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https://www.readbyqxmd.com/read/29160099/safety-of-intradiaphragmatic-delivery-of-adeno-associated-virus-mediated-alpha-glucosidase-raav1-cmv-hgaa-gene-therapy-in-children-affected-by-pompe-disease
#1
Manuela Corti, Cristina Liberati, Barbara K Smith, Lee Ann Lawson, Ibrahim S Tuna, Thomas J Conlon, Kirsten E Erger, Saleem Islam, Roland Herzog, David D Fuller, Shelley Collins, Barry J Byrne
We conducted a first in human trial of diaphragmatic gene therapy (AAV1-CMV-GAA) to treat respiratory and neural dysfunction in early-onset Pompe disease. The primary objective of this study was to assess the safety of rAAV1-CMV-hGAA vector delivered to the diaphragm muscle of Pompe disease subjects with ventilatory insufficiency. Safety was assessed by measurement of change in serum chemistries and hematology, urinalysis, and immune response to GAA and AAV as well as change in level of health. Our data demonstrate that the AAV treatment was safe and there were no adverse events related to the study agent...
November 21, 2017: Human Gene Therapy. Clinical Development
https://www.readbyqxmd.com/read/29158832/clinical-translation-and-first-in-human-use-of-44-sc-sc-psma-617-for-pet-imaging-of-metastasized-castrate-resistant-prostate-cancer
#2
Elisabeth Eppard, Ana de la Fuente, Martina Benešová, Ambreen Khawar, Ralph A Bundschuh, Florian C Gärtner, Barbara Kreppel, Klaus Kopka, Markus Essler, Frank Rösch
BACKGROUND: Various trivalent radiometals are well suited for labeling of DOTA-conjugated variants of Glu-ureido-based prostate-specific membrane antigen (PSMA) inhibitors. The DOTA-conjugate PSMA-617 has proven high potential in PSMA radioligand therapy (PSMA-RLT) of prostate cancer as well as PET imaging when labeled with lutetium-177 and gallium-68 respectively. Considering the relatively short physical half-life of gallium-68 this positron emitter precludes prolonged acquisition periods, as required for pre-therapeutic dosimetry or intraoperative applications...
2017: Theranostics
https://www.readbyqxmd.com/read/29158665/pharmacokinetics-and-tolerability-of-mb12066-a-beta-lapachone-derivative-targeting-nad-p-h-quinone-oxidoreductase-1-two-independent-double-blind-placebo-controlled-combined-single-and-multiple-ascending-dose-first-in-human-clinical-trials
#3
Seokuee Kim, SeungHwan Lee, Joo-Youn Cho, Seo Hyun Yoon, In-Jin Jang, Kyung-Sang Yu
MB12066 is a molecule derived from β-lapachone that shown effects on obesity in previous studies. The present studies were conducted to evaluate the tolerability and pharmacokinetics (PK) of MB12066 after the oral administration of single and multiple doses to healthy volunteers. The study comprised 2 independent, randomized, double-blind, placebo-controlled, combined single and multiple ascending dose first-in-human clinical trials to evaluate the safety, tolerability and PK of MB12066 in healthy Korean volunteers...
2017: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/29154109/development-and-validation-of-a-sensitive-and-rapid-uhplc-ms-ms-method-for-the-simultaneous-quantification-of-the-common-active-and-inactive-metabolites-of-vicagrel-and-clopidogrel-in-human-plasma
#4
Cai Liu, Youming Lu, Hongbin Sun, Jin Yang, Yongqiang Liu, Xiaojuan Lai, Yanchun Gong, Xuefang Liu, Yongguo Li, Yifan Zhang, Xiaoyan Chen, Dafang Zhong
Vicagrel, an analog of clopidogrel, is a novel thienopyridine P2Y12 antagonist in clinical development in China for the treatment of acute coronary syndromes. Vicagrel and clopidogrel are prodrugs requiring metabolic activation to produce a pharmacologically active thiol metabolite (H4) in vivo. The formation of H4 from vicagrel in humans is promising more efficient and consistent than that from clopidogrel. After oral dosing of vicagrel or clopidogrel to humans, the active thiol metabolite H4 and two inactive metabolites closely related to H4 formation (the thiol metabolite H3 and the S-methylated metabolite SM3) were observed in plasma; SM3 was the most abundant drug-related component of vicagrel in circulation...
