Selection Of Endpoints Research Articles

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OBJECTIVES/SPECIFIC AIMS: The objective of this research is to determine under what conditions endpoints based on estimated glomerular filtration rate (eGFR) slope or on relatively small declines in eGFR provide valid and useful surrogate endpoints for pivotal clinical trials in chronic kidney disease (CKD) patients. METHODS/STUDY POPULATION: We consider 2 classes of surrogate endpoints. The first class includes endpoints defined by the average rate of change in eGFR during defined portions of the follow-up period of the trial, following initiation of the randomized treatment interventions. The second class includes composite endpoints defined by the time from randomization until the occurrence of a designated decline in eGFR or kidney failure. The true clinical endpoint is considered to be the time from randomization until kidney failure, irrespective of the trajectory in eGFR measurements prior to kidney failure. We apply statistical simulation to determine conditions under which alternative endpoints within the 2 classes are (1) valid surrogate endpoints, in the sense of preserving a low probability of rejecting the null hypothesis of no treatment effect on the surrogate endpoint when there is no treatment effect on the clinical endpoints and are also (2) useful surrogate endpoints, in the sense of providing increased statistical power that allows significant reductions in sample size and/or duration of follow-up. Input parameters for the simulations include (a) characteristics of the joint distribution of the longitudinal eGFR measurements and the time to occurrence of renal failure, (b) characteristics of the short-term and long-term effects of the treatment, and (c) design parameters, including the duration of accrual and follow-up and the spacing of eGFR measurements during the follow-up period. We use joint analyses of 19 treatment comparisons across 13 previous clinical trials of CKD patients to guide the selection of input parameters for the simulations. We apply longitudinal mixed effects models for analysis of endpoints based on eGFR slope, and Cox regression for analyses of the composite time-to-event endpoints. RESULTS/ANTICIPATED RESULTS: We have previously shown that surrogate endpoints defined by eGFR declines of 30% or 40% can provide valid and useful alternative endpoints in CKD clinical trials for interventions that do not produce short-term effects on eGFR which differ from the longer-term effects of the interventions. Other factors influencing the validity and utility of these endpoints include the average baseline eGFR, the mean rate of change in eGFR, and the extent to which the size of the treatment effect depends on the patient’s underling rate of eGFR decline. We will extend these results by presenting preliminary results describing conditions under which outcomes based on eGFR slope provide valid and useful alternatives to the clinical endpoint of time until occurrence of kidney failure. DISCUSSION/SIGNIFICANCE OF IMPACT: The statistical simulation strategy described in this research can be used during the design of clinical trials of chronic kidney disease to assist in the selection of endpoints that maximize savings in sample size and duration of follow-up while retaining a low risk of producing a false positive conclusion in the absence of a true effect of the treatment on the time until kidney failure.

Improving substance information in USEtox® , part 1: Discussion on data and approaches for estimating freshwater ecotoxicity effect factors.

The scientific consensus model USEtox® is recommended by the European Commission as the reference model to characterize life cycle chemical emissions in terms of their potential human toxicity and freshwater aquatic ecotoxicity impacts in the context of the International Reference Life Cycle Data System Handbook and the Environmental Footprint pilot phase looking at products (PEF) and organizations (OEF). Consequently, this model has been systematically used within the PEF/OEF pilot phase by 25 European Union industry sectors, which manufacture a wide variety of consumer products. This testing phase has raised some questions regarding the derivation of and the data used for the chemical-specific freshwater ecotoxicity effect factor in USEtox. For calculating the potential freshwater aquatic ecotoxicity impacts, USEtox bases the effect factor on the chronic hazard concentration (HC50) value for a chemical calculated as the arithmetic mean of all logarithmized geometric means of species-specific chronic median lethal (or effect) concentrations (L[E]C50). We investigated the dependency of the USEtox effect factor on the selection of ecotoxicological data source and toxicological endpoints, and we found that both influence the ecotoxicity ranking of chemicals and may hence influence the conclusions of a PEF/OEF study. We furthermore compared the average measure (HC50) with other types of ecotoxicity effect indicators, such as the lowest species EC50 or no-observable-effect concentration, frequently used in regulatory risk assessment, and demonstrated how they may also influence the ecotoxicity ranking of chemicals. We acknowledge that these indicators represent different aspects of a chemical's ecotoxicity potential and discuss their pros and cons for a comparative chemical assessment as performed in life cycle assessment and in particular within the PEF/OEF context. Environ Toxicol Chem 2017;36:3450-3462. © 2017 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC.

