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Enriched trial design

Lucilla Parnetti, Paolo Eusebi
Alzheimer's disease (AD) is the most common neurodegenerative disorder, affecting around 35 million people worldwide. Cerebrospinal fluid (CSF) biomarkers entered the diagnostic criteria as support for early diagnosis. The classical biochemical signature of AD includes total tau (T-tau), phosphorylated tau (P-tau), and the 42 amino acid peptide (Aβ42) of amyloid-β. Recent observations suggest that the use of CSF Aβ42:Aβ40 ratio rather than CSF Aβ42 alone could contribute to reduce inter-laboratory variation in Aβ values and increasing diagnostic performance of the CSF AD biomarkers in routine practice...
March 16, 2018: Journal of Alzheimer's Disease: JAD
Julio Rosenstock, Vlado Perkovic, John H Alexander, Mark E Cooper, Nikolaus Marx, Michael J Pencina, Robert D Toto, Christoph Wanner, Bernard Zinman, David Baanstra, Egon Pfarr, Michaela Mattheus, Uli C Broedl, Hans-Juergen Woerle, Jyothis T George, Maximilian von Eynatten, Darren K McGuire
BACKGROUND: Cardiovascular (CV) outcome trials in type 2 diabetes (T2D) have underrepresented patients with chronic kidney disease (CKD), leading to uncertainty regarding their kidney efficacy and safety. The CARMELINA® trial aims to evaluate the effects of linagliptin, a DPP-4 inhibitor, on both CV and kidney outcomes in a study population enriched for cardio-renal risk. METHODS: CARMELINA® is a randomized, double-blind, placebo-controlled clinical trial conducted in 27 countries in T2D patients at high risk of CV and/or kidney events...
March 14, 2018: Cardiovascular Diabetology
Hamid Tayebi Khosroshahi, Nosratola D Vaziri, Behzad Abedi, Bahlol Habibi Asl, Morteza Ghojazadeh, Wanghui Jing, Amir Mansur Vatankhah
INTRODUCTION: Systemic inflammation and oxidative stress play a central role in the pathogenesis of cardiovascular disease and numerous other complications of CKD. Recent studies demonstrated that consumption of a diet enriched with amylose (HAM-RS2), attenuates oxidative stress and inflammation, and improves intestinal microbiome in CKD rats. The present study was designed to explore the effect of dietary amylose supplementation in hemodialysis patients. METHODS: Forty-six stable hemodialysis patients were randomized to receive biscuits containing 20 g/day during the first four weeks and 25 g/day in the next four weeks of either HAM-RS2 or wheat-flour...
March 13, 2018: Hemodialysis International
Jean-Charles Nault, Peter R Galle, Jens U Marquardt
Hepatocellular carcinomas (HCC) are characterized by considerable phenotypic and molecular heterogeneity. Treatment and design of clinical trials are particularly challenging due a co-existing liver disease present in the majority of patients which limits aggressive therapeutic options. Despite positive results in recent phase III clinical trials, that confirmed the high value of antiangiogenic therapies for HCC in both first (sorafenib and lenvatinib) and second line (regorafenib and cabozantinib) treatment modalities, failure of several large randomized controlled clinical trials over the last 10 years underlines the necessity for innovative treatment strategies and implementation of findings from translational studies to overcome this unmet clinical need...
March 2, 2018: Journal of Hepatology
Valentine D Verpaalen, Wendy I Baltzer, Sarah Smith-Ostrin, Jennifer J Warnock, Bernadette Stang, Craig G Ruaux
OBJECTIVE To determine the effects of an omega-3 fatty acid and protein-enriched diet, physical rehabilitation, or both on radiographic findings and markers of synovial inflammation in dogs following tibial plateau leveling osteotomy and arthroscopic surgery for treatment of cranial cruciate ligament disease. DESIGN Randomized, prospective clinical trial. ANIMALS 48 dogs with unilateral cranial cruciate ligament disease. PROCEDURES Dogs were randomly assigned to receive a dry omega-3 fatty acid and protein-enriched dog food formulated to support joint health (test food [TF]), a dry food formulated for adult canine maintenance (control food [CF]), TF plus rehabilitation, or CF plus rehabilitation after surgery...
March 15, 2018: Journal of the American Veterinary Medical Association
Wendy I Baltzer, Sarah Smith-Ostrin, Jennifer J Warnock, Craig G Ruaux
OBJECTIVE To assess clinical effects of an omega-3 fatty acid and protein-enriched diet, physical rehabilitation, or both in dogs following tibial plateau leveling osteotomy (TPLO) and arthroscopic surgery for cranial cruciate ligament (CCL) disease. DESIGN Randomized, prospective clinical trial. ANIMALS 48 dogs with unilateral CCL disease. PROCEDURES Dogs were randomly assigned to receive a dry omega-3 fatty acid and protein-enriched dog food formulated to support joint health (test food [TF]), a dry food formulated for maintenance of adult dogs (control food [CF]), TF plus rehabilitation (TF-R), or CF plus rehabilitation (CF-R)...