November 6, 2017: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/29146695/first-in-human-her2-targeted-imaging-using-89-zr-pertuzumab-pet-ct-dosimetry-and-clinical-application-in-patients-with-breast-cancer
#5
Gary A Ulaner, Serge K Lyashchenko, Christopher Riedl, Shutian Ruan, Pat B Zanzonico, Diana Lake, Komal Jhaveri, Brian Zeglis, Jason S Lewis, Joseph A O'Donoghue
In this first-in-human study, we evaluate the safety and dosimetry of (89)Zr-pertuzumab PET/CT for HER2-targeted imaging in patients with HER2-postive breast cancer. Materials and Methods: Patients with HER2-positive breast cancer and evidence of distant metastases were enrolled in an Institutional Review Board (IRB)-approved prospective clinical trial. Pertuzumab was conjugated with deferoxamine and radiolabeled with (89)Zr. Patients underwent (89)Zr-pertuzumab PET/CT with 74 MBq of (89)Zr-pertuzumab in a total antibody mass of 20-50 mg of pertuzumab...
November 16, 2017: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
https://www.readbyqxmd.com/read/29145039/a-first-in-human-phase-i-study-of-sar125844-a-selective-met-tyrosine-kinase-inhibitor-in-patients-with-advanced-solid-tumours-with-met-amplification
#6
Eric Angevin, Gianluca Spitaleri, Jordi Rodon, Katia Dotti, Nicolas Isambert, Stefania Salvagni, Victor Moreno, Sylvie Assadourian, Corinne Gomez, Marzia Harnois, Antoine Hollebecque, Analia Azaro, Alice Hervieu, Karim Rihawi, Filippo De Marinis
PURPOSE: Dysregulated MET signalling is implicated in oncogenesis. The safety and preliminary efficacy of a highly selective MET kinase inhibitor (SAR125844) was investigated in patients with advanced solid tumours and MET dysregulation. METHODS: This was a phase I dose-escalation (3 + 3 design [50-740 mg/m(2)]) and dose-expansion study. In the dose escalation, patients had high total MET (t-MET) expression by immunohistochemistry (IHC) or MET amplification by fluorescence in situ hybridisation...
November 13, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/29134633/first-in-human-study-with-the-inhaled-tlr9-oligonucleotide-agonist-azd1419-results-in-interferon-responses-in-the-lung-and-is-safe-and-well-tolerated
#7
Sam Jackson, Albert F Candia, Stephen Delaney, Simone Floettmann, Clifford Wong, John D Campbell, Sariah Kell, Jeremy Lum, Edith Hessel, Paula Traquina, Mark McHale, Ian Robinson, John Bell, Rainard Fuhr, David Keeling, Robert L Coffman
Current asthma treatments address symptoms rather than the underlying disease pathophysiology, a better understanding of which has led to the identification of the Th2 high endotype. The activation of Toll-like receptors to induce Type I interferons directly in the lungs represents a novel therapeutic approach to reset this underlying Th2 pathophysiology with the potential to provide long-term disease modification. We present the nonclinical data and phase 1 clinical profile of an inhaled TLR9 agonist, AZD1419, a C-type CpG designed to induce interferon in the lung...
