine (Gardasil®, Merck Sharp & Dohme Corp., Merck & Co., Inc., Whitehouse Station, NJ, USA) in the treatment and prevention of recurrence of anogenital warts is not known. OBJECTIVE: The objective was to compare the efficacy of imiquimod and podophyllotoxin creams to treat anogenital warts and to assess whether or not the addition of quadrivalent human papillomavirus vaccine increases wart clearance or prevention of recurrence. DESIGN: A randomised, controlled, multicentre, partially blinded factorial trial. Participants were randomised equally to four groups, combining either topical treatment with quadrivalent human papillomavirus vaccine or placebo. Randomisation was stratified by gender, a history of previous warts and human immunodeficiency virus status. There was an accompanying economic evaluation, conducted from the provider perspective over the trial duration. SETTING: The setting was 22 sexual health clinics in England and Wales. PARTICIPANTS: Participants were patients with a first or repeat episode of anogenital warts who had not been treated in the previous 3 months and had not previously received quadrivalent human papillomavirus vaccine. INTERVENTIONS: Participants were randomised to 5% imiquimod cream (Aldara®; Meda Pharmaceuticals, Takeley, UK) for up to 16 weeks or 0.15% podophyllotoxin cream (Warticon®; GlaxoSmithKlein plc, Brentford, UK) for 4 weeks, which was extended to up to 16 weeks if warts persisted. Participants were simultaneously randomised to quadrivalent human papillomavirus vaccine (Gardasil) or saline control at 0, 8 and 24 weeks. Cryotherapy was permitted after week 4 at the discretion of the investigator. MAIN OUTCOME MEASURES: The main outcome measures were a combined primary outcome of wart clearance at week 16 and remaining wart free at week 48. Efficacy analysis was by logistic regression with multiple imputation for missing follow-up values; economic evaluation considered the costs per quality-adjusted life-year. RESULTS: A total of 503 participants were enrolled and attended at least one follow-up visit. The mean age was 31 years, 66% of participants were male (24% of males were men who have sex with men), 50% had a previous history of warts and 2% were living with human immunodeficiency virus. For the primary outcome, the adjusted odds ratio for imiquimod cream versus podophyllotoxin cream was 0.81 (95% confidence interval 0.54 to 1.23), and for quadrivalent human papillomavirus vaccine versus placebo, the adjusted odds ratio was 1.46 (95% confidence interval 0.97 to 2.20). For the components of the primary outcome, the adjusted odds ratio for wart free at week 16 for imiquimod versus podophyllotoxin was 0.77 (95% confidence interval 0.52 to 1.14) and for quadrivalent human papillomavirus vaccine versus placebo was 1.30 (95% confidence interval 0.89 to 1.91). The adjusted odds ratio for remaining wart free at 48 weeks (in those who were wart free at week 16) for imiquimod versus podophyllotoxin was 0.98 (95% confidence interval 0.54 to 1.78) and for quadrivalent human papillomavirus vaccine versus placebo was 1.39 (95% confidence interval 0.73 to 2.63). Podophyllotoxin plus quadrivalent human papillomavirus vaccine had inconclusive cost-effectiveness compared with podophyllotoxin alone. LIMITATIONS: Hepatitis A vaccine as control was replaced by a saline placebo in a non-identical syringe, administered by someone outside the research team, for logistical reasons. Sample size was reduced from 1000 to 500 because of slow recruitment and other delays. CONCLUSIONS: A benefit of the vaccine was not demonstrated in this trial. The odds of clearance at week 16 and remaining clear at week 48 were 46% higher with vaccine, and consistent effects were seen for both wart clearance and recurrence separately, but these differences were not statistically significant. Imiquimod and podophyllotoxin creams had similar efficacy for wart clearance, but with a wide confidence interval. The trial results do not support earlier evidence of a lower recurrence with use of imiquimod than with use of podophyllotoxin. Podophyllotoxin without quadrivalent human papillomavirus vaccine is the most cost-effective strategy at the current vaccine list price. A further larger trial is needed to definitively investigate the effect of the vaccine; studies of the immune response in vaccine recipients are needed to investigate the mechanism of action. TRIAL REGISTRATION: Current Controlled Trials. Current Controlled Trials ISRCTN32729817 and EudraCT 2013-002951-14. 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. 47. See the NIHR Journals Library website for further project information.

