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Current Opinion in Urology Sep 2022To evaluate intermediate clinical endpoints that have been proposed as potential surrogates for overall survival amongst patients with locally advanced and metastatic... (Review)
Review
PURPOSE OF REVIEW
To evaluate intermediate clinical endpoints that have been proposed as potential surrogates for overall survival amongst patients with locally advanced and metastatic urothelial carcinoma.
RECENT FINDINGS
Several endpoints have been proposed as potential surrogates for overall survival. They are: pathologic downstaging or complete response after neoadjuvant treatments and progression-free survival in the adjuvant setting and metastatic setting. Formal surrogacy, as per Prentice, has not been established among any of the aforementioned intermediate clinical endpoints and overall survival. Despite that, regulatory agencies have recently approved adjuvant nivolumab for patients with high-risk muscle invasive bladder cancer, based on the results of a trial that had disease-free survival as primary endpoint.
SUMMARY
Despite the lack of proven surrogacy between progression-free survival and overall survival, this endpoint seems adequate for trial design and medication approval, as the recent case of adjuvant nivolumab demonstrates.
Topics: Carcinoma, Transitional Cell; Disease-Free Survival; Humans; Nivolumab; Progression-Free Survival; Urinary Bladder Neoplasms
PubMed: 35849700
DOI: 10.1097/MOU.0000000000001012 -
Journal of Interventional Cardiology Dec 2004In Europe, 1,108 percutaneous coronary interventions (PCIs) per one Mio inhabitants are currently annually performed, most of them with stent implantation. Drug-eluting...
In Europe, 1,108 percutaneous coronary interventions (PCIs) per one Mio inhabitants are currently annually performed, most of them with stent implantation. Drug-eluting stents have been the focus of attention of interventional coronary therapy since the RAVEL study was first presented in September 2001 at the European Society of Cardiology Meeting. Ever since, numerous studies have assessed the effects of various antiproliferative and anti-inflammatory substances and a variety of different stents was used as platform, either covered with polymer carriers of different chemical and physical properties or without a polymer carrier. CE- or FDA-certified drug-eluting stents are increasingly replacing the use of bare metal stents to reduce in-stent restenosis. Today, physicians have a choice of several approved drug-eluting stents and, therefore, need some evidence-based guidance through the "jungle of information" to make the right decisions. Even when focusing on randomized trials, differences between the studies regarding primary endpoints and sample sizes exist, making it difficult to compare the various drug-eluting stent studies. Randomized studies use either nonclinical (i.e., angiographic diameter stenosis, in-stent MLD, or in-stent late lumen loss) or clinical (i.e., TVF, TVR, and MACE) parameters as primary endpoints. Choosing an angiographic parameter as primary endpoint results in two major limitations: first, a significant improvement of an angiographic "surrogate" parameter does not necessarily translate into a better clinical outcome (DELIVER-I); second, conclusions regarding possible improvements of clinical outcome are underpowered, because the sample size calculation is based on the primary endpoint. Usually the number of patients needed is lower for angiographic than for clinical endpoints. Until today, only three trials with a primary clinical endpoint have shown a significantly positive impact on patients' outcome: the SIRIUS trial (Cypher stent) with its reduction of primary endpoint TVF (21.0% vs 8.6%), the TAXUS-IV trial (Taxus stent) with its reduction of primary endpoint TVR (12.0% vs 4.7%) and TAXUS-VI in long lesions with its reduction of primary endpoint TVR (19.4% vs 9.1%). Although the angiographic results of other drug-eluting stents are encouraging, they will have to prove their clinical impact based on adequately powered randomized trials with a primary clinical endpoint at an adequate time interval.
Topics: Cardiac Catheterization; Coronary Restenosis; Everolimus; Humans; Immunosuppressive Agents; Outcome Assessment, Health Care; Paclitaxel; Randomized Controlled Trials as Topic; Sirolimus; Stents; Ultrasonography, Interventional
PubMed: 15546289
DOI: 10.1111/j.1540-8183.2004.04079.x -
Frontiers in Cardiovascular Medicine 2024Cardiovascular (CV) disease remains a leading cause of mortality despite statin therapy. Statin add-on lipid-lowering therapies have been investigated for CV risk... (Review)
Review
INTRODUCTION
Cardiovascular (CV) disease remains a leading cause of mortality despite statin therapy. Statin add-on lipid-lowering therapies have been investigated for CV risk reduction, but their effect on CV mortality has not been reviewed.