March 15, 2018: Journal of the American Veterinary Medical Association
Daniela V Pachito, Alan L Eckeli, Ahmed S Desouky, Mark A Corbett, Timo Partonen, Shantha Mw Rajaratnam, Rachel Riera
BACKGROUND: Exposure to light plays a crucial role in biological processes, influencing mood and alertness. Daytime workers may be exposed to insufficient or inappropriate light during daytime, leading to mood disturbances and decreases in levels of alertness. OBJECTIVES: To assess the effectiveness and safety of lighting interventions to improve alertness and mood in daytime workers. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, seven other databases; ClinicalTrials...
March 2, 2018: Cochrane Database of Systematic Reviews
Ergun Velidedeoglu, Marc W Cavaillé-Coll, Shukal Bala, Ozlem A Belen, Yan Wang, Renata Albrecht
BACKGROUND: Despite major advances in understanding the pathophysiology of antibody mediated rejection (AMR); prevention, diagnosis and treatment remain unmet medical needs. It appears that early T-cell mediated rejection (TCMR), de novo donor specific antibody (dnDSA) formation and AMR result from patient or physician initiated suboptimal immunosuppression, and represent landmarks in an ongoing process rather than separate events. METHODS: On April 12-13, 2017, the Food and Drug Administration (FDA) sponsored a public workshop on AMR in kidney transplantation to discuss new advances, importance of immunosuppressive medication nonadherence in dnDSA formation, associations between AMR, cellular rejection, changes in GFR, and challenges of clinical trial design for the prevention and treatment of AMR...
February 20, 2018: Transplantation
Margaret P Rayman, Kristian Hillert Winther, Roberto Pastor-Barriuso, Frederick Cold, Marianne Thvilum, Saverio Stranges, Eliseo Guallar, Søren Cold
BACKGROUND: Selenium, an essential trace element, is incorporated into selenoproteins with a wide range of health effects. Selenoproteins may reach repletion at a plasma selenium concentration of ~125µg/L, at which point the concentration of selenoprotein P reaches a plateau; whether sustained concentrations higher than this are beneficial, or indeed detrimental, is unknown. OBJECTIVE: In a population of relatively low selenium status, we aimed to determine the effect on mortality of long-term selenium supplementation at different dose levels...
February 14, 2018: Free Radical Biology & Medicine
Gianluigi Savarese, Nicola Orsini, Camilla Hage, Ola Vedin, Francesco Cosentino, Giuseppe M C Rosano, Ulf Dahlström, Lars H Lund
OBJECTIVES: The purpose of this study was to assess the association between N-terminal pro-B-type natriuretic peptide (NT-proBNP) and cardiovascular (CV) versus non-CV events and between NT-proBNP and potential treatment effects in heart failure (HF) with preserved, mid-range, and reduced ejection fraction (HFpEF, HFmrEF, and HFrEF, respectively) and clinically relevant subgroups. BACKGROUND: Optimizing patient eligibility criteria in HF trials requires biomarkers that enrich for CV but not for non-CV events and select patients most likely to respond to the tested intervention...
February 1, 2018: JACC. Heart Failure
Frank Jessen, Annika Spottke, Henning Boecker, Frederic Brosseron, Katharina Buerger, Cihan Catak, Klaus Fliessbach, Christiana Franke, Manuel Fuentes, Michael T Heneka, Daniel Janowitz, Ingo Kilimann, Christoph Laske, Felix Menne, Peter Nestor, Oliver Peters, Josef Priller, Verena Pross, Alfredo Ramirez, Anja Schneider, Oliver Speck, Eike Jakob Spruth, Stefan Teipel, Ruth Vukovich, Christine Westerteicher, Jens Wiltfang, Steffen Wolfsgruber, Michael Wagner, Emrah Düzel
BACKGROUND: Deep phenotyping and longitudinal assessment of predementia at-risk states of Alzheimer's disease (AD) are required to define populations and outcomes for dementia prevention trials. Subjective cognitive decline (SCD) is a pre-mild cognitive impairment (pre-MCI) at-risk state of dementia, which emerges as a highly promising target for AD prevention. METHODS: The German Center for Neurodegenerative Diseases (DZNE) is conducting the multicenter DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE), which focuses on the characterization of SCD in patients recruited from memory clinics...
February 7, 2018: Alzheimer's Research & Therapy
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
S Coe, J Collett, H Izadi, D T Wade, M Clegg, J M Harrison, E Buckingham, A Cavey, G C DeLuca, J Palace, H Dawes
Background: Dietary interventions including consumption of flavonoids, plant compounds found in certain foods, may have the ability to improve fatigue. However, to date, no well-designed intervention studies assessing the role of flavonoid consumption for fatigue management in people with MS (pwMS) have been performed. The hypothesis is that the consumption of a flavonoid-rich pure cocoa beverage will reduce fatigue in pwMS. The aim of this study is to determine the feasibility and potential outcome of running a trial to evaluate this hypothesis...
