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Clinical trial end point and surrogate

Stefano Colagrande, Andrea L Inghilesi, Sami Aburas, Gian G Taliani, Cosimo Nardi, Fabio Marra
Hepatocellular carcinoma (HCC) is an aggressive malignancy, resulting as the third cause of death by cancer each year. The management of patients with HCC is complex, as both the tumour stage and any underlying liver disease must be considered conjointly. Although surveillance by imaging, clinical and biochemical parameters is routinely performed, a lot of patients suffering from cirrhosis have an advanced stage HCC at the first diagnosis. Advanced stage HCC includes heterogeneous groups of patients with different clinical condition and radiological features and sorafenib is the only approved treatment according to Barcelona Clinic Liver Cancer...
September 14, 2016: World Journal of Gastroenterology: WJG
Gabriella Captur, Peter Gatehouse, Kathryn E Keenan, Friso G Heslinga, Ruediger Bruehl, Marcel Prothmann, Martin J Graves, Richard J Eames, Camilla Torlasco, Giulia Benedetti, Jacqueline Donovan, Bernd Ittermann, Redha Boubertakh, Andrew Bathgate, Celine Royet, Wenjie Pang, Reza Nezafat, Michael Salerno, Peter Kellman, James C Moon
BACKGROUND: T1 mapping and extracellular volume (ECV) have the potential to guide patient care and serve as surrogate end-points in clinical trials, but measurements differ between cardiovascular magnetic resonance (CMR) scanners and pulse sequences. To help deliver T1 mapping to global clinical care, we developed a phantom-based quality assurance (QA) system for verification of measurement stability over time at individual sites, with further aims of generalization of results across sites, vendor systems, software versions and imaging sequences...
2016: Journal of Cardiovascular Magnetic Resonance
Melanie B Morillon, Lisa Stamp, William Taylor, Jaap Fransen, Nicola Dalbeth, Jasvinder A Singh, Robin Christensen, Marissa Lassere
INTRODUCTION: Gout is the most common inflammatory arthritis in men over 40 years of age. Long-term urate-lowering therapy is considered a key strategy for effective gout management. The primary outcome measure for efficacy in clinical trials of urate-lowering therapy is serum urate levels, effectively acting as a surrogate for patient-centred outcomes such as frequency of gout attacks or pain. Yet it is not clearly demonstrated that the strength of the relationship between serum urate and clinically relevant outcomes is sufficiently strong for serum urate to be considered an adequate surrogate...
2016: BMJ Open
Andrea Ribeiro de Souza, Maria Reig, Jordi Bruix
INTRODUCTION: Hepatocelullar carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Despite the implementation of screening programs for high-risk individuals, a significant proportion of patients present with advanced disease at the moment of diagnosis. AREAS COVERED: In this review we will focus in the current treatment of advanced HCC, the research that has been done in the past few years, the achievements and failures in this setting and future perspectives...
October 2016: Expert Opinion on Pharmacotherapy
Patricia K Nguyen, June-Wha Rhee, Joseph C Wu
Importance: Stem cell therapy is a promising treatment strategy for patients with heart failure, which accounts for more than 10% of deaths in the United States annually. Despite more than a decade of research, further investigation is still needed to determine whether stem cell regenerative therapy is an effective treatment strategy and can be routinely implemented in clinical practice. Objective: To describe the progress in cardiac stem cell regenerative therapy using adult stem cells and to highlight the merits and limitations of clinical trials performed to date...
August 24, 2016: JAMA Cardiology
Richard J Glassock
A Polar Views discussion by Pozzi and Rauen et al. on the interpretation and clinical application of the recently published Supportive Versus Immunosuppressive Therapy of Progressive IgA Nephropathy (STOP-IgAN) trial has elucidated important points concerning potential strengths and weaknesses of this landmark randomized trial. This critical examination of the impact of steroid monotherapy or steroid plus an immunosuppressive (IS) agent compared with 'supportive' therapy with inhibitors of the renin-angiotensin system (RAS) has enhanced our appreciation of the importance of rigorous application of titrated RAS inhibition in high-risk patients with persistent proteinuria >0...
August 11, 2016: Nephrology, Dialysis, Transplantation
Tsuyoshi Hamada, Yousuke Nakai, Hiroyuki Isayama, Hideo Yasunaga, Hiroki Matsui, Naminatsu Takahara, Suguru Mizuno, Hirofumi Kogure, Saburo Matsubara, Natsuyo Yamamoto, Minoru Tada, Kazuhiko Koike
BACKGROUND: Overall survival (OS), as the primary end-point in first-line chemotherapy trials, requires a prolonged follow-up time and may be confounded by subsequent regimens. This study aimed to evaluate the correlation between OS and surrogate end-points (progression-free survival [PFS], response rate and disease control rate), and to identify a potential surrogate for OS in advanced pancreatic cancer. METHODS: Based on an electronic search, we identified randomized controlled phase II and III trials of first-line chemotherapy for advanced pancreatic cancer...
September 2016: European Journal of Cancer
U Löbel, S Hwang, A Edwards, Y Li, X Li, A Broniscer, Z Patay
INTRODUCTION: Based on clinical observations, we hypothesized that in infiltrative high-grade brainstem neoplasms, such as diffuse intrinsic pontine glioma (DIPG), longitudinal metabolic evaluation of the tumor by magnetic resonance spectroscopy (MRS) may be more accurate than volumetric data for monitoring the tumor's biological evolution during standard treatment. METHODS: We evaluated longitudinal MRS data and corresponding tumor volumes of 31 children with DIPG...
July 20, 2016: Neuroradiology
G Merlini, I Lousada, Y Ando, A Dispenzieri, M A Gertz, M Grogan, M S Maurer, V Sanchorawala, A Wechalekar, G Palladini, R L Comenzo
Amyloid light chain amyloidosis (AL amyloidosis) is a rare and fatal disease for which there are no approved therapies. In patients with AL amyloidosis, light chain (LC) aggregates progressively accumulate in organs, resulting in organ failure that is particularly lethal when the heart is involved. A significant obstacle in the development of treatments for patients with AL amyloidosis, as well as for those with any disease that is rare, severe, and heterogeneous, has been satisfying traditional clinical trial end points (eg, overall survival, progression-free survival)...
July 15, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
H Sun, N Stockbridge, R L Ariagno, D Murphy, R M Nelson, W Rodriguez
OBJECTIVE: To identify suitable end points and surrogates for pediatric pulmonary arterial hypertension (PAH) as the lack of developmentally appropriate end point and clinical trials contribute to the unmet medical need. STUDY DESIGN: Reviewed the efficacy end points and surrogates for all trials (1995 to 2013) that were submitted to the Food and Drug Administration (FDA) to support the approval of PAH therapy and conducted literature search. RESULTS: An increase in the 6 min walking distance (6MWD) was used as a primary end point in 8/9 adult PAH trials...
July 14, 2016: Journal of Perinatology: Official Journal of the California Perinatal Association
Annelies H Boekhout, Jourik A Gietema, Bojana Milojkovic Kerklaan, Erik D van Werkhoven, Renske Altena, Aafke Honkoop, Maartje Los, Willem M Smit, Peter Nieboer, Carolien H Smorenburg, Caroline M P W Mandigers, Agnes J van der Wouw, Lonneke Kessels, Annette W G van der Velden, Petronella B Ottevanger, Tineke Smilde, Jaap de Boer, Dirk J van Veldhuisen, Ido P Kema, Elisabeth G E de Vries, Jan H M Schellens
IMPORTANCE: This is the first randomized placebo-controlled evaluation of a medical intervention for the prevention of trastuzumab-related cardiotoxic effects. OBJECTIVE: To determine as the primary end point whether angiotensin II antagonist treatment with candesartan can prevent or ameliorate trastuzumab-related cardiotoxic effects, defined as a decline in left ventricular ejection fraction (LVEF) of more than 15% or a decrease below the absolute value 45%. DESIGN: This randomized, placebo-controlled clinical study was conducted between October 2007 and October 2011 in 19 hospitals in the Netherlands, enrolling 210 women with early breast cancer testing positive for human epidermal growth factor receptor 2 (HER2) who were being considered for adjuvant systemic treatment with anthracycline-containing chemotherapy followed by trastuzumab...
August 1, 2016: JAMA Oncology
Stephanie J B Vos, Brian A Gordon, Yi Su, Pieter Jelle Visser, David M Holtzman, John C Morris, Anne M Fagan, Tammie L S Benzinger
The National Institute of Aging and Alzheimer's Association (NIA-AA) criteria for Alzheimer disease (AD) treat neuroimaging and cerebrospinal fluid (CSF) markers of AD pathology as if they would be interchangeable. We tested this assumption in 212 cognitively normal participants who have both neuroimaging and CSF measures of β-amyloid (CSF Aβ1-42 and positron emission tomography imaging with Pittsburgh Compound B) and neuronal injury (CSF t-tau and p-tau and structural magnetic resonance imaging) with longitudinal clinical follow-up...
August 2016: Neurobiology of Aging
Parambir S Dulai, Claude B Sirlin, Rohit Loomba
Non-alcoholic fatty liver disease (NAFLD) represents one of the most common causes of chronic liver disease, and its prevalence is rising worldwide. The occurrence of non-alcoholic steatohepatitis (NASH) is associated with a substantial increase in disease related morbidity and mortality. Accordingly, there has been a surge of innovation surrounding drug development in an effort to off-set the natural progression and long-term risks of this disease. Disease assessment within clinical trials and clinical practice for NAFLD is currently done with liver biopsies...
