Surrogate Endpoints In Clinical Trials Research Articles

Longitudinal change of small-vessel disease-related brain abnormalities

Knowledge about the longitudinal change of cerebral small-vessel disease–related magnetic resonance imaging abnormalities increases our pathophysiologic understanding of cerebral microangiopathy. The change of specific lesion types may also serve as secondary surrogate endpoint in clinical trials. A surrogate endpoint needs to progress fast enough to allow monitoring of treatment effects within a reasonable time period, and change of the brain abnormality needs to be correlated with clinical change. Confluent white matter lesions show fast progression and correlations with cognitive decline. Thus, the change of confluent white matter lesions may be used as a surrogate marker in proof-of-concept trials with small patient numbers needed to show treatment effects on lesion progression. Nonetheless if the expected change in cognitive performance resulting from treatment effects on lesion progression is used as outcome, the sample size needed to show small to moderate treatment effects becomes very large. Lacunes may also fulfill the prerequisites of a surrogate marker, but in the general population the incidence of lacunes over short observational periods is small. For other small-vessel disease–related brain abnormalities including microbleeds and microstructural changes in normal-appearing white matter longitudinal change and correlations with clinical decline is not yet fully determined.

Pharmacodynamic Modeling of Bacillary Elimination Rates and Detection of Bacterial Lipid Bodies in Sputum to Predict and Understand Outcomes in Treatment of Pulmonary Tuberculosis.

Antibiotic-tolerant bacterial persistence prevents treatment shortening in drug-susceptible tuberculosis, and accumulation of intracellular lipid bodies has been proposed to identify a persister phenotype of Mycobacterium tuberculosis cells. In Malawi, we modeled bacillary elimination rates (BERs) from sputum cultures and calculated the percentage of lipid body-positive acid-fast bacilli (%LB + AFB) on sputum smears. We assessed whether these putative measurements of persistence predict unfavorable outcomes (treatment failure/relapse). Adults with pulmonary tuberculosis received standard 6-month therapy. Sputum samples were collected during the first 8 weeks for serial sputum colony counting (SSCC) on agar and time-to positivity (TTP) measurement in mycobacterial growth indicator tubes. BERs were extracted from nonlinear and linear mixed-effects models, respectively, fitted to these datasets. The %LB + AFB counts were assessed by fluorescence microscopy. Patients were followed until 1 year posttreatment. Individual BERs and %LB + AFB counts were related to final outcomes. One hundred and thirty-three patients (56% HIV coinfected) participated, and 15 unfavorable outcomes were reported. These were inversely associated with faster sterilization phase bacillary elimination from the SSCC model (odds ratio [OR], 0.39; 95% confidence interval [CI], .22-.70) and a faster BER from the TTP model (OR, 0.71; 95% CI, .55-.94). Higher %LB + AFB counts on day 21-28 were recorded in patients who suffered unfavorable final outcomes compared with those who achieved stable cure (P = .008). Modeling BERs predicts final outcome, and high %LB + AFB counts 3-4 weeks into therapy may identify a persister bacterial phenotype. These methods deserve further evaluation as surrogate endpoints for clinical trials.

Rheumatoid arthritis affects left ventricular mass: Systematic review and meta-analysis