Advances and Challenges in Cardiovascular Gene Therapy.

Many promising cardiovascular gene therapy approaches have failed to fulfill expectations in clinical trials. However, 20 years of research and method development has laid a solid groundwork for future therapies, and the need for new treatment options still exists. The safety of gene therapy has been established with various viral vectors, transgenes and delivery methods. Improving success in clinical settings requires careful consideration of the translational process. This requires both improving animal models and preclinical end points, and new approach in patient recruitment and selection of clinical end points. This review focuses on bidirectional translationality from bench to bedside and back and proposes ways to improve the process. Developing a highly complex new therapy has taken an enormous amount of work and resources, but perhaps now after the hard lessons cardiovascular gene therapy is ready become a clinical reality.

Improving Treatment Strategies for Patients with Follicular Lymphoma: How to Translate Novel Study Data into Clinical Practice

Prof Bruce Cheson opened the symposium by highlighting the unmet needs for patients with follicular lymphoma (FL) and the potential application of prognostic scores, imaging techniques, and genomics to stratify patients. Ms Rosmarie Pfau detailed the challenges faced by patients with FL around the world, particularly a desire for improved quality of life (QoL) and effective treatments with less toxicity. Prof Mathias Rummel discussed modern methods of assessing FL risk and predicting treatment outcomes, particularly regarding endpoint selection for clinical trials. Dr Andrew Davies presented data from the GALLIUM study, showing that obinutuzumab-chemotherapy and maintenance is superior to rituximabchemotherapy and maintenance in untreated advanced FL patients, while Prof Gilles Salles provided insight into future options being developed for patients with FL.

A Pediatric Review of Facioscapulohumeral Muscular Dystrophy.

Facioscapulohumeral dystrophy is one of the most common forms of muscular dystrophies worldwide. It is a complex and heterogeneous disease secondary to insufficient epigenetic repression of D4Z4 repeats and aberrant expression of DUX4 in skeletal muscles. Type 1 facioscapulohumeral muscular dystrophy (FSHD) is caused by contraction of D4Z4 repeats on 4q35, whereas type 2 FSHD is associated with mutations of the SMCHD1 or DNMT3B gene in the presence of a disease-permissive 4qA haplotype. Classical FSHD is a slowly progressive disorder with gradual-onset of muscle atrophy and a descending pattern of muscle weakness. In contrast, early-onset FSHD is associated with a large deletion of D4Z4 repeats and a more severe disease phenotype, including early loss of independent ambulation as well as extramuscular manifestations, such as retinal vasculopathy, hearing loss, and central nervous system (CNS) involvement. However, the correlation between D4Z4 repeats and disease severity remains imprecise. The current standard of care guidelines offers comprehensive assessment and symptomatic management of secondary complications. Several clinical trials are currently underway for FSHD. New and emerging treatments focus on correcting the transcriptional misregulation of D4Z4 and reversing the cytotoxic effects of DUX4. Other potential therapeutic targets include reduction of inflammation, improving muscle mass, and activating compensatory molecular pathways. The utility of disease-modifying treatments will depend on selection of sensitive clinical endpoints as well as validation of muscle magnetic resonance imaging (MRI) and other biomarkers to detect meaningful changes in disease progression. Correction of the epigenetic defects using new gene editing as well as other DUX4 silencing technologies offers potential treatment options for many individuals with FSHD.

