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1. Aldafermin in patients with non-alcoholic steatohepatitis (ALPINE 2/3): a randomised, double-blind, placebo-controlled, phase 2b trial

Author

Harrison, Stephen A, Abdelmalek, Manal F, Neff, Guy, Gunn, Nadege, Guy, Cynthia D, Alkhouri, Naim, Bashir, Mustafa R, Freilich, Bradley, Kohli, Anita, Khazanchi, Arun, Sheikh, Muhammad Y, Leibowitz, Mark, Rinella, Mary E, Siddiqui, Mohammad S, Kipnes, Mark, Moussa, Sam E, Younes, Ziad H, Bansal, Meena, Baum, Seth J, Borg, Brian, Ruane, Peter J, Thuluvath, Paul J, Gottwald, Mildred, Khan, Mujib, Chen, Charles, Melchor-Khan, Liza, Chang, William, DePaoli, Alex M, Ling, Lei, and Lieu, Hsiao D

Published
2022
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3. Selonsertib for patients with bridging fibrosis or compensated cirrhosis due to NASH: Results from randomized phase III STELLAR trials

Author

Gadano, Adrian, Martins, Marcelo, Angus, Peter, Bate, John, Danta, Mark, George, Jacob, Hodge, Alexander, Kontorinis, Nickolas, Roberts, Stuart, Sanagapalli, Santosh, Skoien, Richard, Thompson, Alexander, Zekry, Amany, Stauber, Rudolf, Trauner, Michael, Moreno, Christophe, Reynaert, Hendrik, Verbeke, Len, Silva, Mario Reis Alvares da, Parise, Edison, Oliveira, Claudia Pinto Marques Souza de, Araujo, Roberta Chaves, Martinelli, Ana de Lourdes Candolo, Borman, Meredith, Chandok, Natasha, Elkhashab, Magdy, Fraser, Hughie, Kaita, Kelly, Ma, Mang, Marotta, Paul, Ramji, Alnoor, Tam, Edward, Yoshida, Eric, Swain, Mark, Sebastiani, Giada, Petrunia, Denis, Abergel, Armando, Anty, Rodolphe, Bourlière, Marc, Boursier, Jérôme, Bureau, Christophe, Castera, Laurent, Habersetzer, François, Hézode, Christophe, Ledinghen, Victor De, Leroy, Vincent, Loustaud-Ratti, Véronique, Mathurin, Philippe, Pol, Stanislas, Zoulim, Fabien, Hinrichsen, Holger, Ingiliz, Patrick, Lammert, Frank, Manns, Michael, Schattenberg, Jörn, Schiefke, Ingolf, Trautwein, Christian, Zeuzem, Stefan, Hui, Aric, Li, King-Kong, Wong, