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Surrogate endpoints

David Jiménez, Carlos Andrés Quezada, Pilar Escribano
No abstract text is available yet for this article.
February 20, 2018: Journal of the American College of Cardiology
Edward L Korn, Boris Freidlin
Establishing trial-level surrogacy of an intermediate endpoint for predicting survival benefit in future trials is extremely challenging because of the extrapolations required, but there are other useful drug development and patient management applications of intermediate endpoints.
February 12, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Janusz Sledz, Michal Labus, Mariusz Mazij, Monika Klank-Szafran, Dariusz Karbarz, Bartosz Ludwik, Jacek Kusa, Karol Deutsch, Leslaw Szydlowski, Adrian Mscisz, Jerzy Spikowski, Aleksandra Morka, Tomasz Kameczura, Aleksandra Swietoniowska, Sebastian Stec
PURPOSE: During incremental atrial pacing in patients with atrioventricular nodal reentrant tachycardia, the PR interval often exceeds the RR interval (PR > RR) during stable 1:1 AV conduction. However, the PR/RR ratio has never been evaluated in a large group of patients with pacing from the proximal coronary sinus and after isoproterenol challenge. Our study validates new site of pacing and easier method of identification of PR > RR. MATERIAL AND METHODS: A prospective protocol of incremental atrial pacing from the proximal coronary sinus was carried out in 398 patients (AVNRT-228 and control-170)...
February 9, 2018: Advances in Medical Sciences
Kiattisa Sommat, Nelson Ling Fung Yit, Fuqiang Wang, John Heng Chi Lim
OBJECTIVE: This study aimed to evaluate the predictive factors for survival and acute toxicities in older patients with NPC treated with curative intent IMRT. MATERIALS AND METHODS: Older patients aged 65 years and above with non-metastatic NPC treated with curative intent IMRT between 2003 and 2013 were retrospectively analysed. Variables examined were gender, age, overall stage, chemotherapy use, Eastern Cooperative Oncology Group (ECOG) performance status and comorbidity...
February 9, 2018: Journal of Geriatric Oncology
Gerald F Cox
An important challenge in rare disease clinical trials is to demonstrate a clinically meaningful and statistically significant response to treatment. Selecting the most appropriate and sensitive efficacy endpoints for a treatment trial is part art and part science. The types of endpoints should align with the stage of development (e.g., proof of concept vs. confirmation of clinical efficacy). The patient characteristics and disease stage should reflect the treatment goal of improving disease manifestations or preventing disease progression...
February 9, 2018: American Journal of Medical Genetics. Part A
Chao Chen
Clinical proof-of-concept trials crucially inform major resource deployment decisions. This paper discusses several mechanisms for enhancing their rigour and efficiency. The importance of careful consideration when using a surrogate endpoint is illustrated; situational effectiveness of run-in patient enrichment is explored; a versatile tool is introduced to ensure a high probability of pharmacological success; the benefits of dose-titration are revealed by simulation; and the importance of adequately scheduled observations is shown...
January 31, 2018: Drug Discovery Today
Hiddo J L Heerspink, Dennis L Andress, George Bakris, John J Brennan, Ricardo Correa-Rotter, Jyotirmoy Dey, Fan-Fan Hou, Dalane W Kitzman, Donald Kohan, Hirofumi Makino, John McMurray, Vlado Perkovic, Sheldon Tobe, Melissa Wigderson, Hans-Henrik Parving, Dick de Zeeuw
AIMS: People with diabetes and chronic kidney disease (CKD) are at high risk for renal events. Recent trials of novel treatments have been negative, possibly because of variability in response to treatment of the target risk factor. Atrasentan is a selective endothelin A receptor antagonist that reduces urinary albumin-to-creatinine ratio (UACR) with a large variability between patients. We are assessing its effect on renal outcomes in the Study of Diabetic Nephropathy with atrasentan (SONAR; NCT01858532) with an enrichment design (>30% lowering of albuminuria) to select patients most likely to benefit...
February 6, 2018: Diabetes, Obesity & Metabolism
Claudia Filozof, Shein-Chung Chow, Lara Dimick-Santos, Yeh-Fong Chen, Richard N Williams, Barry J Goldstein, Arun Sanyal
Due to the increasing prevalence of nonalcoholic steatohepatitis (NASH) and its associated health burden, there is a high need to develop therapeutic strategies for patients with this disease. Unfortunately, its long and asymptomatic natural history, the uncertainties about disease progression, the fact that most patients are undiagnosed, and the requirement for sequential liver biopsies create substantial challenges for clinical development. Adaptive design methods are increasingly used in clinical research as they provide the flexibility and efficiency for identifying potential signals of clinical benefit of the test treatment under investigation and make prompt preplanned adaptations without undermining the validity or integrity of the trial...
September 2017: Hepatology Communications
Selena S Au, Philippe Couillard, Amanda Roze des Ordons, Kirsten M Fiest, Dianne L Lorenzetti, Nathalie Jette
OBJECTIVES: Clinical ethics consultation as a mechanism for supporting patients, family, and staff during ethically challenging situations has become standard of care. Despite this, there is a lack of consensus about the effectiveness of clinical ethics consultation consultation in the ICU. We performed a systematic review of outcomes associated with clinical ethics consultation within adult ICUs. DATA SOURCES: We searched MEDLINE, PubMed, Cochrane CENTRAL, Embase, PsycINFO, and Cumulative Index to Nursing and Allied Health Literature from 1984 to May 2017...
February 1, 2018: Critical Care Medicine
Jonathan Krug, Michael Lewandowski, John H Offenberg, John Turlington, William A Lonneman, Nabanita Modak, Q Todd Krantz, Charly King, Stephen Gavett, M Ian Gilmour, David M DeMarini, Tadeusz Edward Kleindienst
The production of photochemical atmospheres under controlled conditions in an irradiation chamber permits the manipulation of parameters that influence the resulting air pollutant chemistry and potential biological effects. To date no studies have examined how contrasting atmospheres with a similar Air Quality Health Index (AQHI), but with differing ratios of criteria air pollutants, might differentially affect health endpoints. Here we produced two atmospheres with similar AQHIs based on the final concentrations of ozone, nitrogen dioxide, and particulate matter (PM2...
January 30, 2018: Environmental Science & Technology
Jean-David Zeitoun, Joseph S Ross, Ignacio Atal, Alexandre Vivot, Nicholas S Downing, Gabriel Baron, Philippe Ravaud
We examined whether drug-related characteristics - conditions, development, manufacturers, revenues - were associated with post-marketing research in terms of the number of trials and total population to be enrolled. We included 63 drugs, corresponding to 3867 post-marketing trials of approved indications. On multivariable analysis, both the number of post-marketing trials and population to be enrolled were associated with expected length of treatment (ratio of means [RoM]=2.35 and RoM=8.65) and number of patients in pivotal trials (RoM=1...
January 29, 2018: Clinical Pharmacology and Therapeutics
Chong Hyun Suh, Ho Sung Kim, Seung Chai Jung, Choong Gon Choi, Sang Joon Kim
OBJECTIVE: To evaluate the value of multiparametric MRI for determination of early treatment response following concurrent chemoradiotherapy in patients with newly diagnosed glioblastoma. METHODS: A computerized search of Ovid-MEDLINE and EMBASE up to 1 October 2017 was performed to find studies on the diagnostic performance of multiparametric MRI for differentiating true progression from pseudoprogression. The beginning search date was not specified. Pooled estimates of sensitivity and specificity were obtained using hierarchical logistic regression modeling...
January 26, 2018: European Radiology
Wen Xiu Chang, Ning Xu, Takanori Kumagai, Ryutaro Iijima, Kaito Waki, Masaki Yamanaka, Michito Nagura, Shigeyuki Arai, Yoshifuru Tamura, Shigeru Shibata, Yoshihide Fujigaki, Shunya Uchida
BACKGROUND/AIMS: Higher level of serum uric acid (SUA) predicts early entry to dialysis in chronic kidney disease (CKD) patients. However, a short-term effect of SUA remains to be elucidated using a novel surrogate endpoint. METHODS: Japanese CKD stage 3 to 4 patients were retrospectively examined (n= 701). The follow-up level of SUA was estimated as time-averaged uric acid (TA-UA). A propensity score for 6.0, 6.5 or 7.0 mg/dL of TA-UA was respectively calculated using baseline 23 covariates...
2017: Kidney & Blood Pressure Research
Diab Mutlak, Jonathan Lessick, Shehrban Khalil, Sergey Yalonetsky, Yoram Agmon, Doron Aronson
Aim: Significant tricuspid regurgitation (TR) is common in heart failure (HF) and portends poor prognosis. We sought to determine whether the poor outcome results from the TR itself, or whether the TR is a surrogate marker of advanced left-sided myocardial or valvular heart disease. Methods and results: We studied 639 patients admitted for acute HF. The relationship between TR severity and the endpoint of readmission for HF or mortality was assessed after adjustment for multiple clinical and echocardiographic parameters...
