Weng Kit Lye

Novel joint selection methods can reduce sample size for rheumatoid arthritis clinical trials with ultrasound endpoints

To determine whether novel methods of selecting joints through (i) ultrasonography (individualized‐ultrasound [IUS] method), or (ii) ultrasonography and clinical examination (individualized‐composite‐ultrasound [ICUS] method) translate into smaller rheumatoid arthritis (RA) clinical trial sample sizes when compared to existing methods utilizing predetermined joint sites for ultrasonography.

Dichotomous versus semi-quantitative scoring of ultrasound joint inflammation in rheumatoid arthritis using novel individualized joint selection methods

The aim of the study is to compare the responsiveness of two joint inflammation scoring systems (dichotomous scoring (DS) versus semi-quantitative scoring (SQS)) using novel individualized ultrasound joint selection methods and existing ultrasound joint selection methods. Responsiveness measured by the standardized response means (SRMs) using the DS and the SQS system (for both the novel and existing ultrasound joint selection methods) was derived using the baseline and the 3-month total inflammatory scores from 20 rheumatoid arthritis patients. The relative SRM gain ratios (SRM-Gains) for both scoring system (DS and SQS) comparing the novel to the existing methods were computed. Both scoring systems (DS and SQS) demonstrated substantial SRM-Gains (ranged from 3.31 to 5.67 for the DS system and ranged from 1.82 to 3.26 for the SQS system). The SRMs using the novel methods ranged from 0.94 to 1.36 for the DS system and ranged from 0.89 to 1.11 for the SQS system. The SRMs using the existing methods ranged from 0.24 to 0.32 for the DS system and ranged from 0.34 to 0.49 for the SQS system. The DS system appears to achieve high responsiveness comparable to SQS for the novel individualized ultrasound joint selection methods.

Rationale and design of the East-West late lumen loss study: Comparison of late lumen loss between Eastern and Western drug-eluting stent study cohorts

BACKGROUNDnThe contemporary evaluation of novel drug-eluting stents (DES) includes mechanistic observations that characterize postdeployment stent behavior. Quantification of late lumen loss due to neointimal hyperplasia 8-13 months after stent implantation, via quantitative coronary angiography (QCA), constitutes such an observation and is required by most regulatory authorities. Late lumen loss, as determined by QCA, has been validated as a surrogate for clinical endpoints such as target vessel revascularization. The mechanistic response to DES has not been directly compared across predominantly Asian or Western populations, whereas understanding their comparability across geographic populations could enhance global DES evaluation.nnnOBJECTIVEnThe East-West late lumen loss study is designed to demonstrate whether the residual differences in late lumen loss, as assessed by QCA, is different between Eastern and Western DES recipients from studies with protocol angiography at 8-13 months of follow-up.nnnMETHODSnData from independent core laboratories that have characterized angiographic late lumen loss in DES clinical trials with protocol follow-up angiography will be compiled and dichotomized into Eastern and Western populations. A prospectively developed propensity score model incorporating clinical and anatomic variables affecting late lumen loss will be used to adjust comparisons of QCA measurements.nnnCONCLUSIONnDocumentation of whether there are clinically meaningful differences in mechanistic response to DES implantation across genetically unique geographies could facilitate both the quality and efficiency of global device evaluation requiring invasive follow-up for novel stent designs.

Greater rheumatoid arthritis joint improvement with more subjects achieving response across improvement categories using novel versus existing ultrasound methods

We compared the change in joint inflammation and the proportion of subjects achieving threshold levels of improvement using the existing methods employing ultrasonography on pre-determined joint sites versus novel methods. These novel methods select the most affected joints based on (i) ultrasonography—the Individualized-Ultrasound (IUS) method, or (ii) ultrasonography and clinical joint assessment—the individualized-Composite-Ultrasound (ICUS) method. Mean 3-month change in total inflammation score (ΔTIS) and 95% CI was computed for each method on 24 RA subjects initiated or escalated on treatment. Individual improvement in TIS per subject, calculated as the 3-month ΔTIS divided by the maximum possible TIS score expressed as a percentage, was used to obtain the proportion of subjects achieving response across improvement categories. Mean 3-month ΔTIS was significantly greater (p values ranging from 0.0003 to 0.0026) for novel versus existing methods using 12- and 7-joint approaches. Using 12-joint approach, percentages of subjects in improvement categories ≥5%, ≥10%, ≥15% and ≥20% were, respectively, 50, 37.5, 12.5 and 8.3% for IUS; 58.3, 37.5, 12.5 and 8.3% for ICUS; and 16.7, 0, 0 and 0% for the existing method. Using 7-joint approach, the respective category percentages were 62.5, 37.5, 25 and 12.5% for IUS; 62.5, 41.7, 16.7 and 8.3% for ICUS; and 12.5, 4.2, 4.2 and 0% for the existing method. Novel ultrasound methods are more likely to detect improvement in joint inflammation, with more subjects achieving response across improvement categories, thereby representing a substantial advantage over the existing methods. However, this requires confirmation in larger RA cohorts.