METHODS
This review describes CV outcomes trials of add-on therapies to statins, highlighting findings related to the primary composite CV endpoints and the more patient-centric endpoint of CV-related mortality.
RESULTS
Add-on ezetimibe met its primary composite CV endpoint vs. statin alone (= 0.016); however, the individual endpoint of death from CV causes did not differ between groups. Add-on therapy with proprotein convertase subtilisin/kexin type 9 inhibitors achieved the primary composite CV endpoints in the respective CV outcomes trials for alirocumab (< 0.001) and evolocumab (< 0.001); however, neither CV outcomes trial found a difference vs. placebo in CV-related mortality. In its CV outcomes trial, icosapent ethyl added to statin therapy significantly reduced the occurrence of the primary composite CV endpoint (< 0.001) and the individual endpoint of risk of CV-related death (= 0.03) vs. placebo. A CV outcomes trial of bempedoic acid monotherapy achieved its primary composite CV endpoint vs. placebo (= 0.004) but not the endpoint of death from CV causes.
DISCUSSION
Statin add-on therapies achieved their CV outcomes trial composite CV endpoints. Proprotein convertase subtilisin/kexin type 9 inhibitors and icosapent ethyl have approved indications for CV risk reduction. Only add-on therapy with icosapent ethyl demonstrated a significant reduction in CV mortality in the overall intent-to-treat population, possibly due to the unique pleiotropic mechanisms of eicosapentaenoic acid independent of lipid-lowering effects.
PubMed: 38545344
DOI: 10.3389/fcvm.2024.1308695 -
Trials Dec 2022Our randomized controlled clinical trial will explore the potential of bazedoxifene plus conjugated estrogen to modulate breast tissue-based risk biomarkers as a... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Our randomized controlled clinical trial will explore the potential of bazedoxifene plus conjugated estrogen to modulate breast tissue-based risk biomarkers as a surrogate for breast cancer risk reduction. This paper investigates the statistical design features of the trial and the rationale for the final choice of its design. Group sequential designs are a popular design approach to allow a trial to stop early for success or futility, potentially saving time and money over a fixed trial design. While Bayesian adaptive designs enjoy the same properties as group sequential designs, they have the added benefit of using prior information as well as inferential interpretation conditional on the data. Whether a frequentist or Bayesian trial, most adaptive designs have interim analyses that allow for early stopping, typically utilizing only the primary endpoint. A drawback to this approach is that the study may not have enough data for adequate comparisons of a single, key secondary endpoint. This can happen, for example, if the secondary endpoint has a smaller effect than the primary endpoint.
METHODS
In this paper, we investigate a trial design called two-endpoint adaptive, which stops early only if a criterion is met for primary and secondary endpoints. The approach focuses the final analysis on the primary endpoint but ensures adequate data for the secondary analysis. Our study has two arms with a primary (change in mammographic fibroglandular volume) and secondary endpoint (change in mammary tissue Ki-67).
RESULTS
We present operating characteristics including power, trial duration, and type I error rate and discuss the value and risks of modeling Bayesian group sequential designs with primary and secondary endpoints, comparing against alternative designs. The results indicate that the two-endpoint adaptive design has better operating characteristics than competing designs if one is concerned about having adequate information for a key secondary endpoint.
DISCUSSION
Our approach balances trial speed and the need for information on the single, key secondary endpoint.
Topics: Humans; Female; Bayes Theorem; Breast Neoplasms; Research Design; Medical Futility; Chemoprevention
PubMed: 36471449
DOI: 10.1186/s13063-022-06930-5 -
Pharmaceutical Statistics Jul 2021In late-phase confirmatory clinical trials in the oncology field, time-to-event (TTE) endpoints are commonly used as primary endpoints for establishing the efficacy of...
In late-phase confirmatory clinical trials in the oncology field, time-to-event (TTE) endpoints are commonly used as primary endpoints for establishing the efficacy of investigational therapies. Among these TTE endpoints, overall survival (OS) is always considered as the gold standard. However, OS data can take years to mature, and its use for measurement of efficacy can be confounded by the use of post-treatment rescue therapies or supportive care. Therefore, to accelerate the development process and better characterize the treatment effect of new investigational therapies, other TTE endpoints such as progression-free survival and event-free survival (EFS) are applied as primary efficacy endpoints in some confirmatory trials, either as a surrogate for OS or as a direct measure of clinical benefits. For evaluating novel treatments for acute myeloid leukemia, EFS has been gradually recognized as a direct measure of clinical benefits. However, the application of an EFS endpoint is still controversial mainly due to the debate surrounding definition of treatment failure (TF) events. In this article, we investigate the EFS endpoint with the most conservative definition for the timing of TF, which is Day 1 since randomization. Specifically, the corresponding non-proportional hazard pattern of the EFS endpoint is investigated with both analytical and numerical approaches.