BackgroundCardiovascular disease represents one of the most important extra-articular causes of morbidity and mortality in patients with rheumatoid arthritis (RA). Evidences showed that several cardiac structures can be affected during the course of the disease as well as abnormalities of left ventricular diastolic filling. Contrasting data are available about left ventricular mass (LVM) involvement in patients asymptomatic for cardiovascular disease.The purpose of this systematic review and meta-analysis is to summarize the effects of RA on LVM in rheumatoid arthritis patients without cardiovascular disease. MethodsA systematic research of the current case–control studies was conducted in Medline on November 20th, 2013. Studies were included if data of measurements of LVM were reported. The pooled mean effect size estimate was calculated according to methods described by Hedges and Olkin. ResultsSixteen eligible studies were included in this meta-analysis. RA determines an increase of absolute and indexed LVM compared with control patients [standardized mean difference (95% CI): 0.41(0.15–0.66) and 0.47(0.32–0.62), respectively]. On the contrary, posterior wall thickness did not show a significant RA effect. Finally, a significant positive effect of RA on interventricular wall thickness was found [standardized mean difference (95% CI): 0.39 (0.07–0.71)]. ConclusionsResults of this meta-analysis suggest that increased absolute and indexed LVM seem to be characteristic of RA patients with a fundamental clinical significance since they are related to an increased risk of cardiovascular morbidity and mortality. Our data suggest the use of LVM as surrogate end-point for clinical trials involving RA patients.

Technical Advances and Clinical Applications of Quantitative Myocardial Blood Flow Imaging With Cardiac MRI

The recent FAME 2 study highlights the importance of myocardial ischemia assessment, particularly in the post-COURAGE trial era of managing patients with stable coronary artery disease. Qualitative assessment of myocardial ischemia by stress cardiovascular magnetic resonance imaging (CMR) has gained widespread clinical acceptance and utility. Despite the high diagnostic and prognostic performance of qualitative stress CMR, the ability to quantitatively assess myocardial perfusion reserve and absolute myocardial blood flow remains an important and ambitious goal for non-invasive imagers. Quantitative perfusion by stress CMR remains a research technique that has yielded progressively more encouraging results in more recent years. The ability to safely, rapidly, and precisely procure quantitative myocardial perfusion data would provide clinicians with a powerful tool that may substantially alter clinical practice and improve downstream patient outcomes and the cost effectiveness of healthcare delivery. This may also provide a surrogate endpoint for clinical trials, reducing study population sizes and costs through increased power. This review will cover emerging quantitative CMR techniques for myocardial perfusion assessment by CMR, including novel methods, such as 3-dimensional quantitative myocardial perfusion, and some of the challenges that remain before more widespread clinical adoption of these techniques may take place.

7. Neurophysiology in diagnosis and prognosis of multiple sclerosis in age of magnetic resonance imaging

Objective The advent of magnetic resonance imaging techniques has greatly reduced the diagnostic value of neurophysiological tests in MS, particularly evoked potentials. In disease progression, most of MS patients accumulate inflammatory lesions, axonal damage, and progressive brain atrophy, along with an increasing degree of disability. More promising is the utilization of neurophysiological tests to quantify the severity of white matter involvement. Methods Evoked potentials (EP) have been still used in multiple sclerosis (MS) especially in its early diagnosis. Recently, multimodal EPs appears to be a prognostic factor for disease progression ( Schlaeger et al., 2012 , Invernizzi et al., 2011 , Schlaeger et al., 2012 ). Deeper insights about causal and functional relationships in plasticity of the motor system in patients with MS were gained by neurophysiological techniques, predominantly by transcranial magnetic stimulation. Results Visual evoked potential (VEP) are preferentially used in early diagnosis of MS for detection of subclinical optic neuritis. Somatosensory (SEP) and motor (MEP) evoked potentials reveal subclinical lesions in the CNS and could be a supplementary diagnostic tests for sensory and motor system disturbances. MEP abnormalities correlate with the degree of motor impairment and disability. A number of functional imaging studies have assessed patterns of brain activation during simple motor tasks in MS patients and their relationship with CNS damage and motor function. Conclusion Evoked potentials are functional neurophysiological methods highly sensitive in revealing ,,silent lesions“ especially at the beginning of MS. Multimodal evoked potentials have indisputable benefit of prognostic value to determine non-responders, ,,benign“ course of the disease and identification of patients with significant disease progression. A battery of neurophysiological tests could be useful in monitoring the disease progression in individual patient and as surrogate endpoints in clinical trials. Supported by Research Project of Charles University PRVOUK P34, Czech Republic.