INCIDENCE OF LUNG CANCER AMONG SOLITARY PULMONARY NODULES INCIDENTALLY DETECTED ON CARDIAC COMPUTED TOMOGRAPHY ANGIOGRAM IN A MULTIETHNIC POPULATION: DO WE INCORPORATE FLEISCHNER GUIDELINES 2017 INTO LOCAL PRACTICE?

Incidental solitary pulmonary nodules (SPN) found on coronary computed tomography angiography (CCTA) are largely benign requiring no further evaluation, which would otherwise cause unnecessary healthcare cost and patient anxiety. The Fleischner guidelines 2017 for management of incidental SPN

The East–West late lumen loss study: Comparison of angiographic late lumen loss between Eastern and Western drug-eluting stent study cohorts

Background Regulatory decisions approving new coronary drug‐eluting stent (DES) require mechanistic observations of angiographic late lumen loss (LLL). Patient safety and device approval times could be enhanced if angiographic follow‐up data were found to be generalizable across jurisdictions and geographies. The objectives were to assess the comparability of in‐segment LLL in Eastern and Western DES populations using the worlds largest compilation of follow‐up quantitative coronary angiography data. Methods Data from 4 manufacturers involving 29 DES clinical trials in Eastern and Western hemispheres were compiled. “East” and “West” cohorts were defined by trial location. Independent core laboratories quantified in‐segment LLL for all studies. East and West were compared before and after adjustment for clinical and anatomic covariates known to correlate with LLL via conditioning on propensity score quintiles. An international panel of experts and regulators prospectively established a clinically meaningful difference between East and West mean in‐segment LLL of ±0.40 mm. Results The data set comprised 2,047 East and 4,456 West patients. Unadjusted mean ± SD for West and East in‐segment LLL (mm) was 0.25 ± 0.46 and 0.12 ± 0.42, respectively (difference 0.13 mm; 95% CI 0.11‐0.16). Propensity score–adjusted in‐segment LLL East and West least squares means were 0.11 and 0.26 mm, respectively (difference 0.15 mm; 95% CI 0.13‐0.18). Conclusions In the worlds largest compilation of DES protocol 8‐ to 13‐month angiographic follow‐up data, clinically meaningful comparability of in‐segment LLL by independent core laboratory quantitative coronary angiography in East and West cohorts was demonstrated in both unadjusted and adjusted comparisons. These findings suggest that DES LLL, once characterized, could be generalized across regulatory jurisdictions over the course of global registration efforts.

SAT0666 Sample size for RA clinical trials using ultrasound outcome measures may be reduced by novel joint selection methods: a pilot study

Background Novel outcome measures selecting a reduced joint count for ultrasonography can be highly responsive in demonstrating the improvement in joint inflammation seen in rheumatoid arthritis (RA) patients on treatment [1]. Objectives To determine whether the use of the novel methods can translate into smaller sample sizes for subject recruitment into RA clinical trials. Results from the existing methods are used for comparison. Methods 24 RA patients with treatment starts or escalation had clinical and ultrasound joint assessment at baseline and 3 months. The novel methods select joints based on (A) ultrasound joint findings (i.e. Individualized Ultrasound (IUS) method) or (B) a composite of ultrasound and clinical joint findings (i.e. Individualized Composite Ultrasound (ICUS) method). In contrast, the existing methods utilize pre-determined joint sites for ultrasonography. Scores at the relevant joints per patient are summed up to obtain the total inflammatory score (TIS). The effect size (ES) was measured as the mean change of the TIS divided by the standard deviation of the change in the TIS. Sample sizes were calculated from confidence intervals (CIs) on ES that reflect uncertainty in estimating ES. For a given CI on ES, sample sizes are computed as the minimum number of patients required to provide ≥80% power at α =0.05 for rejecting the null hypothesis (defined as no difference in the 3-month mean change in TIS comparing novel versus existing methods). Results Based on the 95% CI analysis, sample sizes using existing joint assessment methods in conjunction with the 12-joint approach ranged from 10 to 234. The corresponding sample sizes using the ICUS method with the 12-joint approach ranged from 7 to 39, and using the IUS method with the 12-joint approach ranged from 6 to 37. The corresponding sample sizes using the ICUS method with the 7-joint approach ranged from 6 to 24, and using the IUS method with the 7-joint approach ranged from 6 to 35.Table 1. Summary statistics for novel versus existing methods on 3-month change in scores Method/Approach Sample Estimates 95% CI Mean 3-month change in TIS SD of change in TIS Effect Size Post-hoc Sample Size Effect Size Sample Size ICUS/7-joint 0.61 0.54 1.13 9 0.61, 1.64 6, 24 ICUS/12-joint 0.87 0.91 0.96 11 0.46, 1.43 7, 39 IUS/7-joint 0.66 0.67 0.99 11 0.49, 1.47 6, 35 IUS/12-joint 0.91 0.94 0.97 11 0.47, 1.45 6, 37 Existing/7-joint 0.10 0.29 0.34 70 -0.07, 0.75 16, –1 Existing/12-joint 0.22 0.35 0.63 68 0.18, 1.06 10, 234 CI: Confidence Interval; SD: Standard Deviation. 1Interval contains zero which corresponds to the null hypothesis, so upper limit cannot be calculated. Conclusions Our findings strongly suggest that novel ultrasound joint selection methods result in smaller sample size requirements compared to existing methods, and provide justification for larger studies to confirm these observations. References Tan YK et al. Novel Ultrasound Joint Selection Methods Using a Reduced Joint Number Demonstrate Inflammatory Improvement when Compared to Existing Methods and Disease Activity Score at 28 Joints. J Rheumatol. 2016;43:34–7. Disclosure of Interest None declared