Treatment of social cognition in schizophrenia: Current status and future directions

Efforts to develop psychosocial interventions that specifically target social cognition in schizophrenia spectrum disorders began nearly two decades ago. The field has matured considerably since then and has engendered a great deal of optimism about this treatment approach. Indeed, the efficacy of social cognitive interventions, especially those that address multiple domains of social cognition, has received substantial support. This article critically evaluates the current evidence for social cognitive interventions, identifies limitations and open questions, and suggests priorities and directions for further research. Limitations of available studies include a frequent lack of methodological rigor, suboptimal selection of endpoints, and sparse evidence for generalization to functional improvements. We highlight several emerging psychosocial and non-psychosocial approaches that may enhance the efficacy of social cognitive interventions and promote generalization to improvements in real world functioning. We conclude that cautious optimism is warranted as the field moves forward into the next wave of social cognitive treatment studies.

Recommendations on clinical trial design for treatment of Mucopolysaccharidosis Type III

BackgroundMucopolysaccharidosis type III is a progressive, neurodegenerative lysosomal storage disorder for which there is currently no effective therapy. Though numerous potential therapies are in development, there are several challenges to conducting clinical research in this area. We seek to make recommendations on the approach to clinical research in MPS III, including the selection of outcome measures and trial endpoints, in order to improve the quality and impact of research in this area.ResultsAn international workshop involving academic researchers, clinical experts and industry groups was held in June 2015, with presentations and discussions on disease pathophysiology, biomarkers, potential therapies and clinical outcome measures. A set of recommendations was subsequently prepared by a working group and reviewed by all delegates. We present a series of 11 recommendations regarding the conduct of clinical research, outcome measures and management of natural history data in Mucopolysaccharidosis type III.ConclusionsImproving the quality of clinical research in Mucopolysaccharidosis type III will require an open, collaborative and systematic approach between academic researchers, clinicians and industry. Natural history data should be published as soon as possible and ideally collated in a central repository. There should be agreement on outcome measures and instruments for evaluation of clinical outcomes to maximise the effectiveness of current and future clinical research.

The Direct Cost of Managing a Rare Disease: Assessing Medical and Pharmacy Costs Associated with Duchenne Muscular Dystrophy in the United States.

A Duchenne muscular dystrophy (DMD) cohort was identified using a claims-based algorithm to estimate health care utilization and costs for commercially insured DMD patients in the United States. Previous analyses have used broad diagnosis codes that include a range of muscular dystrophy types as a proxy to estimate the burden of DMD. To estimate DMD-associated resource utilization and costs in a sample of patients identified via a claims-based algorithm using diagnosis codes, pharmacy prescriptions, and procedure codes unique to DMD management based on DMD clinical milestones. DMD patients were selected from a commercially insured claims database (2000-2009). Patients with claims suggestive of a non-DMD diagnosis or who were aged 30 years or older were excluded. Each DMD patient was matched by age, gender, and region to controls without DMD in a 1:10 ratio (DMD patients n = 75; controls n = 750). All-cause health care resource utilization, including emergency department, inpatient, outpatient, and physician office visits, and all-cause health care costs were examined over a minimum 1-year period. Costs were computed as total health-plan and patient-paid amounts of adjudicated medical claims (in annualized U.S. dollars). The average age of the DMD cohort was 13 years. Patients in the DMD cohort had a 10-fold increase in health care costs compared with controls ($23,005 vs. $2,277, P < 0.001). Health care costs were significantly higher for the DMD cohort across age strata and, in particular, for DMD patients aged 14-29 years ($40,132 vs. $2,746, P < 0.001). In the United States, resource use and medical costs of DMD are substantial and increase with age. Funding for this study (GHO-10-4441) was provided by GlaxoSmithKline (GSK). Optum was contracted by GSK to conduct the study. Thayer was an employee of Optum Health Economics and Outcomes Research at the time of this study and was not compensated for her participation as an author of this manuscript. Bell is an employee and shareholder of GSK. McDonald has been a consultant for GSK, Sarepta, PTC Therapeutics, Biomarin, and Catabasis on clinical trials regarding Duchenne muscular dystrophy clinical trial design, endpoint selection, and data analysis; Mitobridge for drug development; and Eli Lilly as part of a steering committee for clinical trials. Study concept and design were contributed primarily by Bell, along with Thayer and McDonald. Thayer collected the data, and data interpretation was performed by Thayer and Bell, along with McDonald. The manuscript was written by Thayer and Bell, along with McDonald, and revised by all the authors.