The HIPvac [Human papillomavirus infection: 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] trial compared two commonly used creams to treat genital warts: 0.15% podophyllotoxin cream (Warticon^®; GlaxoSmithKlein plc, Brentford, UK) and 5% imiquimod cream (Aldara^®; Meda Pharmaceuticals, Takeley, UK). It also investigated whether or not a vaccine used to prevent human papillomavirus infection, quadrivalent human papillomavirus vaccine (Gardasil^®, Merck Sharp & Dohme Corp., Merck & Co., Inc., Whitehouse Station, NJ, USA), could help treat warts or prevent them from coming back in patients whose warts had been cleared. The HIPvac trial was a randomised controlled trial involving 503 patients with warts attending sexual health clinics in England and Wales. The creams and the vaccine were well tolerated; there was some soreness where the cream was applied, but no unexpected side effects. When deciding which treatment was better, we looked at whether or not the warts had cleared by 16 weeks after starting treatment and, if cleared, whether or not they returned by 48 weeks. We compared the creams against each other, and the addition of vaccine against no vaccine (a placebo injection). Patients were allowed to have cryotherapy (freezing treatment) as well, if the investigator advised this. We also calculated the value for money of each type of treatment. The two creams were very similar in how well they worked to clear the warts. One difference was that podophyllotoxin cream worked slightly quicker. The number of patients given cryotherapy was about the same for both types of cream. We had expected that recurrence of warts after treatment with imiquimod cream might be less than after treatment with podophyllotoxin cream, but, in fact, the two creams were similar. Quadrivalent human papillomavirus vaccine did not improve clearance of warts or reduce the chance of recurrence, but the result remains inconclusive. If we had been able to recuit 1000 participants as originally planned, we might have been able to be more certain about whether there was any benefit of vaccination. Further research would be needed to investigate any possible effect. The two creams offered similar value for money in treating warts. Giving patients the vaccine in addition to the cream is not good value for money at its current list price, given the uncertainty about the benefit it offers.

Femtosecond laser-assisted cataract surgery compared with phacoemulsification cataract surgery: randomized noninferiority trial with 1-year outcomes.

PURPOSE: To report the 1-year outcomes of a randomized trial comparing femtosecond laser-assisted cataract surgery (FLACS) and phacoemulsification cataract surgery (PCS). SETTING: Moorfields Eye Hospital, New Cross Hospital, and Sussex Eye Hospital, United Kingdom. DESIGN: Multicenter, randomized controlled noninferiority trial. METHODS: Patients undergoing cataract surgery were randomized to FLACS or PCS. Postoperative assessments were masked. Outcomes included uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), complications, corneal endothelial cell count, and patient-reported outcomes measures. RESULTS: The study enrolled 785 participants. A total of 311 of 392 (79%) participants were allocated to FLACS and 292 of 393 (74%) participants were allocated to PCS attended follow-up at 1 year. Mean UDVA was 0.14 (SD = 0.22) for FLACS and 0.17 (0.25) for PCS with difference of -0.03 logarithm of the minimum angle of resolution (logMAR) (95%, -0.06 to 0.01, P = .17). Mean CDVA was 0.003 (0.18) for FLACS and 0.03 (0.23) for PCS with difference of -0.03 logMAR (95% CI, -0.06 to 0.01, P = .11); 75% of both FLACS (230/307) and PCS (218/290) cases were within ±0.5 diopters (D) refractive target, and 292 (95%) of 307 eyes of FLACS and 279 (96%) of 290 eyes of PCS groups were within ±1.0 D. There were no significant differences between arms for all other outcomes with the exception of binocular CDVA mean difference -0.02 (-0.05 to 0.002) logMAR (P = .036) favoring FLACS. Mean cost difference was £167.62 per patient greater for FLACS (95% iterations between -£14.12 and £341.67). CONCLUSIONS: PCS is not inferior to FLACS regarding vision, patient-reported health, and safety outcomes after 1-year follow-up. A difference was found for binocular CDVA, which, although statistically significant, was not clinically important. FLACS was not cost-effective.

Safety and efficacy of belimumab after B cell depletion therapy in systemic LUPUS erythematosus (BEAT-LUPUS) trial: statistical analysis plan.