November 14, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/29132918/the-first-in-human-experience-with-a-minimally-invasive-ambulatory-counterpulsation-heart-assist-system-for-advanced-congestive-heart-failure
#8
Valluvan Jeevanandam, Tae Song, David Onsager, Takeyoshi Ota, Colleen Juricek LaBuhn, Thomas Lammy, Gabriel Sayer, Gene Kim, Sonna Patel-Raman, Nir Uriel
BACKGROUND: The intravascular ventricular assist system (iVAS) is a new, minimally invasive, ambulatory counterpulsation heart assist system delivered via the subclavian artery and powered by a portable driver. It is designed for recovery, bridge to transplantation (BTT) or for prolonging medical therapy. We report the first-in-human (FIH) experience with iVAS. METHODS: This is a prospective, non-randomized single arm, U.S. Food and Drug Administration (FDA)-approved early feasibility trial in patients listed for cardiac transplantation...
November 10, 2017: Journal of Heart and Lung Transplantation
https://www.readbyqxmd.com/read/29129011/embodiment-and-estrangement-results-from-first-in-human-intelligent-bci-trial
#9
F Gilbert, M Cook, T O'Brien, J Illes
While new generations of implantable brain computer interface (BCI) devices are being developed, evidence in the literature about their impact on the patient experience is lagging. In this article, we address this knowledge gap by analysing data from the first-in-human clinical trial to study patients with implanted BCI advisory devices. We explored perceptions of self-change across six patients who volunteered to be implanted with artificially intelligent BCI devices. We used qualitative methodological tools grounded in phenomenology to conduct in-depth, semi-structured interviews...
November 11, 2017: Science and Engineering Ethics
https://www.readbyqxmd.com/read/29127458/safety-pharmacokinetics-and-pharmacodynamics-of-single-rising-doses-of-bi-655064-an-antagonistic-anti-cd40-antibody-in-healthy-subjects-a-potential-novel-treatment-for-autoimmune-diseases
#10
Fredrik N Albach, Frank Wagner, Andreas Hüser, Julia Igel, David Joseph, James Hilbert, Corinna Schoelch, Steven J Padula, Jürgen Steffgen
PURPOSE: The CD40-CD40L pathway is a promising treatment target for autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus and lupus nephritis. The safety, pharmacokinetics and pharmacodynamics of BI 655064, a novel humanised antagonistic anti-CD40 monoclonal antibody, were investigated in this first-in-human trial. METHODS: Healthy male subjects (n = 72) were randomised 3:1, within each BI 655064 dose group, to single intravenous (IV; 0...
November 10, 2017: European Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29127268/sickle-mice-are-sensitive-to-hypoxia-ischemia-induced-stroke-but-respond-to-tissue-type-plasminogen-activator-treatment
#11
Yu-Yo Sun, Jolly Lee, Henry Huang, Mary B Wagner, Clinton H Joiner, David R Archer, Chia-Yi Kuan
BACKGROUND AND PURPOSE: The effects of lytic stroke therapy in patients with sickle cell anemia are unknown, although a recent study suggested that coexistent sickle cell anemia does not increase the risk of cerebral hemorrhage. This finding calls for systemic analysis of the effects of thrombolytic stroke therapy, first in humanized sickle mice, and then in patients. There is also a need for additional predictive markers of sickle cell anemia-associated vasculopathy. METHODS: We used Doppler ultrasound to examine the carotid artery of Townes sickle mice tested their responses to repetitive mild hypoxia-ischemia- and transient hypoxia-ischemia-induced stroke at 3 or 6 months of age, respectively...