Predictive Value of MRI for Clinical Outcomes

The meeting outlined the evidence that the use of magnetic resonance imaging (MRI) markers as surrogate endpoints in clinical trials of relapsing-remitting multiple sclerosis (MS) is both valid and informative. The mechanisms of action of teriflunomide (Aubagio®) and alemtuzumab (Lemtrada®), both treatments for relapsing-remitting MS, were discussed, and their Phase II and III safety and efficacy data were reviewed alongside the MRI-derived outcome measures.

Downstage migration after neoadjuvant chemoradiotherapy for rectal cancer: the reverse of the Will Rogers phenomenon?

Downstaging after neoadjuvant treatment is increasingly used as a prognostic factor and surrogate endpoint in clinical trials. However, in recent trials of neoadjuvant 5-fluorouracil-based chemoradiotherapy for rectal cancer, downstaging did not translate into a benefit with regard to either disease-free survival (DFS) or overall survival. By analyzing the 10-year outcome data of the German CAO/ARO/AIO-94 phase 3 trial, the authors demonstrated that significantly fewer patients had poor prognostic features (eg, ypT3-4, ypN1-2) after preoperative 5-fluorouracil-based chemoradiotherapy. Nevertheless, these patients with International Union for Cancer Control stage II disease were found to be at a higher risk of developing distant metastases and had poorer DFS compared with patients with corresponding TNM tumor (sub)groups in the postoperative treatment arm, whereas patients with International Union for Cancer Control stage III disease demonstrated a nonsignificant trend toward a worse outcome after preoperative treatment. Overall, DFS remained identical in both treatment arms. Thus, "downstage migration" after neoadjuvant treatment resembles the reverse of the Will Rogers phenomenon and therefore may not be a reliable endpoint for long-term outcomes.

Minimal Residual Disease (MRD) in Myeloma: Independent Outcome Prediction and Sequential Survival Benefits per Log Tumour Reduction

