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Clinical trials -- Analysis

Summary Background Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. Methods In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH, non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2--F3, or F1 with at least one accompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpoints for the month-18 interim analysis were fibrosis improvement ([greater than or equal to]1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2--F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. Findings Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1--F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2--F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0*045), and 71 (23%) in the obeticholic acid 25 mg group (p=0*0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0*18], and 36 [12%] in the obeticholic acid 25 mg group [p=0*13]). In the safety population (1968 patients with fibrosis stages F1--F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). Interpretation Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes. Funding Intercept Pharmaceuticals. Author Affiliation: (a) Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, VA, USA (b) Sorbonne Universite, Assistance Publique-Hopitaux de Paris, Hopital Pitie--Salpetriere, Institute for Cardiometabolism and Nutrition, Paris, France (c) NAFLD Rsearch Center, University of California San Diego, San Diego, CA, USA (d) Feinberg School of Medicine, Northwestern University, Chicago, IL, USA (e) The Newcastle Liver Research Group, Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK (f) Newcastle NIHR Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK (g) Service d'Anatomie Pathologique, Hopital Beaujon, Assistance Publique-Hopitaux de Paris, Paris, France (h) Department of Hepatology, University of Wuerzburg, Wuerzburg, Germany (i) St Josef-Krankenhaus Kupferdreh, Essen, Germany (j) National Institute for Health Research Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust and University of Birmingham, Birmingham, UK (k) Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK (l) Institute of Translational & Stratified Medicine, University of Plymouth and University Hospitals Plymouth NHS Trust, Plymouth, UK (m) Fresno Clinical Research Center, Fresno, CA, USA (n) Baylor Health, Liver Consultants of Texas, Dallas, TX, USA (o) Arkansas Gastroenterology, North Little Rock, AR, USA (p) Texas Liver Institute, University of Texas Health San Antonio, San Antonio, TX, USA (q) Division of Gastroenterology and Hepatology, Duke University Medical Center, Durham, NC, USA (r) Swedish Liver Center, Seattle, WA, USA (s) Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, Canada (t) HIFIH Laboratory, UPRES EA3859, SFR 4208, Angers University, Angers, France (u) Hepato-Gastroenterology Department, Angers University Hospital, Angers, France (v) Hepato-gastroenterology, CHU Lille, Lille, France (w) Department of Medical Sciences, University of Turin, Turin, Italy (x) Dipartimento di Scienze Mediche e Chirurgiche, University of Bologna, Bologna, Italy (y) Department of Gastroenterology, Hospital Universitario La Paz, Madrid, Spain (z) Clinica Universitaria de Gastrenterologia, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal (aa) Liver Unit, Hospital Clinic de Barcelona, Barcelona, Spain (ab) Institut D'investigacions Biomediques August Pi I Sunyer, Barcelona, Spain (ac) Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas, Barcelona, Spain (ad) New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand (ae) The Gastrounit, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark (af) University Clinic for Visceral Surgery and Medicine, Inselspital, University of Bern, Bern, Switzerland (ag) Intercept Pharmaceuticals, San Diego, CA, USA (ah) Pinnacle Clinical Research Center, San Antonio, TX, USA (ai) Department of Internal Medicine, Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, Richmond, VA, USA * Correspondence to: Prof Arun J Sanyal, Department of Internal Medicine, Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, Richmond, VA 23298, USA (footnote)* Joint first authors (footnote)[Dagger] Joint senior authors Byline: Zobair M Younossi, MD (a), Vlad Ratziu, MD (b), Rohit Loomba, MD (c), Mary Rinella, MD (d), Quentin M Anstee, MD (e,f), Zachary Goodman, MD (a), Pierre Bedossa, MD (g), Andreas Geier, MD (h), Susanne Beckebaum, MD (i), Philip N Newsome, MD (j,k), David Sheridan, MD (l), Muhammad Y Sheikh, MD (m), James Trotter, MD (n), Whitfield Knapple, MD (o), Eric Lawitz, MD (p), Manal F Abdelmalek, MD (q), Prof Kris V Kowdley, MD (r), Aldo J Montano-Loza, MD (s), Jerome Boursier, MD (t,u), Philippe Mathurin, MD (v), Elisabetta Bugianesi, MD (w), Giuseppe Mazzella, MD (x), Antonio Olveira, MD (y), Helena Cortez-Pinto, MD (z), Isabel Graupera, MD (aa,ab,ac), David Orr, MD (ad), Lise Lotte Gluud, MD (ae), Jean-Francois Dufour, MD (af), David Shapiro, MD (ag), Jason Campagna, MD (ag), Luna Zaru, PhD (ag), Leigh MacConell, PhD (ag), Reshma Shringarpure, PhD (ag), Stephen Harrison, MD (ah,[Dagger]), Prof Arun J Sanyal, MD [arun.sanyal@vcuhealth.org] (ai,[Dagger]), Manal Abdelmalek, Gary Abrams, Humberto Aguilar, Aijaz Ahmed, Elmar Aigner, Guruprasad Aithal, Aftab Ala, William Alazawi, Agustin Albillos, Michael Allison, Sfa Al-Shamma, Raul Andrade, Pietro Andreone, Mario Angelico, Victor Ankoma-Sey, Quentin Anstee, Rodolphe Anty, Victor Araya, Juan Ignacio Arenas Ruiz, Perttu Arkkila, Marty Arora, Tarik Asselah, Jennifer Au, Oyekoya Ayonrinde, Robert James Bailey, Maya Balakrishnan, Kiran Bambha, Meena Bansal, Sidney Barritt, John Bate, Jorge Beato, Susanne Beckebaum, Jaideep Behari, Pablo Bellot, Ziv Ben Ari, Michael Bennett, Marina Berenguer, Benedetta Terziroli Beretta-Piccoli, Thomas Berg, Maurizio Bonacini, Lucia Bonet, Brian Borg, Marc Bourliere, Jerome Boursier, William Bowman, David Bradley, Marija Brankovic, Marius Braun, Jean-Pierre Bronowicki, Savino Bruno, Elisabetta Bugianesi, Cindy Cai, Jose Luis Calleja Panero, Elizabeth Carey, Michal Carmiel, Jose Antonio Carrion, Matthew Cave, Cristina Chagas, Tawfik Chami, Alan Chang, Allan Coates, Jeremy Cobbold, Kathleen Corey, Lynsey Corless, Helena Cortez-Pinto, Javier Crespo, Oscar Cruz Pereira, Victor de Ledinghen, Andrew deLemos, Moises Diago, Jean-Francois Dufour, Predrag Dugalic, Winston Dunn, Magby Elkhashab, Michael Epstein, Maria Desamparados Escudero-Garcia, Ohad Etzion, Larry Evans, Robert Falcone, Conrado Fernandez, Jose Ferreira, Scott Fink, Kevin Finnegan, Roberto Firpi-Morell, Annarosa Floreani, Thierry Fontanges, Ryan Ford, Ewan Forrest, Andrew Fowell, Anna Ludovica Fracanzani, Sven Francque, Bradley Freilich, Juan Frias, Michael Fuchs, Javier Fuentes, Michael Galambos, Juan Gallegos, Anja Geerts, Andreas Geier, Jacob George, Maged Ghali, Reem Ghalib, Pierre Gholam, Pere Gines, Norman Gitlin, Lise Lotte Gluud, Tobias Goeser, John Goff, Stuart Gordon, Frederic Gordon, Odile Goria, Shaun Greer, Alla Grigorian, Henning Gronbaek, Maeva Guillaume, Naresh Gunaratnam, Dina Halegoua-De Marzio, Bilal Hameed, Stephanie Hametner, James Hamilton, Stephen Harrison, Marek Hartleb, Tarek Hassanein, Dieter Haussinger, Paul Hellstern, Robert Herring, Eva Heurich, Christophe Hezode, Holger Hinrichsen, Peter Holland Fischer, Yves Horsmans, Jonathan Huang, Antoine Jakiche, Lennox Jeffers, Blake Jones, Rosa Jorge, Francisco Jorquera, Alisan Kahraman, Kelly Kaita, Nicholas Karyotakis, Zeid Kayali, Stergios Kechagias, Thomas Kepczyk, Mandana Khalili, Hicham Khallafi, Johannes Kluwe, Whitfield Knapple, Anita Kohli, Kevin Korenblat, Kris Kowdley, Aleksander Krag, Richard Krause, Andreas Kremer, Karen Krok, Miodrag Krstic, Marcelo Kugelmas, Sonal Kumar, Damien Labarriere, Michelle Lai, Pietro Lampertico, Eric Lawitz, Alice Lee, Vincent Leroy, Steven Lidofsky, Tina Huey Lim, Joseph Lim, Donald Lipkis, Ester Little, Amadeo Lonardo, Michelle Long, Rohit Loomba, Yoav Lurie, Guilherme Macedo, Mihaly Makara, Benedict Maliakkal, Michael Manns, Pinelopi Manousou, Parvez Mantry, Giulio Marchesini, Carla Marinho, Paul Marotta, Hanns-Ulrich Marschall, Philippe Mathurin, Marlyn Mayo, Giuseppe Mazzella, Mark McCullen, William McLaughlin, Raphael Merriman, Apurva Modi, Esther Molina, Aldo Montano-Loza, Carlos Monteverde, Sulleman Moreea, Christophe Moreno, Filomena Morisco, Abdullah