Cardiovascular outcome trials in patients with chronic kidney disease: challenges associated with selection of patients and endpoints.

Although cardiovascular disease is a major health burden for patients with chronic kidney disease, most cardiovascular outcome trials have excluded patients with advanced chronic kidney disease. Moreover, the major cardiovascular outcome trials that have been conducted in patients with end-stage renal disease have not demonstrated a treatment benefit. Thus, clinicians have limited evidence to guide the management of cardiovascular disease in patients with chronic kidney disease, particularly those on dialysis. Several factors contribute to both the paucity of trials and the apparent lack of observed treatment effect in completed studies. Challenges associated with conducting trials in this population include patient heterogeneity, complexity of renal pathophysiology and its interaction with cardiovascular disease, and competing risks for death. The Investigator Network Initiative Cardiovascular and Renal Clinical Trialists (INI-CRCT), an international organization of academic cardiovascular and renal clinical trialists, held a meeting of regulators and experts in nephrology, cardiology, and clinical trial methodology. The group identified several research priorities, summarized in this paper, that should be pursued to advance the field towards achieving improved cardiovascular outcomes for these patients. Cardiovascular and renal clinical trialists must partner to address the uncertainties in the field through collaborative research and design clinical trials that reflect the specific needs of the chronic and end-stage kidney disease populations, with the shared goal of generating robust evidence to guide the management of cardiovascular disease in patients with kidney disease.

A quantitative analysis of statistical power identifies obesity end points for improved in vivo preclinical study design.

The design of well-powered in vivo preclinical studies is a key element in building knowledge of disease physiology for the purpose of identifying and effectively testing potential anti-obesity drug targets. However, as a result of the complexity of the obese phenotype, there is limited understanding of the variability within and between study animals of macroscopic endpoints such as food intake and body composition. This, combined with limitations inherent in the measurement of certain endpoints, presents challenges to study design that can have significant consequences for an anti-obesity program. Here, we analyze a large, longitudinal study of mouse food intake and body composition during diet perturbation to quantify the variability and interaction of key metabolic endpoints. To demonstrate how conclusions can change as a function of study size, we show that a simulated pre-clinical study properly powered for one endpoint may lead to false conclusions based on secondary endpoints. We then propose guidelines for endpoint selection and study size estimation under different conditions to facilitate proper power calculation for a more successful in vivo study design.

New medicinal products for chronic heart failure: advances in clinical trial design and efficacy assessment.