▪Minimal residual disease (MRD), as assessed by flow cytometry is a powerful predictor of outcome in multiple myeloma (MM). We and others have previously demonstrated that such analyses are informative in patients treated with autologous stem cell transplant (ASCT) and non-transplant regimens. It predicts outcome in patients in conventional CR and is applicable to patients with standard and adverse risk cytogenetics. As a consequence MRD assessment is under consideration as a surrogate endpoint for clinical trials. This is urgently needed in MM as >5yrs follow-up is typically required to demonstrate survival differences in trials of upfront therapy. If surrogate end points are to be used in clinical trials it is essential that a reproducible effect is demonstrable using multivariate models. Previous studies have confirmed the effect of MRD on PFS but a consistent effect on OS has been not been definitively shown. This may in part be due to the availability of effective salvage therapy but it is also possible that the traditional threshold of 10-4 for analysis and the categorization of patients as MRD-postive or negative is suboptimal. Flow cytometry does provide a quantitative assessment of residual tumour over a large range and the degree of tumour depletion may be more informative than a positive-negative analysis.397 patients from the MRC Myeloma IX trial were included in this analysis. Patients were randomly assigned to CTD (cyclophosphamide, thalidomide, and dexamethasone) or CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) induction for 4-6 cycles followed by standard high-dose melphalan (HDM) ASCT. BM aspirates were obtained at day 100 for MRD analysis. 500,000 cells were evaluated with six-colour antibody combinations including CD138/CD38/CD45/CD19 with CD56/CD27 in all cases and CD81/CD117 in additional cases as required. PFS and OS data analysis was landmarked from the date of the MRD assesment.Of the 397 patients with MRD data available at day 100 after ASCT, 247/397 (62.2%) achieved <0.01% MRD. The level of residual disease varied across four logs in MRD-positive patients (0.01-<0.1% in 49/397, 0.1-<1% in 72/397, 1-<10% in 26/397 and ≥10% in 3/397). The PFS and OS for individuals with ≥1% residual disease was comparable to individuals with a PR/MR/SD confirming that MRD assessment is most relevant in CR. The level of MRD correlated with outcome. The median PFS for patients with ≥10% MRD at day 100 after ASCT was 0.8 years, with 1-<10% MRD was 1.7 years, with 0.1-<1% MRD was 1.9 years, with 0.01-<0.1% MRD was 2.7 years and for patients with <0.01% MRD was 3.1 years (P<0.001). The median OS for these groups was 1 yr, 4 yrs, 5.9 yrs, 6.8 yrs and for patients with <0.01% MRD not reached with >7.5 yrs median follow-up (P<0.001, see figure).A Cox proportional hazards model was used to further evaluate factors influencing outcome. B2M and MRD were log-transformed and along with age were considered as continuous variables. ISS, haemoglobin (<115g/l), platelets (<150x10^9/l) and cytogenetics were used as stratification factors. Cytogenetic groups were classified as unfavourable for patients with gain(1q), del(1p32), t(4;14), t(14;20), t(14;16), and del(17p), or favourable for hyperdiploidy, t(11;14) and t(6;14), or unknown/inevaluable. MRD assessment (χ2 11.8, P=0.0006) and cytogenetics (χ2 35.5, P=<0.0001) were the only factors that retained significance in this multivariate model. Conventional categorical response, ISS and B2M were not predictive of OS (p=0.99, 0.16 and 0.56 respectively).We would conclude that MRD quantitation is more informative than a positive or negative categorization with a 10-4 threshold and independently predicts outcome. In this analysis we were able to demonstrate an approximate 1 year survival benefit per log tumour depletion. A lower cutpoint for predicting improved outcome was not reached and more sensitive assays will likely improve outcome prediction further. This data strongly supports the role of MRD assessment as a surrogate endpoint in clinical trials. [Display omitted] DisclosuresRawstron:Celgene: Consultancy; BD Biosciences: Consultancy, Intrasure Patents & Royalties. Gregory:Celgene: Consultancy. Davies:Celgene: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Novartis: Consultancy. Cook:Celgene: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria. Jackson:Celgene: Honoraria; Janssen-Cilag: Honoraria. Morgan:Celgene: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Owen:Celgene: Consultancy, Honoraria, Research Funding.

The use of FDG-PET in diffuse large B cell lymphoma (DLBCL): predicting outcome following first line therapy

Positron emission tomography (PET) using 18fluoro-2-deoxyglucose (FDG) has become a standard clinical tool for staging and response assessment in aggressive lymphomas. The use of PET scans in clinical trials is still under exploration, however. In this review, we examine current data regarding PET in DLBCL, and its potential applicability to development of a surrogate endpoint to expedite clinical trial conduct. Interim PET scanning in DLBCL shows mixed results, with qualitative assessment variably associated with outcome. Addition of quantitative assessment might improve predictive power of interim scans. Data from multiple retrospective studies support that PET-defined response at end of treatment correlates with outcome in DLBCL. Optimal technical criteria for standardization of acquisition and criteria for interpretation of scans require further study. Prospective studies to define the correlation of PET-defined response and time-dependent outcomes such as progression free survival (PFS) and overall survival (OS), critical for development of PET as a surrogate endpoint for clinical trials, are ongoing. In conclusion, evolving data regarding utility of PET in predictcing outcome of patients with DLBCL show promise to support the use of PET as a surrogate endpoint in clinical trials of DLBCL in the future.

Intima media thickness, pulse wave velocity, and flow mediated dilation.