Mubarak, Beat Muellhaupt, Sandeep Mukherjee, Tobias Muller, Aleksandar Nagorni, Jahnavi Naik, Guy Neff, Moises Nevah, Philip Newsome, Eric Nguyen-Khac, Mazen Noureddin, Jude Oben, Antonio Olveira, Hans Orlent, David Orr, James Orr, Grisell Ortiz-Lasanta, Violaine Ozenne, Prashant Pandya, Angelo Paredes, James Park, Joykumar Patel, Keyur Patel, Merle Uta, Heather Patton, Markus Peck-Radosavljevic, Salvatore Petta, Stephen Pianko, Anna Piekarska, Neville Pimstone, Paul Pockros, Stanislas Pol, Michael Porayko, John Poulos, David Pound, Joe Pouzar, Jose Presa Ramos, Nikolaos Pyrsopoulos, Nila Rafiq, Kate Muller, Alnoor Ramji, Vlad Ratziu, Ravi Ravinuthala, Chakradhar Reddy, Gautham Reddy K G, K. Rajender Reddy K R, Frederic Regenstein, Robert Reindollar, Andres Riera, Mary Rinella, Jose Rivera Acosta, Geert Robaeys, Stuart Roberts, Federico Rodriguez-Perez, Manuel Romero-Gomez, Raymond Rubin, Mariagrazia Rumi, Simon Rushbrook, Christian Rust, Michael Ryan, Rifaat Safadi, Adnan Said, Kimmo Salminen, Didier Samuel, John Santoro, Arun Sanyal, Souvik Sarkar, Cynthia Schaeffer, Jorn Schattenberg, Ingolf Schiefke, Eugene Schiff, Wolfgang Schmidt, Jeffrey Schneider, Jeoffrey Schouten, Michael Schultz, Giada Sebastiani, David Semela, Thomas Sepe, Aasim Sheikh, Muhammad Sheikh, David Sheridan, Kenneth Sherman, Oren Shibolet, Mitchell Shiffman, Asma Siddique, Cyril Sieberhagen, Samuel Sigal, Katarzyna Sikorska, Krzysztof Simon, Marie Sinclair, Richard Skoien, Joel Solis, Siddharth Sood, Bob Souder, James Spivey, Per Stal, Laura Stinton, Simone Strasser, Petar Svorcan, Gyongzi Szabo, Andrew Talal, Edward Tam, Brent Tetri, Paul Thuluvath, Hillel Tobias, Krzysztof Tomasiewicz, Dawn Torres, Michael Trauner, Christian Trautwein, James Trotter, Emanuel Tsochatzis, Esther Unitt, Victor Vargas, Istvan Varkonyi, Ella Veitsman, Umberto Vespasiani Gentilucci, David Victor, John Vierling, Catherine Vincent, Aron Vincze, Manfred von der Ohe, Natasha Von Roenn, Raj Vuppalanchi, Michael Waters, Kymberly Watt, Martin Weltman, Amanda Wieland, Gregory Wiener, Alonzo Williams A, Jeffrey Williams J, Jason Wilson, Maria Yataco, Eric Yoshida, Ziad Younes, Liyun Yuan, Adam Zivony, Donald Zogg, Heinz Zoller, Fabien Zoulim, Eli Zuckerman, Massimo Zuin

Breast cancer -- Drug therapy, Tamoxifen -- Dosage and administration, Menopause -- Physiological aspects, Cancer -- Adjuvant treatment, and Cancer -- Usage

Rice -- Physiological aspects, Rice -- Genetic aspects, Plant diseases -- Prevention, Plant diseases -- Physiological aspects, Plant diseases -- Genetic aspects, Plant parasites -- Prevention, Plant parasites -- Genetic aspects, and Plant genetics -- Research

The BROWN PLANTHOPPER is one of the most serious insect pests of rice (O. sativa L.) and can cause significant yield losses. In addition to direct damage, BPH also acts [...]
Brown plant hopper (BPH), Nilaparvata lugens (Stal.), is a serious insect pest of rice in Asia, causing direct losses and vectoring Rice grassy stunt virus (RGSV) and Rice ragged stunt virus (RRSV). Recombinant inbred lines (RILs) developed from a cross between `IR50' and `IR54745-2-21-12-17-6' were used to identify random amplified polymorphic DNA (RAPD) markers closely linked to a BPH Biotype-4 resistance gene [Bph13 (t)] derived from Oryza officinalis Wall. Bulked segregant analysis (BSA) using RAPD primers identified 11 polymorphic fragments. Six fragments, AJ09 [sub.260]a, AL05 [sub.220]a, AK10 [sub.690]a, AK10 [sub.430]c, AK10 [sub.380]d, and AJ01 [sub.200]a, were linked in coupling phase to the Bph13 (t) locus. The remaining five fragments, AJ09 [sub.230]b, AJ09 [sub.180]c, AJ09 [sub.100]d, AL05 [sub.400]b, and AK10 [sub.340]e, were linked in repulsion. The most closely linked RAPD marker, AJ09 [sub.230]b, was converted to a codominant linked sequence tagged sites (STS) marker. This marker mapped 1.3 centimorgans (cM) from the resistance gene and was placed on rice chromosome 3 by means of `IR64' x `Azucena' doubled haploid (DH) population. The tightly linked STS marker could be used for marker-assisted selection (MAS). In addition, these markers will be useful for a positional cloning strategy to isolate the resistance gene.