June 14, 2016: Journal of Hepatology
Fernando Alfonso, Javier Cuesta, Teresa Bastante, Fernando Rivero, Marcos García-Guimaraes, Teresa Alvarado, Amparo Benedicto, Bernardo Cortese, Robert Byrne, Adnan Kastrati
Bioresorbable vascular scaffolds (BVS) represent a disruptive technology that has caused a new revolution in interventional cardiology. BVS appear to be particularly appealing in patients presenting with an acute myocardial infarction (MI). The available evidence on the value of BVS implantation in this challenging scenario is very promising but still limited. Results come from preliminary small observational studies, prospective registries that include a control group, and from scarce randomized clinical trials with surrogate mechanistic or angiographic primary end-points...
June 2016: Journal of Thoracic Disease
Jan T Poleszczuk, Peter A Johnstone, Heiko Enderling
It is estimated that about 10% of new prostate cancer (PCa) cases are lymph node-positive (LN+). We have previously discussed the role of the inflection point (IP) of an inverse Gompertzian survival curve as a surrogate for disease incurability. In this study, we aimed to stratify curability of different patient cohorts with pathologically positive lymph nodes through modeling survival curves by different percentages of LN involvement (%LN+) postoperatively and calculating associated IPs. From the Surveillance, Epidemiology, and End Results (SEER) database, we selected LN+ PCa patients undergoing radical prostatectomy...
August 2016: Cancer Medicine
G Colloca, A Venturino, D Guarneri
AIMS: Progression-free survival is recognised as an appropriate end point for randomised clinical trials of chemotherapy of patients with metastatic colorectal cancer, although it is not clear if it is reliable after chemotherapy plus bevacizumab. MATERIALS AND METHODS: A literature search of randomised trials of systemic treatment including chemotherapy plus bevacizumab versus chemotherapy in patients with metastatic colorectal cancer was undertaken. For each trial the differences in overall survival and in either time-to-event or response-related end points were calculated...
October 2016: Clinical Oncology: a Journal of the Royal College of Radiologists
Jean-Marc G Guedon, Geraldine Longo, Lisa A Majuta, Michelle L Thomspon, Michelle N Fealk, Patrick W Mantyh
Recent studies have suggested that in humans and animals with significant skeletal pain, changes in the mechanical hypersensitivity of the skin can be detected. However, whether measuring changes in skin hypersensitivity can be a reliable surrogate for measuring skeletal pain itself remains unclear. To explore this question, we generated skeletal pain by injecting and confining GFP-transfected NCTC 2472 osteosarcoma cells unilaterally to the femur of C3H male mice. Beginning at day 7 post-tumor injection, animals were administered vehicle, an antibody to the P2X3 receptor (anti-P2X3) or anti-NGF antibody...
June 2016: Pain
Barbara E Bierer, Rebecca Li, Mark Barnes, Ida Sim
Sharing clinical trial data is critical in order to inform clinical and regulatory decision making and honor trial participants who put themselves at risk to advance science. A recent Institute of Medicine (IOM) report argues that availability of deidentified (anonymized) patient-level data from..
June 23, 2016: New England Journal of Medicine
Gregory Piazza, Venkatesh Mani, Samuel Z Goldhaber, Michael A Grosso, Michele Mercuri, Hans J Lanz, Steven Schussler, Ching Hsu, Amy Chinigo, Bruce Ritchie, Venkatesh Nadar, Kevin Cannon, John Pullman, Mauricio Concha, Marlin Schul, Zahi A Fayad
The feasibility of magnetic resonance venography (MRV) for measuring change in thrombus volume with a novel anticoagulation regimen versus standard anticoagulation in patients with symptomatic deep vein thrombosis (DVT) has not been assessed. Our aim was to study the feasibility of MRV to measure change in thrombus volume in patients with acute symptomatic objectively confirmed proximal DVT in an open-label multicenter trial (edoxaban Thrombus Reduction Imaging Study, eTRIS). We randomized patients in a 2:1 allocation ratio to edoxaban 90 mg/day for 10 days followed by 60 mg/day versus parenteral anticoagulation bridging to warfarin for 3 months...
August 2016: Vascular Medicine
Sunil V Badve, Suetonia C Palmer, Giovanni F M Strippoli, Matthew A Roberts, Armando Teixeira-Pinto, Neil Boudville, Alan Cass, Carmel M Hawley, Swapnil S Hiremath, Elaine M Pascoe, Vlado Perkovic, Gillian A Whalley, Jonathan C Craig, David W Johnson
BACKGROUND: Left ventricular mass (LVM) is a widely used surrogate end point in randomized trials involving people with chronic kidney disease (CKD) because treatment-induced LVM reductions are assumed to lower cardiovascular risk. The aim of this study was to assess the validity of LVM as a surrogate end point for all-cause and cardiovascular mortality in CKD. STUDY DESIGN: Systematic review and meta-analysis. SETTING & POPULATION: Participants with any stages of CKD...
October 2016: American Journal of Kidney Diseases: the Official Journal of the National Kidney Foundation
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