The identification of vascular alterations at the sub-clinical, asymptomatic stages are potentially useful for screening, prevention and improvement of cardiovascular risk stratification beyond classical risk factors.Increased intima-media thickness of the common carotid artery is a well-known marker of early atherosclerosis, which significantly correlates with the development of cardiovascular diseases. More recently, other vascular parameters evaluating both structural and functional arterial proprieties of peripheral arteries have been introduced, for cardiovascular risk stratification and as surrogate endpoints in clinical trials. Increased arterial stiffness, which can be detected by applanation tonometry as carotid-femoral pulse wave velocity, has been shown to predict future cardiovascular events and to significantly improve risk stratification.Finally, earlier vascular abnormalities such as endothelial dysfunction in the peripheral arteries, detected as reduced flow-mediated dilation of the brachial artery, are useful in the research setting and as surrogate endpoints in clinical trials and have also been suggested for their possible clinical use in the future.This manuscript will briefly review clinical evidence supporting the use of these different vascular markers for cardiovascular risk stratification, focusing on the correct methodology, which is a crucial issue to address in order to promote their use in future for routine clinical practice.

Simplifying electronic data capture in clinical trials: workflow embedded image and biosignal file integration and analysis via web services.

To improve data quality and save cost, clinical trials are nowadays performed using electronic data capture systems (EDCS) providing electronic case report forms (eCRF) instead of paper-based CRFs. However, such EDCS are insufficiently integrated into the medical workflow and lack in interfacing with other study-related systems. In addition, most EDCS are unable to handle image and biosignal data, although electrocardiography (EGC, as example for one-dimensional (1D) data), ultrasound (2D data), or magnetic resonance imaging (3D data) have been established as surrogate endpoints in clinical trials. In this paper, an integrated workflow based on OpenClinica, one of the world's largest EDCS, is presented. Our approach consists of three components for (i) sharing of study metadata, (ii) integration of large volume data into eCRFs, and (iii) automatic image and biosignal analysis. In all components, metadata is transferred between systems using web services and JavaScript, and binary large objects (BLOBs) are sent via the secure file transfer protocol and hypertext transfer protocol. We applied the close-looped workflow in a multicenter study, where long term (7days/24h) Holter ECG monitoring is acquired on subjects with diabetes. Study metadata is automatically transferred into OpenClinica, the 4GB BLOBs are seamlessly integrated into the eCRF, automatically processed, and the results of signal analysis are written back into the eCRF immediately.

Biomarkers in Connective Tissue Disease-Associated Interstitial Lung Disease

This article reviews major biomarkers in serum and bronchoalveolar lavage fluid (BALF) with respect to their diagnostic and prognostic value in connective tissue disease-associated interstitial lung disease (CTD-ILD). In some CTD such as systemic sclerosis (SSc), the incidence of ILD is up to two-third of patients, and currently ILD represents the leading cause of death in SSc. Because of the extremely variable incidence and outcome of ILD in CTD, progress in the discovery and validation of biomarkers for diagnosis, prognosis, patients' subtyping, response to treatment, or as surrogate endpoints in clinical trials is extremely important. In contrast to idiopathic interstitial pneumonias, autoantibodies play a crucial role as biomarkers in CTD-ILD because their presence is strictly linked to the pathogenesis and tissue damage. Patterns of autoantibodies, for instance, anticitrullinated peptide antibodies in rheumatoid arthritis or aminoacyl-tRNA synthetases (ARS) in polymyositis/dermatomyositis, have been found to correlate with the presence and occasionally with the course of ILD in CTD. Besides autoantibodies, an increase in serum or BALF of a biomarker of pulmonary origin may be able to predict or reflect the development of fibrosis, the impairment of lung function, and ideally also the prognosis. Promising biomarkers are lung epithelium-derived proteins such as KL-6 (Krebs von den Lungen-6), SP-D (surfactant protein-D), SP-A (surfactant protein-A), YKL-40 (chitinase-3-like protein 1 [CHI3L1] or cytokines such as CCL18 [chemokine (C-C) motif ligand 18]). In the future, genetic/epigenetic markers, such as human leukocyte antigen (HLA) haplotypes, single nucleotide polymorphisms, and micro-RNA, may help to identify subtypes of patients with different needs of management and treatment strategies.