Despite the availability of a number of different classes of therapeutic agents with proven efficacy in heart failure, the clinical course of heart failure patients is characterized by a reduction in life expectancy, a progressive decline in health-related quality of life and functional status, as well as a high risk of hospitalization. New approaches are needed to address the unmet medical needs of this patient population. The European Medicines Agency (EMA) is undertaking a revision of its Guideline on Clinical Investigation of Medicinal Products for the Treatment of Chronic Heart Failure. The draft version of the Guideline was released for public consultation in January 2016. The Cardiovascular Round Table of the European Society of Cardiology (ESC), in partnership with the Heart Failure Association of the ESC, convened a dedicated two-day workshop to discuss three main topic areas of major interest in the field and addressed in this draft EMA guideline: (i) assessment of efficacy (i.e. endpoint selection and statistical analysis); (ii) clinical trial design (i.e. issues pertaining to patient population, optimal medical therapy, run-in period); and (iii) research approaches for testing novel therapeutic principles (i.e. cell therapy). This paper summarizes the key outputs from the workshop, reviews areas of expert consensus, and identifies gaps that require further research or discussion. Collaboration between regulators, industry, clinical trialists, cardiologists, health technology assessment bodies, payers, and patient organizations is critical to address the ongoing challenge of heart failure and to ensure the development and market access of new therapeutics in a scientifically robust, practical and safe way.

Diabetic patients with acute coronary syndromes in contemporary European registries: characteristics and outcomes.

Among patients with acute coronary syndromes (ACS), those with diabetes mellitus (DM) are at particularly high risk of recurrent cardiovascular events and premature death. We aimed to provide a descriptive overview of unadjusted analyses of patient characteristics, ACS management, and outcomes up to 1 year after hospital admission for an ACS/index-ACS event, in patients with DM in contemporary registries in Europe. A total of 10 registries provided data in a systematic manner on ACS patients with DM (total n =28899), and without DM (total n= 97505). In the DM population, the proportion of patients with ST-Segment Elevation Myocardial Infarction (STEMI) ranged from 22.1% to 64.6% (other patients had non-ST-Segment Elevation Myocardial Infarction (NSTEMI-ACS) or unstable angina). All-cause mortality in the registries ranged from 1.4% to 9.4% in-hospital; 2.8% to 7.9% at 30 days post-discharge; 5.1% to 10.7% at 180 days post-discharge; and 3.3% to 10.5% at 1 year post-discharge. Major bleeding events were reported in up to 3.8% of patients while in hospital (8 registries); up to 1.3% at 30 days (data from two registries only), and 2.0% at 1 year (one registry only). Registries differed substantially in terms of study setting, site, patient selection, definition and schedule of endpoints, and use of various P2Y12 inhibitors. In most, but not all, registries, event rates in DM patients were higher than in patients without DM. Pooled risk ratios comparing cohorts with DM vs. no DM were in-hospital significantly higher in DM for all-cause death (1.66; 95% CI 1.42-1.94), for cardiovascular death (2.33; 1.78 - 3.03), and for major bleeding (1.35; 1.21-1.52). These registry data from real-life clinical practice confirm a high risk for recurrent events among DM patients with ACS, with great variation across the different registries.

Pirfenidone for the treatment of idiopathic pulmonary fibrosis

ABSTRACTIntroduction: Idiopathic pulmonary fibrosis (IPF) is a diffuse parenchymal lung disease with no cure. Up until recently, no treatment had been proven to alter its natural history as judged by rate of lung function decline. In 2014 however, the emergence of two novel anti-fibrotic agents, Pirfenidone and Nintedanib revolutionized the management of this condition. Both have demonstrated the ability to deliver a major reduction in the rate of chronic IPF progression.Areas Covered: This review article focuses on Pirfenidone – a pyridone derivative initially designed as an analgesic and anti-pyretic agent. Here we describe the history of the drug from its inception through to exploratory pre-clinical in-vitro and in-vivo studies where its anti-fibrotic potential was identified, and eventually to large multicenter randomized controlled trials.Expert Commentary: This article also summarizes some of the difficulties surrounding clinical end-point selection in IPF trials and addresses some of the challenges facing the IPF community over the coming years.

Bottlenecks in the development of topical analgesics: molecule, formulation, dose-finding, and phase III design.