2018: Pilot and Feasibility Studies
Eric Tse, Yok-Lam Kwong
PURPOSE OF THE REVIEW: T-cells and natural killer (NK) cells share the same ontogeny, and lymphomas derived from them are clinically diverse, occurring in nodal and extranodal sites. In addition to inherent properties of these lymphomas, their microenvironment also impacts on pathogenesis and response to therapy. An understanding of the milieu of T-cell and NK cell lymphomas has important implications on treatment. RECENT FINDINGS: Components of the microenvironment include tumour-associated macrophages (TAM), non-neoplastic T-cells and B-cells, eosinophils, dendritic cells, endothelial cells and blood vessels...
February 2, 2018: Current Hematologic Malignancy Reports
Takeshi Ishikawa, Tetsuya Okayama, Naoyuki Sakamoto, Mitsuko Ideno, Kaname Oka, Tatsuji Enoki, Junichi Mineno, Naohisa Yoshida, Kazuhiro Katada, Kazuhiro Kamada, Kazuhiko Uchiyama, Osamu Handa, Tomohisa Takagi, Hideyuki Konishi, Satoshi Kokura, Kazuko Uno, Yuji Naito, Yoshito Itoh
Natural killer (NK) cells exhibit strong cytotoxic activity against tumor cells without prior sensitization, and have the potential to exert antibody-dependent cellular cytotoxicity (ADCC). In this clinical trial, we examined the safety and efficacy of the use of NK cells, generated using a novel expansion system, in combination with IgG1 antibodies for the treatment of advanced gastric or colorectal cancers. Treatment consisted of trastuzumab- or cetuximab-based chemotherapy, plus adoptive NK cell therapy...
January 31, 2018: International Journal of Cancer. Journal International du Cancer
Sterling C Johnson, Rebecca L Koscik, Erin M Jonaitis, Lindsay R Clark, Kimberly D Mueller, Sara E Berman, Barbara B Bendlin, Corinne D Engelman, Ozioma C Okonkwo, Kirk J Hogan, Sanjay Asthana, Cynthia M Carlsson, Bruce P Hermann, Mark A Sager
The Wisconsin Registry for Alzheimer's Prevention is a longitudinal observational cohort study enriched with persons with a parental history (PH) of probable Alzheimer's disease (AD) dementia. Since late 2001, Wisconsin Registry for Alzheimer's Prevention has enrolled 1561 people at a mean baseline age of 54 years. Participants return for a second visit 4 years after baseline, and subsequent visits occur every 2 years. Eighty-one percent (1270) of participants remain active in the study at a current mean age of 64 and 9 years of follow-up...
2018: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring
Jenny Downs, Jenny Rodger, Chen Li, Xuesong Tan, Nan Hu, Kingsley Wong, Nicholas de Klerk, Helen Leonard
BACKGROUND: Rett syndrome is caused by a pathogenic mutation in the MECP2 gene with major consequences for motor and cognitive development. One of the effects of impaired MECP2 function is reduced production of Brain Derived Neurotrophic Factor (BDNF), a protein required for normal neuronal development. When housed in an enriched environment, MECP2 null mice improved motor abilities and increased levels of BDNF in the brain. We investigated the effects of environmental enrichment on gross motor skills and blood BDNF levels in girls with Rett syndrome...
January 10, 2018: Orphanet Journal of Rare Diseases
Robert E Becker, Nigel H Greig, Debomoy K Lahiri, Joseph Bledsoe, Sarah Majercik, Clive Ballard, Dag Aarsland, Lon S Schneider, Douglas Flanagan, Ramprakash Govindarajan, Mary Sano, Luigi Ferrucci, Dimitrios Kapogiannis
BACKGROUND: Concussion (mild) and other moderate traumatic brain injury (TBI) and Alzheimer's disease (AD) share overlapping neuropathologies, including neuronal pre-programmed cell death (PPCD), and clinical impairments and disabilities. Multiple clinical trials targeting mechanisms based on the Amyloid Hypothesis of AD have so far failed, indicating that it is prudent for new drug developments to also pursue mechanisms independent of the Amyloid Hypothesis. To address these issue, we have proposed the use of an animal model of concussion/TBI as a supplement to AD transgenic mice to provide an indication of an AD drug candidate's potential for preventing PPCD and resulting progression towards dementia in AD...
January 10, 2018: Current Alzheimer Research
Shuangtao Zhao, Jiangyong Yu, Luhua Wang
OBJECTIVES: MicroRNAs (miRNAs) play a key role in governing posttranscriptional regulation through binding to the mRNAs of target genes. This study is to assess miRNAs expression profiles for identifying brain metastasis-related miRNAs to develop the predictive model by microarray in tumor tissues. METHODS: For this study, we screened the significant brain metastasis-related miRNAs from 77 lung adenocarcinoma (LUAD) patients with brain metastasis (BM+) or non-brain metastasis (BM-)...
December 27, 2017: Translational Oncology
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