Abstract MP30: Chronic Kidney Disease Progression and Risk of End-Stage Renal Disease: The Use of Change in Novel Kidney Filtration Markers

Introduction: Chronic kidney disease (CKD) progression assessed by estimated GFR from creatinine (eGFR-Cr) is a risk factor for cardiovascular disease and end-stage renal disease (ESRD) and has been proposed as a surrogate endpoint for clinical trials. It is unclear if CKD progression assessed by change in different filtration markers has similar risk associations with ESRD. Hypothesis: We hypothesized that percent change in novel kidney filtration markers (β 2 -microglobulin and cystatin C) over a 6-year period would be independently associated with increased risk of ESRD during 15 years of follow-up, similar to the risk seen with change in eGFR-Cr. Methods: We conducted prospective analyses of the ARIC study (N=9,703). β 2 -microglobulin, cystatin C, and creatinine were measured at study visits 1 (1990-92) and 2 (1996-98). Incident ESRD (kidney dialysis or transplant) was defined as entry into the U.S. Renal Data System registry between study visit 2 and September 30, 2011. Cox proportional hazards regression was used to estimate the association between percent change in filtration marker and incident ESRD, adjusting for demographics, kidney disease risk factors, and 1 st measurement of the filtration marker. Results: During a median follow-up of 13.1 years, there were 142 incident ESRD cases. Median eGFR-Cr was 97.3 mL/min/1.73 m 2 at 1 st measurement and 89.0 mL/min/1.73 m 2 at 2 nd measurement. Percent change in eGFR-Cr was moderately correlated with percent change in the inverse of β 2 -microglobulin (r = 0.34) and the inverse of cystatin C (r = 0.36). Progression of CKD (10-25% and &gt;25% decline in filtration function) was associated with increased ESRD risk, with novel markers (β 2 -microglobulin, cystatin C) showing an association at least as strong as the creatinine and eGFR-Cr estimates (Table). Conclusions: CKD progression assessed using novel filtration markers is independently associated with ESRD risk, suggesting the potential utility of measuring change in β 2 -microglobulin and cystatin C in clinical trials.

Health economic evaluation of treatments for Alzheimer′s disease: impact of new diagnostic criteria

The socio-economic impact of Alzheimer's disease (AD) and other dementias is enormous, and the potential economic challenges ahead are clear given the projected future numbers of individuals with these conditions. Because of the high prevalence and cost of dementia, it is very important to assess any intervention from a cost-effectiveness viewpoint. The diagnostic criteria for preclinical AD suggested by the National Institute on Aging and Alzheimer's Association workgroups in combination with the goal of effective disease-modifying treatment (DMT) are, however, a challenge for clinical practice and for the design of clinical trials. Key issues for future cost-effectiveness studies include the following: (i) the consequences for patients if diagnosis is shifted from AD-dementia to predementia states, (ii) bridging the gap between clinical trial populations and patients treated in clinical practice, (iii) translation of clinical trial end-points into measures that are meaningful to patients and policymakers/payers and (iv) how to measure long-term effects. To improve cost-effectiveness studies, long-term population-based data on disease progression, costs and outcomes in clinical practice are needed not only in dementia but also in predementia states. Reliable surrogate end-points in clinical trials that are sensitive to detect effects even in predementia states are also essential as well as robust and validated modelling methods from predementia states that also take into account comorbidities and age. Finally, the ethical consequences of early diagnosis should be considered.

Past and present definitions of epileptogenesis and its biomarkers.