BACKGROUND: There is limited evidence that rituximab, a B cell depletion therapy, is an effective treatment for systemic lupus erythematosus (SLE). Data on the mechanisms of B cell depletion in SLE indicate that the combination of rituximab and belimumab may be more effective than rituximab alone. The safety and efficacy of belimumab after B cell depletion therapy in systemic LUPUS erythematosus (BEAT-LUPUS) trial aims to determine whether belimumab is superior to placebo, when given 4-8 weeks after treatment with rituximab. This article describes the statistical analysis plan for this trial as an update to the published protocol. It is written prior to the end of patient follow-up, while the outcome of the trial is still unknown. DESIGN AND METHODS: BEAT-LUPUS is a randomised, double-blind, phase II trial of 52 weeks of belimumab versus placebo, initiated 4-8 weeks after rituximab treatment. The primary outcome is anti-dsDNA antibodies at 52 weeks post randomisation. Secondary outcomes include lupus flares and damage, adverse events, doses of concomitant medications, quality of life, and clinical biomarkers. We describe the trial's clinical context, outcome measures, sample size calculation, and statistical modelling strategy, and the supportive analyses planned to evaluate for mediation of the treatment effect through changes in concomitant medication doses and bias from missing data. DISCUSSION: The analysis will provide detailed information on the safety and effectiveness of belimumab. It will be implemented from July 2020 when patient follow-up and data collection is complete. TRIAL REGISTRATION: ISRCTN: 47873003 . Registered on 28 November 2016. EudracT: 2015-005543-14 . Registered on 19 November 2018.

Corneal cross-linking versus standard care in children with keratoconus - a randomised, multicentre, observer-masked trial of efficacy and safety (KERALINK): a statistical analysis plan.

BACKGROUND: The KERALINK trial tests the hypothesis that corneal cross-linking (CXL) treatment reduces the progression of keratoconus in comparison to standard care in patients aged 10-16 years. This article describes the statistical analysis plan for this trial as an update to the published protocol. It is written before the end of the patient follow-up, while the outcome of the trial is still unknown. DESIGN AND METHODS: KERALINK is a randomised controlled, observer-masked, multicentre trial in progressive keratoconus comparing epithelium-off CXL with standard care, including spectacles or contact lenses as necessary for best-corrected acuity. Keratoconus is a disorder of the shape of the cornea in which the normally round dome-shaped clear front window of the eye (cornea) thins progressively leading to a cone-like bulge. This impairs the ability of the eye to focus properly, causing reduced vision which requires spectacle or contact lens wear or, in a minority of patients, eventually corneal replacement by a transplant for best vision. The primary outcome measure is the between-group difference in K2 at 18 months adjusted for K2 at baseline examination. K2 is the value of the steepest corneal meridian as measured on Pentacam topography. Secondary outcomes are keratoconus progression, time to keratoconus progression, visual acuity, refraction, apical corneal thickness and adverse events. Patient-reported effects will be explored by questionnaires. We describe in detail the statistical aspects of KERALINK: the outcome measures, the sample size calculation, general analysis principles, the planned descriptive statistics and statistical models, and planned subgroup and sensitivity analyses. DISCUSSION: The KERALINK statistical analysis will provide comprehensive and precise information on the relative effectiveness of the two treatments. The plan will be implemented in May 2020 when follow-up for the trial is completed. TRIAL REGISTRATION: EudraCT, 2016-001460-11. Registered on 19 May 2016.

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.

A randomised, multi-centre trial of total ankle replacement versus ankle arthrodesis in the treatment of patients with end stage ankle osteoarthritis (TARVA): statistical analysis plan.