January 15, 2018: European Heart Journal Cardiovascular Imaging
Giedre Zurauskaite, Marc Meier, Alaadin Voegeli, Daniel Koch, Sebastian Haubitz, Alexander Kutz, Luca Bernasconi, Andreas Huber, Mario Bargetzi, Beat Mueller, Philipp Schuetz
BACKGROUND: Red cell distribution width (RDW) predicts disease outcome in several patient populations, but its prognostic value in addition to other disease parameters in unselected medical inpatients remains unclear. Our aim was to investigate the association of admission RDW levels and mortality adjusted for several disease pathways in unselected medical patients from a previous multicenter study. METHODS: We included consecutive adult, medical patients at the time point of hospital admission through the emergency department into this observational, cohort study...
2018: PloS One
Takuya Kawahara, Musashi Fukuda, Koji Oba, Junichi Sakamoto, Marc Buyse
BACKGROUND: Individual patient data (IPD) meta-analysis is considered to be a gold standard when the results of several randomized trials are combined. Recent initiatives on sharing IPD from clinical trials offer unprecedented opportunities for using such data in IPD meta-analyses. METHODS: First, we discuss the evidence generated and the benefits obtained by a long-established prospective IPD meta-analysis in early breast cancer. Next, we discuss a data-sharing system that has been adopted by several pharmaceutical sponsors...
January 12, 2018: International Journal of Clinical Oncology
Bruno Branco Castro, Carlos Silva, Inês Patrunilho Efe Macário, Bruno Oliveira, Fernando Gonçalves, Joana Luísa Pereira
Bivalves are commonly used in biomonitoring programs to track pollutants. Several features, including its filter-feeding abilities, cumulatively argue in favour of the use of the Asian clam (Corbicula fluminea) as a biosentinel and an ecotoxicological model. Filtration in bivalves is very sensitive to external stimuli and its control is dictated by regulation of the opening/closure of the valves, which may be used as an avoidance defence against contaminants. Here, we investigate the filter-feeding behaviour of the Asian clam as an endpoint for assessing exposure to pollutants, driven by two complementary goals: (i) to generate relevant and sensitive toxicological information based on the ability of C...
January 4, 2018: Aquatic Toxicology
Sirisha L Mushti, Flora Mulkey, Rajeshwari Sridhara
PURPOSE: With the approval of immunotherapies for a variety of indications, methods to assess treatment benefit addressing the response patterns observed are important. We evaluated RECIST criteria based objective response rate (ORR) and progression-free survival (PFS) as potential surrogate endpoints of overall survival (OS), and explored a modified definition of PFS by altering the threshold percentage determining disease progression to assess the association with survival benefit in immunotherapy trials...
January 11, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
G M Haag, I Zoernig, J C Hassel, N Halama, J Dick, N Lang, L Podola, J Funk, C Ziegelmeier, S Juenger, M Bucur, L Umansky, C S Falk, A Freitag, I Karapanagiotou-Schenkel, P Beckhove, A Enk, D Jaeger
BACKGROUND: Immune checkpoint therapy has dramatically changed treatment options in patients with metastatic melanoma. However, a relevant part of patients still does not respond to treatment. Data regarding the prognostic or predictive significance of preexisting immune responses against tumour antigens are conflicting. Retrospective data suggested a higher clinical benefit of ipilimumab in melanoma patients with preexisting NY-ESO-1-specific immunity. PATIENTS AND METHODS: Twenty-five patients with previously untreated or treated metastatic melanoma and preexisting humoural immune response against NY-ESO-1 received ipilimumab at a dose of 10 mg/kg in week 1, 4, 7, 10 followed by 3-month maintenance treatment for a maximum of 48 weeks...
January 4, 2018: European Journal of Cancer
William C Jackson, Krithika Suresh, Vasu Tumati, Steven G Allen, Robert T Dess, Simpa S Salami, Arvin George, Samuel D Kaffenberger, David C Miller, Jason W D Hearn, Shruti Jolly, Rohit Mehra, Brent K Hollenbeck, Ganesh S Palapattu, Matthew Schipper, Felix Y Feng, Todd M Morgan, Neil B Desai, Daniel E Spratt
BACKGROUND: Intermediate clinical endpoints (ICEs) prognostic for overall survival (OS) are needed for men receiving postprostatectomy radiation therapy (PORT) to improve clinical trial design. OBJECTIVE: To identify a potential ICE for men receiving PORT. DESIGN, SETTING, AND PARTICIPANTS: We performed an institutional review board-approved multi-institutional retrospective study of 566 men consecutively treated with PORT at tertiary care centers from 1986 to 2013...
January 3, 2018: European Urology
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