Descriptions of epileptic seizures and epilepsy date back to antiquity, and research into fundamental mechanisms of epilepsy in animal models, as well as patients, has been carried out for over a century. Studies of epileptogenesis, however, as distinct from ictogenesis, have been pursued for only a few decades, and antiepileptogenesis, the prevention of epilepsy or its progression, and the reversal of the epileptogenic process or cure, are relatively recent interests of the basic research community. The goal to develop antiepileptogenic interventions would be greatly facilitated by the identification of reliable biomarkers of epileptogenesis that could be used to create cost-effective, high-throughput screening models for potential antiepileptogenic compounds, as well as enrich patient populations and serve as surrogate endpoints for clinical trials. Without such biomarkers, the cost for clinical validation of antiepileptogenic interventions would be prohibitive. Epileptogenic mechanisms, antiepileptogenic interventions, and biomarkers are likely to be specific for the many different causes of epilepsy, which include genetic influences, cell loss and synaptic plasticity, malformations of cortical development, and autoimmune disorders, to name but a few. A high priority is currently being placed on investigations to elucidate fundamental mechanisms of epileptogenesis and identify biomarkers for specific models of human epilepsy, such as mesial temporal lobe epilepsy with hippocampal sclerosis, traumatic brain injury, and a variety of pediatric diseases, including tuberous sclerosis and West syndrome.

CMRSegTools: an Osirix plugin for myocardial infarct sizing on DE-CMR images

Background CMR is an established method for the diagnosis and assessment of myocardial infarction in routine exams. In addition, there has been a growing interest in using infarct size as a surrogate endpoint for clinical trials assessing the efficacy of acute MI reperfusion treatments and MI size is reported to be a stronger predictor of outcome than LVEF and LV volumes[1].Various methods have been proposed for infarct size (IS) measurement without reference standard method and side-by-side comparison among them. The goal was to develop a user-friendly cardiac segmentation toolbox implemented as a plugin in the open-source OsiriX software with a set a commonly proposed semi-automatic algorithms

Surrogacy assessment using principal stratification when surrogate and outcome measures are multivariate normal

In clinical trials, a surrogate outcome variable (S) can be measured before the outcome of interest (T) and may provide early information regarding the treatment (Z) effect on T. Using the principal surrogacy framework introduced by Frangakis and Rubin (2002. Principal stratification in causal inference. Biometrics 58, 21-29), we consider an approach that has a causal interpretation and develop a Bayesian estimation strategy for surrogate validation when the joint distribution of potential surrogate and outcome measures is multivariate normal. From the joint conditional distribution of the potential outcomes of T, given the potential outcomes of S, we propose surrogacy validation measures from this model. As the model is not fully identifiable from the data, we propose some reasonable prior distributions and assumptions that can be placed on weakly identified parameters to aid in estimation. We explore the relationship between our surrogacy measures and the surrogacy measures proposed by Prentice (1989. Surrogate endpoints in clinical trials: definition and operational criteria. Statistics in Medicine 8, 431-440). The method is applied to data from a macular degeneration study and an ovarian cancer study.

Circulating tumor cells as a prognostic marker in metastatic non-small-cell lung cancer patients receiving chemotherapy.

11041 Background: Radiographic response remains the gold standard for assessment of the chemotherapy effect and has been used as a surrogate endpoint in clinical trials. Recently, circulating tumor cells (CTC) have emerged as a novel prognostic marker in many types of cancer; however, their significance has not been fully examined in patients with non-small-cell lung cancer (NSCLC). Methods: We conducted a prospective study to evaluate the clinical significance of CTC in metastatic NSCLC patients treated with chemotherapy. Peripheral blood samples were collected for CTC analysis before chemotherapy, after 1 cycle of chemotherapy, and after 2 cycles of chemotherapy. CTC analysis was performed using CellSearch (Veridex). Results: One hundred and forty-eight patients wereenrolledbetween August 2009 and January 2012, and 121 patients were eligible for the analysis. CTC was positive (CTC ≥1) in 30.6% (37/121) before chemotherapy, in 21.0% (26/118) after 1 cycle of chemotherapy, and in 21.6% (24/111) after 2 cycles of chemotherapy, respectively. CTC counts were higher in patients with N3 lymph node metastases (vs. N0-2, p = 0.0001), M1b status (vs. M1a, p = 0.0081) or ≥2 metastasis sites (vs. 1 metastasis site, p = 0.0342). Although not statistically significant, a positive trend was observed between the radiographic response and the dynamic change of CTC counts (p = 0.0734). In multivariate analysis, including the radiographic response (responder vs. non-responder), baseline CTC was a significant negative predictive factor for PFS (HR = 1.867; p = 0.0080) and OS (HR = 2.753; p = 0.0006). Considering pre- and post-treatment time points (before and after 2 cycles of chemotherapy) together, CTC-positive patients at either time point experienced significantly worse PFS (HR = 1.747; p = 0.0143) and OS (HR = 2.031; p = 0.0123) than those who were CTC negative at both time points. Conclusions: CTC was an independent prognostic factor in patients with metastatic NSCLC who was treated with chemotherapy.