Topical analgesics can be defined as topical formulations containing analgesics or co-analgesics. Since 2000, interest in such formulations has been on the rise. There are, however, four critical issues in the research and development phases of topical analgesics: 1) The selection of the active pharmaceutical ingredient. Analgesics and co-analgesics differ greatly in their mechanism of action, and it is required to find the most optimal fit between such mechanisms of action and the pathogenesis of the targeted (neuropathic) pain. 2) Issues concerning the optimized formulation. For relevant clinical efficacy, specific characteristics for the selected vehicle (eg, cream base or gel base) are required, depending on the physicochemical characteristics of the active pharmaceutical ingredient(s) to be delivered. 3) Well-designed phase II dose-finding studies are required, and, unfortunately, such trials are missing. In fact, we will demonstrate that underdosing is one of the major hurdles to detect meaningful and statistically relevant clinical effects of topical analgesics. 4) Selection of clinical end points and innovatively designed phase III trials. End point selection can make or break a trial. For instance, to include numbness together with tingling as a composite end point for neuropathic pain seems stretching the therapeutic impact of an analgesic too far. Given the fast onset of action of topical analgesics (usually within 30 minutes), enrichment designs might enhance the chances for success, as the placebo response might decrease. Topical analgesics may become promising inroads for the treatment of neuropathic pain, once sufficient attention is given to these four key aspects.

The effect of remifentanil on propofol requirements to achieve loss of response to command vs. loss of response to pain.

When providing total intravenous anaesthesia, careful selection of end-points is required in titrating dose to effect during induction. Although propofol and remifentanil have predominantly different pharmacodynamic effects, they are seen to interact in achieving loss of consciousness and analgesia. To highlight these differences, we performed a double-blind, randomised controlled trial, comparing one group of patients receiving propofol alone (n = 42) with another group receiving remifentanil plus propofol (n = 46) as a target-controlled infusion of remifentanil (Minto; 3 ng.ml-1 ). Propofol was also titrated using a target-controlled infusion (Marsh effect model) to produce loss of response to tactile and vocal stimuli, and subsequently to loss of response to pain. The effect-site concentration of propofol at which 50% of patients lost tactile/verbal response was 2.9 μg.ml-1 in the propofol only group and 2.4 μg.ml-1 in the remifentanil with propofol group. In contrast, loss of pain response occurred at 4.4 μg.ml-1 in the propofol group, and 2.7 μg.ml-1 in the remifentanil with propofol group, with correspondingly lower bispectral index values. Judicious use of analgesia in total intravenous anaesthesia can have a propofol-sparing effect and potentially minimise the suppression of brain electrical activity. .

Angiogenic gene therapy in cardiovascular diseases: dream or vision?

Chronic cardiovascular diseases are significant health problems. Although current treatment strategies have tremendously improved disease management, up to 30% of these patients cannot be successfully treated with current treatment approaches and new treatment strategies are clearly needed. Gene therapy and therapeutic vascular growth may provide a new treatment option for these patients. Several growth factors, like vascular endothelial growth factors, fibroblast growth factors and hepatocyte growth factor have been tested in clinical trials. However, apart from demonstration of increased vascularity, very few results with clinical significance have been obtained. Problems with gene transfer efficiency, short duration of transgene expression, selection of endpoints, and suboptimal patients for gene therapy have been recognized. Ongoing gene therapy trials have included improvements in study protocols, vector delivery and endpoints, addressing the identified problems. Better, targeted delivery systems and new, more optimal growth factors have been taken to clinical testing. Recent advances in these areas will be discussed and the concept of angiogenic therapy as a sole treatment is re-evaluated. A combination with regenerative therapies or standard revascularization operations might be needed to improve tissue function and clinical benefits.