CORONARY ARTERY CALCIUM SCORE AMONGST OBSTRUCTIVE SLEEP APNEA PATIENTS

Obstructive sleep apnea (OSA) is increasingly common and is associated with coronary artery disease (CAD). Coronary CT enables quantification of coronary artery calcification score (CACS), which is a well-established index of atherosclerosis. We aim to determine the prevalence of CAD amongst OSA

AB0982 Dichotomous Scoring of Ra Ultrasound Inflammation Demonstrates Good Responsiveness Compared To Semi-Quantitative Scoring When Using Novel Joint Selection Methods: Table 1.

Background Novel joint selection methods using semi-quantitative scoring (SQS) of ultrasound (US) joint inflammation (power Doppler (PD) vascularity and grey-scale synovial hypertrophy (GSSH)) have shown good sensitivity to change versus existing methods and DAS28 in RA (1). However SQS may have more variability than dichotomous scoring (DS) as SQS requires grading across multiple categories. Objectives Compare responsiveness of DS of US joint inflammation versus SQS using 2 novel and 2 existing joint selection methods. Methods Novel methods were Individualized US [IUS], which selects up to 7 or 12 most inflamed joints on US and Individualized Composite-US [ICUS], which additionally considers joint symptoms. Existing methods were a pre-defined 7-joint count and a 12-joint count derived from an US data reduction method. PD vascularity and GSSH at the joints were scored via a DS system [USDSS] as Y/N or via a SQS system [USSQS] on a 0–3 severity scale. Both systems scored tenosynovitis (PD and GS changes), tender and swollen joints as Y/N. Joint pain was scored as Y/N (with USDSS) or using a 0–3 severity scale (with USSQS). Responsiveness at 3 months was measured using the standardized response mean (SRM). Relative gains in SRM magnitude (SRM-Gains) were reported comparing novel to existing methods. Results 20 RA subjects (mean DAS28 at baseline and 3-months =4.68 and 4.19, respectively) starting/escalating on DMARDs and corticosteroid therapy were followed for 3 months. SRMs using existing methods were modest for both USDSS and USSQS (ranged from 0.30 to 0.49). SRMs ranged from 0.94 to 1.06 using novel methods with both systems. There were substantial SRM-Gains (ranged from 1.94 to 3.47) for both systems using ICUS and IUS with the 7 or 12 joint approaches.Table 1. Results of USDSS and USSQS Approach 7-joint 12-joint USDSS USSQS USDSS USSQS ICUS# u2003Baseline TIS* 2.30 (0.79) 1.87 (0.82) 3.16 (1.18) 2.46 (1.11) u20033 month TIS 1.62 (0.71) 1.25 (0.68) 2.04 (0.94) 1.67 (0.87) u2003SRM (95% CI) 0.94 (0.40, 1.46) 1.05 (0.49, 1.59) 1.06 (0.50, 1.60) 0.96 (0.42, 1.48) u2003SRM-Gain 3.13 2.92 3.31 1.96 IUS† u2003Baseline TIS 2.83 (1.32) 1.81 (1.08) 3.59 (1.88) 2.24 (1.47) u20033 month TIS 1.89 (0.95) 1.22 (0.69) 2.44 (1.26) 1.49 (0.88) u2003SRM (95% CI) 1.04 (0.48, 1.58) 0.98 (0.43, 1.50) 1.02 (0.47, 1.55) 0.95 (0.41, 1.47) u2003SRM-Gain 3.47 2.72 3.19 1.94 Existing† u2003Baseline TIS 0.62 (0.39) 0.43 (0.29) 1.97 (1.12) 1.17 (0.76) u20033 month TIS 0.51 (0.39) 0.35 (0.28) 1.78 (1.07) 1.02 (0.67) u2003SRM (95% CI) 0.30 (−0.15, 0.75) 0.36 (−0.09, 0.81) 0.32 (−0.13, 0.77) 0.49 (0.02, 0.95) *TIS: Total inflammatory score reported as mean (SD). †TIS of IUS and existing methods = sum of individual joint scores (IJSs) derived from US subscores from relevant joints per patient. #TIS of ICUS = sum of IJSs derived from clinical and US subscores from relevant joints per patient. Conclusions Results of this small study suggest USDSS may be as responsive as USSQS (both had substantial SRM-Gains) using novel joint selection methods. References Tan YK et al. J Rheumatol. 2016;43(1):34–7 Acknowledgement NCS grant and Estate of Tan Sri Khoo Teck Puat for funding support and the NUS Disclosure of Interest None declared