November 10, 2017: Stroke; a Journal of Cerebral Circulation
https://www.readbyqxmd.com/read/29113291/treatment-of-advanced-gastrointestinal-cancer-with-genetically-modified-autologous-mesenchymal-stem-cells-treat-me-1-a-phase-i-first-in-human-first-in-class-trial
#12
Jobst C von Einem, Sylvia Peter, Christine Günther, Hans-Dieter Volk, Gerald Grütz, Christoph Salat, Oliver Stoetzer, Peter J Nelson, Marlies Michl, Dominik P Modest, Julian W Holch, Martin Angele, Christiane Bruns, Hanno Niess, Volker Heinemann
Purpose: This phase I, first in human, first in class clinical study aimed at evaluating the safety, tolerability and efficacy of treatment with genetically modified mesenchymal stromal cells (MSC) in combination with ganciclovir (GCV). MSC_apceth_101 are genetically modified autologous MSCs used as vehicles for a cell-based gene therapy in patients with advanced gastrointestinal adenocarcinoma. Experimental design: The study design consisted of a dose-escalation 3 + 3 design...
October 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/29109773/quantitative-three-dimensional-dynamic-contrast-enhanced-ultrasound-imaging-first-in-human-pilot-study-in-patients-with-liver-metastases
#13
Ahmed El Kaffas, Rosa Maria Silveira Sigrist, George Fisher, Sunitha Bachawal, Joy Liau, Huaijun Wang, Alexander Karanany, Isabelle Durot, Jarrett Rosenberg, Dimitre Hristov, Jürgen K Willmann
Purpose: To perform a clinical assessment of quantitative three-dimensional (3D) dynamic contrast-enhanced ultrasound (DCE-US) feasibility and repeatability in patients with liver metastasis, and to evaluate the extent of quantitative perfusion parameter sampling errors in 2D compared to 3D DCE-US imaging. Materials and Methods: Twenty consecutive 3D DCE-US scans of liver metastases were performed in 11 patients (45% women; mean age, 54.5 years; range, 48-60 years; 55% men; mean age, 57.6 years; range, 47-68 years)...
2017: Theranostics
https://www.readbyqxmd.com/read/29108355/a-phase-i-clinical-trial-of-binimetinib-in-combination-with-folfox-in-patients-with-advanced-metastatic-colorectal-cancer-who-failed-prior-standard-therapy
#14
May Cho, Jun Gong, Paul Frankel, Timothy W Synold, Dean Lim, Vincent Chung, Joseph Chao, Daneng Li, Yuan Chen, Stephen Sentovich, Kurt Melstrom, Gagandeep Singh, Eloise Luevanos, Marwan Fakih
Background: This was a first in-human, open-label, dose-escalation phase I study conducted to evaluate the maximum tolerated dose (MTD), safety, and efficacy of the combination of oral binimetinib and FOLFOX. Materials and Methods: Patients with metastatic colorectal cancer (mCRC) who progressed on prior standard therapies received twice daily binimetinib continuously or intermittently with FOLFOX. Dose-limiting toxicities (DLTs) were assessed in the first 2 cycles of study treatment...
October 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/29105746/promoting-safe-early-clinical-research-of-novel-drug-candidates-a-european-union-regulatory-perspective
#15
Stefano Ponzano, Kevin Blake, Milton Bonelli, Harald Enzmann
The European Medicines Agency (EMA) revises its guideline on minimizing risk in first-in-human trials to reflect changing practice and in light of a recent tragic incident.
November 6, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/29103049/challenges-to-informed-consent-in-first-in-human-trials-involving-novel-treatments-a-case-study-of-parkinson-s-disease
#16
Kristina Hug, Mats Johansson
Obtaining informed consent in clinical trials can be challenging both for researchers and for patients, albeit in different ways. The challenge concerns not only how to provide the needed information, but also what information to focus on when dealing with individual patients who have different goals, needs, histories, etc. This paper aims to contribute to a better informed consent process for Parkinson's patients taking part in first-in-human clinical trials of cell replacement therapies. It outlines a range of problems which patients and researchers may face in this process and provides practical advice to researchers engaged in such trials...