YI01a.01 How to Implement an Idea/Hypothesis into a Clinical Trial

Last decades have shown an impressive advance in terms of biological knowledge in cancer. Traditional way to bring new ideas/hypothesis into clinical trials was overcoming by this fact. New agents directed against specific molecular targets have important impact in terms of response rate (RR), response duration (RD), progression free survival and eventually overall survival (OS) as well as quality of life (QoL). If you have an interesting idea/hypothesis, today you have to take on account several points that can exclude it. Select population becomes a very important issue. How to do this? Selecting a target, a tumor, both, other conditions? Following the tradition of research phases, Phase I refers to measure safety and pharmacokinetics assessing maximum tolerated dose (MTD) but a number of new agents have a non-reachable MTD because they have a low toxicity. On the other hand, phase II refers to the assessing of efficacy in a certain tumor as well as safety, but, in the case of new agents you may select a tumor (as usual), a specific target no matter what tumor carry it (basket), or other conditions. In this phase measurement of response is important as a precedent of next phase trials and the challenge is the method you will use to do it. New immunotherapeutic agents probably need a different way to do this. Also, to have predictive biomarkers for most of these agents will help to select the potential populations that will achieve the more benefit and avoid futile toxicity and a waste of time and resources. We have to remember that biological effects not always mean clinical benefit. Breaking barriers, for phase III comparator selection, primary and secondary end points as well as inclusion and exclusion criteria become a very important point and are different in the traditional way and in a proposed new way. OS is the gold standard end point but there are many more very important like PFS, RR, DoR, QoL. Again, measurement methods are very important and may be different related with biological mechanism and length of response for different agents than chemotherapy. As phase III trials select (include and exclude) patients throughout very strict criteria and there are some late toxicities that can be as important as the acute and subacute toxicities, phase IV trials are very important because they represent better the daily patient we see at office practice and is a powerful pharmacovigilance mechanism. Sanctuaries have to be considered as far as the prevalent tumors have a very frequent involvement of Central Nervous System and these patient are mostly excluded from clinical trials at the beginning. Ethics is a fundamental point as far as the most important objective is the patient safety and treatment accessibility. If we went throughout these restriction points and our idea/hypothesis has survive, we can follow the development of trials around wasting less time and resources. clinical trial, Targeted Therapies, idea/hypothesis, Response criteria

An analysis of clinical trials on the registration of similars of the original disease-modifying therapies

The article discusses the design and results of recently published study of an analog of the original glatiramer acetate. The necessity of the correct planning and analysis of the data of such studies is stressed, showing equal efficacy, tolerability and safety of analog and original drug. The optimal design of such studies, their duration, selection of primary endpoint, adequate assessment of clinical and MRI changes and side-effects are discussed. The authors reckon that it is impossible to plan studies the results of which are based on the design, i.e. the absence of differences from the original drug. The authors invite specialists in MS to participate in the discussion.

Understanding Neurologic Complications Following TAVR.

Transcatheter aortic valve replacement is a groundbreaking treatment modality for severe, symptomatic aortic stenosis. Despite the rapid progression in indications to include intermediate-risk patients, the risk of peri-procedural stroke remains, with a higher incidence rate than previously reported. Accurate assessment of peri-procedural stroke rates requires selection of careful and meaningful trial endpoints during evaluation of neuroprotective devices. In this article, we review recommendations and stroke definitions from academic research consortiums along with device trial results.

Alternative of clinical end point selection for metronomic studies

The dose of a therapeutic agent is decided by its tolerability. The metronomic chemotherapy is a repeated administration of the chemotherapeutic agents at the low dose. It is difficult to establish the best dose in metronomic chemotherapy through tolerance level. The clinical benefit of any treatment efficacy is demonstrated by overall survival; however, it takes longer duration follow-up. Defining the earlier end points is important as it is a parameter that helps determine the timing of occurrence the event of interest. The surrogate biomarker can be considered as a substitute for a clinical end point. A surrogate end point can provide earlier measurement in comparison to a traditional clinical end point. It also requires lesser follow-up time and hence small sample size. This paper explores the importance of surrogate marker to be considered for assessing the metronomic studies. It is concluded that the surrogate marker can be considered as an alternative of traditional clinical end points to assess the earlier outcome effect of metronomic chemotherapy.