Topics: Clinical Trials as Topic; Disease-Free Survival; Endpoint Determination; Humans; Progression-Free Survival
PubMed: 33594827
DOI: 10.1002/pst.2103 -
European Respiratory Review : An... Sep 2022There is a need for clinical trial end-points to better assess how patients feel and function, so that interventions can be developed which alleviate symptoms and... (Review)
Review
There is a need for clinical trial end-points to better assess how patients feel and function, so that interventions can be developed which alleviate symptoms and improve quality of life. Use of 6-min walk test (6MWT) outcomes as a primary end-point in interstitial lung disease (ILD) trials is growing, particularly for drugs targeting concurrent pulmonary hypertension. However, 6MWT outcomes may be influenced differentially by interstitial lung and pulmonary vascular components of ILD, making interpretation complicated. We propose that using 6MWT outcomes, including 6-min walk distance or oxygen desaturation, as primary end-points should depend upon the study population (how advanced the ILD is; whether vasculopathy is significant), the degree of disease progression, and, importantly, the effect of study treatment expected. We argue that the 6MWT as a single outcome measure is suitable as a primary end-point if the treatment goal is to improve functional performance or prevent disease progression within a study population of patients with advanced ILD or those with ILD and co-existent vasculopathy. In addition, we discuss the potential of composite primary end-points incorporating 6MWT outcomes, outlining important considerations to ensure that they are appropriate for the study population and treatment goals.
Topics: Disease Progression; Exercise Test; Humans; Lung Diseases, Interstitial; Quality of Life; Walk Test
PubMed: 36002171
DOI: 10.1183/16000617.0087-2022 -
Journal of Hepatology Oct 2008Design and endpoints of clinical trials in hepatocellular carcinoma. Llovet JM, Di Bisceglie AM, Bruix J, Kramer BS, Lencioni R, Zhu AX, Sherman M, Schwartz M, Lotze M,...
Design and endpoints of clinical trials in hepatocellular carcinoma. Llovet JM, Di Bisceglie AM, Bruix J, Kramer BS, Lencioni R, Zhu AX, Sherman M, Schwartz M, Lotze M, Talwalkar J, Gores GJ; for the Panel of Experts in HCC-Design Clinical Trials. The design of clinical trials in hepatocellular carcinoma (HCC) is complex because many patients have concurrent liver disease, which can confound the assessment of clinical benefit. There is an urgent need for high-quality trials in this disease. An expert panel was convened by the American Association for the Study of Liver Diseases to develop guidelines that provide a common framework for designing trials to facilitate comparability of results. According to these guidelines, randomized phase 2 trials with a time-to-event primary endpoint, such as time to progression, are pivotal in clinical research on HCC. Survival remains the main endpoint to measure effectiveness in phase 3 studies, whereas time to recurrence is proposed as an appropriate endpoint in the adjuvant setting. Because progression-free survival and disease-free survival are composite endpoints, they are more vulnerable than others in HCC clinical studies and may not be able to capture clinical benefits. Selection of the target population should be based on the Barcelona Clinic Liver Cancer staging system. New drugs should be tested in patients with well-preserved liver function (Child-Pugh A class). Patients assigned to the control arm should receive standard-of-care therapy, that is, chemoembolization for patients with intermediate-stage disease and sorafenib for patients with advanced-stage disease. Further research is needed to incorporate biomarkers and molecular imaging into clinical research in HCC. These surrogate markers may help to enrich study populations and maximize the cost-benefit ratio of trial execution. Design and conduct of phase 3 trials should be coordinated by centers with appropriate expertise in HCC. [Abstract reproduced by permission of J Natl Cancer Inst 2008;100:698-711.] Link to free abstract at: (http://jnci.oxfordjournals.org/cgi/content/abstract/100/10/698).