2017: Journal of Parkinson's Disease
https://www.readbyqxmd.com/read/29100944/regulatory-dendritic-cells-for-promotion-of-liver-transplant-operational-tolerance-rationale-for-a-clinical-trial-and-accompanying-mechanistic-studies
#17
REVIEW
Angus W Thomson, Abhinav Humar, Fadi G Lakkis, Diana M Metes
Dendritic cells (DC) are rare, bone marrow (BM)-derived innate immune cells that critically maintain self-tolerance in the healthy steady-state. Regulatory DC (DCreg) with capacity to suppress allograft rejection and promote transplant tolerance in pre-clinical models can readily be generated from BM precursors or circulating blood monocytes. These DCreg enhance allograft survival via various mechanisms, including promotion of regulatory T cells. In non-human primates receiving minimal immunosuppressive drug therapy (IS), infusion of DCreg of donor origin, one week before transplant, safely prolongs renal allograft survival and selectively attenuates anti-donor CD8(+) memory T cell responses in the early post-transplant period...
October 31, 2017: Human Immunology
https://www.readbyqxmd.com/read/29096426/results-and-evaluation-of-a-first-in-human-study-of-rg7342-a-mglu5-positive-allosteric-modulator-utilizing-bayesian-adaptive-methods
#18
Stefan Sturm, Marie-Laure Delporte, Salah Hadi, Scott Schobel, Lothar Lindemann, Robert Weikert, Georg Jaeschke, Michael Derks, Giuseppe Palermo
AIM: The objectives of this first-in-human study were to evaluate the safety and tolerability, pharmacokinetics and pharmacodynamics, and to determine the maximum tolerated dose (MTD) of single ascending oral doses of RG7342, a positive allosteric modulator (PAM) of the metabotropic glutamate receptor 5 (mGlu5) for the treatment of schizophrenia, in healthy male subjects. METHODS: This was a single-centre, randomized, double-blind, adaptive study of 37 subjects receiving single ascending oral doses of RG7342 (ranging from 0...
November 2, 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29093180/the-fcrn-inhibitor-rozanolixizumab-reduces-human-serum-igg-concentration-a-randomized-phase-1-study
#19
Peter Kiessling, Rocio Lledo-Garcia, Shikiko Watanabe, Grant Langdon, Diep Tran, Muhammad Bari, Louis Christodoulou, Emma Jones, Graham Price, Bryan Smith, Frank Brennan, Ian White, Stephen Jolles
Pathogenic immunoglobulin G (IgG) autoantibodies characterize some human autoimmune diseases; their high concentration and long half-life are dependent on recycling by the neonatal Fc receptor (FcRn). Inhibition of FcRn is an attractive new treatment concept for IgG-mediated autoimmune diseases. Rozanolixizumab (UCB7665; CA170_01519.g57 IgG4P) is an anti-human FcRn monoclonal antibody. In cynomolgus monkeys, rozanolixizumab reduced IgG (maximum 75 to 90% by about day 10), was well tolerated, and did not increase risk of infection...
November 1, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/29084372/a-phase-i-ii-exploratory-clinical-trial-for-intracordal-injection-of-recombinant-hepatocyte-growth-factor-for-vocal-fold-scar-and-sulcus
#20
Shigeru Hirano, Atsuhiko Kawamoto, Ichiro Tateya, Masanobu Mizuta, Yo Kishimoto, Nao Hiwatashi, Yoshitaka Kawai, Takuya Tsuji, Ryo Suzuki, Mami Kaneko, Yasushi Naito, Tatsuo Kagimura, Tatsuo Nakamura, Shin-Ichi Kanemaru
BACKGROUND: Vocal fold scar and sulcus are intractable diseases with no effective established treatments. Hepatocyte growth factor (HGF) has preclinically proven to have potent anti-fibrotic and regenerative effects on vocal fold scar. The current phase I/II clinical trial aims to examine the safety and effectiveness of intracordal injection of a recombinant human HGF drug for patients with vocal fold scar or sulcus. STUDY DESIGN: Phase I/II, open-label, dose-escalating, first-in-human clinical trial...
October 30, 2017: Journal of Tissue Engineering and Regenerative Medicine
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