Carotid Intima-Media Thickness Testing as an Asymptomatic Cardiovascular Disease Identifier and Method for Making Therapeutic Decisions

Cardiovascular disease (CVD) is the leading cause of death and disability in the United States. Although current therapies can reduce the risk for CVD, they are only given to patients who are considered to be at risk, and are therefore only beneficial if a patient's risk is accurately predicted before he or she sustains a cardiovascular (CV) event. Unfortunately, even relatively accurate risk factor analyses, such as the Reynolds Risk Score algorithm, fail to identify some patients who will sustain a CV event within 10 years. In contrast, the presence of an atheroma is an absolute predictor for the potential of an atherothrombotic event to occur, and it is therefore reasonable to anchor clinical decisions based on this knowledge. Carotid intima-media thickness (CIMT) testing via B-mode ultrasound is a safe, simple, and inexpensive method for evaluating CV risk by measuring the combined thickness of the intimal and medial layers of the arterial wall. Use of CIMT testing can also detect marked thickening of the arterial wall, possibly indicating plaques or atheromas that are associated with accelerated atherosclerotic disease and increased risk for coronary artery disease, myocardial infarction, and stroke. These characteristics make CIMT a practical supplemental method that physicians can use when making decisions. Moreover, the ability of CIMT testing to identify and quantify atherosclerotic disease has led to the adoption of CIMT as a surrogate endpoint in clinical trials, allowing the efficacy of new drugs to be assessed much more rapidly than would be possible by focusing solely on CV event or mortality rates. To date, several trials have provided evidence to indicate that some CVD therapies slow, stop, or reverse the progression of CIMT. Although many of these studies show that changes in CIMT predict future CV events, the value of CIMT testing in CVD risk assessment is still vigorously debated. In this article, we clarify the utility of CIMT testing for risk classification and reexamine its usefulness as a method for assessing therapeutic efficacy.

On Subregional Analysis of Cartilage Loss from Knee MRI.

Objective:Understanding how knee cartilage is affected by osteoarthritis (OA) is critical in the development of sensitive biomarkers that may be used as surrogate endpoints in clinical trials. The objective of this study was to analyze longitudinal changes in cartilage thickness using detailed change maps and to examine if current methods for subregional analysis are able to capture the underlying cartilage changes.Materials and Methods:MRI images of 267 knees from 135 participants were acquired at baseline and 21-month follow-up and processed using a fully automatic framework for cartilage segmentation and quantification. The framework provides an anatomical coordinate system that allows for direct comparison across cartilage thickness maps. The reproducibility of this method was evaluated on 37 scan–rescan image pairs.Results:In OA knees, an annualized thickness loss of 3.7% was observed in the medial femoral cartilage plate (MF) whereas subregional measurements varied between −9.0% (loss) and 1.6%. The largest changes were observed in the posterior part of the MF. In the medial tibial cartilage plate (MT), a thickness increase of 0.4% was observed whereas subregional measurements varied between −0.8% (loss) and 1.6%. In addition, notable differences in the patterns of cartilage change were observed between genders.Conclusions:This study indicated that the spatial changes, although highly heterogeneous, showed distinct patterns of cartilage thinning and cartilage thickening in both the MF and the MT. These patterns were not accurately reflected when thickness changes were averaged over large, predefined subregions as defined in current methods for subregional analysis.