BACKGROUND: The total ankle replacement versus ankle arthrodesis (TARVA) trial aims to determine which surgical procedure confers the greatest improvement in pain-free function for patients with end-stage ankle osteoarthritis. Both procedures are effective but there has not yet been a direct comparison to establish which is superior. This article describes the statistical analysis plan for this trial as an update to the published protocol. It is written prior to the end of patient follow-up, while the outcome of the trial is still unknown. DESIGN AND METHODS: TARVA is a randomised, un-blinded, parallel group trial of total ankle replacement versus ankle arthrodesis. The primary outcome is the Manchester-Oxford Foot Questionnaire walking/standing domain score at 52 weeks post-surgery. Secondary outcomes include measures of pain, social interaction, physical function, quality of life, and range of motion. We describe in detail the statistical aspects of TARVA: the outcome measures, the sample size calculation, general analysis principles including treatment of missing data, the planned descriptive statistics and statistical models, and planned subgroup and sensitivity analyses. DISCUSSION: The TARVA statistical analysis will provide comprehensive and precise information on the relative effectiveness of the two treatments. The plan will be implemented in January 2020 when follow-up for the trial is completed. TRIAL REGISTRATION: ISRCTN registry number 60672307, ClinicalTrials.gov registration number NCT02128555. Registered 1 May 2014. Recruitment started in January 2015 and ended in January 2019.

Belimumab after B cell depletion therapy in patients with systemic lupus erythematosus (BEAT Lupus) protocol: a prospective multicentre, double-blind, randomised, placebo-controlled, 52-week phase II clinical trial.

INTRODUCTION: Few treatment options exist for patients with systemic lupus erythematosus (SLE) who fail conventional therapy. Although widely used to treat lupus, the efficacy of B cell depletion therapy using rituximab has not been demonstrated in randomised clinical trials. Following rituximab, elevated levels of serum B cell activating factor (BAFF) have been associated with failure to remit or subsequent lupus relapse. The administration of belimumab, a monoclonal antibody specific for BAFF and approved for lupus therapy, could potentiate the efficacy of rituximab and enable longer periods of disease remission. The aim of this trial is to assess the safety and efficacy of belimumab following rituximab in patients with SLE. METHODS AND ANALYSIS: BEAT Lupus is a double-blind, randomised, placebo controlled, phase II clinical trial. Patients with SLE commencing a treatment cycle of rituximab (two 1g infusions, 2 weeks apart) as standard of care will be randomised to receive belimumab or placebo, 4 to 8 weeks following the first rituximab infusion. Belimumab or placebo infusions are administered for 52 weeks. The primary outcome measure is anti-double stranded DNA (anti-dsDNA) antibody levels at 52 weeks. Secondary outcomes include measures of adverse events, lupus disease activity and cumulative steroid dose. The kinetics of B cell repopulation will be assessed in a subgroup of participants. Belimumab administration after rituximab may provide a novel therapeutic pathway for patients with active lupus if safety is demonstrated in this proof of concept study, and lower anti-dsDNA antibodies levels are achieved in those patients treated with belimumab compared with placebo. ETHICS AND DISSEMINATION: The protocol has been reviewed and approved by the Hampstead Research Ethics Committee - London (reference 16/LO/1024). Trial information is available at https://www.isrctn.com/ISRCTN47873003, and the results of this trial will be submitted for publication in relevant peer-reviewed journals. Key findings will also be presented at national and international conferences. TRIAL REGISTRATION NUMBER: ISRCTN47873; date assigned to the registry: 28 November 2016. The stage is pre-results.

A randomised, controlled, observer-masked trial of corneal cross-linking for progressive keratoconus in children: the KERALINK protocol.

INTRODUCTION: The KERALINK trial tests the hypothesis that corneal cross-linking (CXL) treatment reduces the progression of keratoconus in comparison to standard care in patients under 17 years old. KERALINK is a randomised controlled, observer-masked, multicentre trial in progressive keratoconus comparing epithelium-off CXL with standard care, including spectacles or contact lenses as necessary for best-corrected acuity. METHODS AND ANALYSIS: A total of 30 participants will be randomised per group. Eligible participants aged 10-16 years with progressive keratoconus in one or both eyes will be recruited. Following randomisation, participants will be followed up 3-monthly for 18 months. The effect on progression will be determined by K2 on corneal topography. The primary outcome measure is between-group difference in K2 at 18 months adjusted for K2 at baseline examination. Secondary outcomes are the effect of CXL on (1) keratoconus progression, (2) time to keratoconus progression, (3) visual acuity, (4) refraction, (5) apical corneal thickness and (6) adverse events. Patient-reported effects will be explored by questionnaires. ETHICS AND DISSEMINATION: Research Ethics Committee Approval was obtained on 30 June 2016 (ref: 14/LO/1937). Current protocol: V.5.0 (08/11/2017). Study findings will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: European Union clinial trials register (EudraCT) 2016-001460-11.