PubMed: 18718690
DOI: 10.1016/j.jhep.2008.07.012 -
Current Opinion in Organ Transplantation Feb 2020Clinical trials testing novel kidney transplant therapies are challenged by low rates of long-term clinical outcomes such as death and graft loss. Herein, we critically... (Review)
Review
PURPOSE OF REVIEW
Clinical trials testing novel kidney transplant therapies are challenged by low rates of long-term clinical outcomes such as death and graft loss. Herein, we critically review traditional and more recent strategies to expedite new therapies by minimizing sample size and follow-up duration using surrogates (alone or in the context of composite endpoints), or using different clinical endpoints.
RECENT FINDINGS
Multiple surrogate endpoints are increasingly important for organ transplantation trial design: glomerular filtration rate slope, albuminuria, donor-specific alloantibodies, and histological score at graft protocol biopsies. However, surrogate endpoint use is limited by bias when data are missing. Hierarchical multiple primary endpoints - that are successfully used in other settings and frequently utilize surrogate endpoints - have not yet been integrated into kidney transplant studies. New clinical endpoints, focusing on treatment safety and patient quality of life have been recently standardized and should be reported regardless of the primary endpoint of any randomized controlled trial.
SUMMARY
Defining surrogates, standards for outcome reporting, and statistical strategies to appropriately analyze them are critical to effectively testing and implementing novel therapeutic strategies to improve long-term clinical outcomes in kidney transplantation.
Topics: Biomarkers; Humans; Kidney Transplantation; Quality of Life
PubMed: 31815790
DOI: 10.1097/MOT.0000000000000719 -
American Journal of Respiratory and... May 2012Definitive evidence of clinical efficacy in a Phase 3 trial is best shown by a beneficial impact on a clinically meaningful endpoint-that is, an endpoint that directly...
Definitive evidence of clinical efficacy in a Phase 3 trial is best shown by a beneficial impact on a clinically meaningful endpoint-that is, an endpoint that directly measures how a patient feels (symptoms), functions (the ability to perform activities in daily life), or survives. In idiopathic pulmonary fibrosis (IPF), we believe the endpoints that best meet these criteria are all-cause mortality and all-cause nonelective hospitalization. There are no validated measures of symptoms or broader constructs such as health status or functional status in IPF. A surrogate endpoint is defined as an indirect measure that is intended to substitute for a clinically meaningful endpoint. Surrogate endpoints can be appropriate outcome measures if validated. However, validation requires substantial evidence that the effect of an intervention on a clinically meaningful endpoint is reliably predicted by the effect of an intervention on the surrogate endpoint. For patients with IPF, there are currently no validated surrogate endpoints.
Topics: Biomarkers; Clinical Trials, Phase III as Topic; Endpoint Determination; Hospitalization; Humans; Idiopathic Pulmonary Fibrosis; Lung Transplantation; Respiratory System Agents; Severity of Illness Index; Survival Analysis; Treatment Outcome
PubMed: 22505745
DOI: 10.1164/rccm.201201-0006PP -
Transplantation Jan 2015Prospective clinical trials are constructed with high levels of internal validity. Sample size and power considerations usually address primary endpoints. Primary... (Review)
Review
Prospective clinical trials are constructed with high levels of internal validity. Sample size and power considerations usually address primary endpoints. Primary endpoints have traditionally included events that are becoming increasingly less common and thus have led to growing use of composite endpoints and noninferiority trial designs in transplantation. This approach may mask real clinical benefit in one or the other domain with regard to either clinically relevant secondary endpoints or other unexpected findings. In addition, endpoints solely chosen based on power considerations are prone to misjudgment of actual treatment effect size as well as consistency of that effect. In the instances where treatment effects may have been underestimated, valuable information may be lost if buried within a composite endpoint. In all these cases, analyses and post hoc analyses of data become relevant in informing practitioners about clinical benefits or safety signals that may not be captured by the primary endpoint. On the other hand, there are many pitfalls in using post hoc determined endpoints. This short review is meant to allow readers to appreciate post hoc analysis not as an entity with a single approach, but rather as an analysis with unique limitations and strengths that often raise new questions to be addressed in further inquiries.
Topics: Clinical Trials as Topic; Data Interpretation, Statistical; Endpoint Determination; Humans; Models, Statistical; Prospective Studies; Reproducibility of Results; Research Design; Sample Size; Treatment Outcome
PubMed: 25525920
DOI: 10.1097/TP.0000000000000581