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 domeshaped 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 201

Ophthalmic statistics note 8: missing data - exploring the unknown

Medical research is conducted to answer uncertainties and to identify effective treatments for patients. Different questions are best addressed by different types of study design—but the randomised, controlled clinical trial is typically viewed as the gold standard, providing a very high level of evidence, when examining efficacy. While clinical trial methodology has advanced considerably with clear guidance provided as to how to avoid sources of bias, even the most robustly designed study can succumb to missing data. In this statistics note, we discuss strategies for dealing with missing data but what we hope emerges is a very clear message that there is no ideal solution to missing data and prevention is the best strategy

Rivaroxaban in antiphospholipid syndrome (RAPS) protocol: a prospective, randomized controlled phase II/III clinical trial of rivaroxaban versus warfarin in patients with thrombotic antiphospholipid syndrome, with or without SLE

Introduction: The current mainstay of the treatment of thrombotic antiphospholipid syndrome (APS) is long-term anticoagulation with vitamin K antagonists (VKAs) such as warfarin. Non-VKA oral anticoagulants (NOACs), which include rivaroxaban, have been shown to be effective and safe compared with warfarin for the treatment of venous thromboembolism (VTE) in major phase III prospective, randomized controlled trials (RCTs), but the results may not be directly generalizable to patients with APS. Aims: The primary aim is to demonstrate, in patients with APS and previous VTE, with or without systemic lupus erythematosus (SLE), that the intensity of anticoagulation achieved with rivaroxaban is not inferior to that of warfarin. Secondary aims are to compare rates of recurrent thrombosis, bleeding and the quality of life in patients on rivaroxaban with those on warfarin. Methods: Rivaroxaban in antiphospholipid syndrome (RAPS) is a phase II/III prospective non-inferiority RCT in which eligible patients with APS, with or without SLE, who are on warfarin, target international normalized ratio (INR) 2.5 for previous VTE, will be randomized either to continue warfarin (standard of care) or to switch to rivaroxaban. Intensity of anticoagulation will be assessed using thrombin generation (TG) testing, with the primary outcome the percentage change in endogenous thrombin potential (ETP) from randomization to day 42. Other TG parameters, markers of in vivo coagulation activation, prothrombin fragment 1.2, thrombin antithrombin complex and D-dimer, will also be assessed. Discussion: If RAPS demonstrates i) that the anticoagulant effect of rivaroxaban is not inferior to that of warfarin and ii) the absence of any adverse effects that cause concern with regard to the use of rivaroxaban, this would provide sufficient supporting evidence to make rivaroxaban a standard of care for the treatment of APS patients with previous VTE, requiring a target INR of 2.5

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)

Risk factors for visual field deterioration in the United Kingdom Glaucoma Treatment Study

OBJECTIVE: 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, multicentre trial. PARTICIPANTS: Five hundred sixteen participants with previously untreated OAG were prospectively recruited in 10 UK centres. 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) whilst accounting for the correlation within sites. Model selection was guided by backwards stepwise selection conducted on the model containing all variables which were significant at the 0.2 level in the univariable analysis. Follow-up variables which showed collinearity with baseline values were not retained in the final model. MAIN OUTCOME MEASURES: 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 versus 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 haemorrhage 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 haemorrhage were confirmed as risk factors for deterioration; smoking history appeared to be protective against VF deterioration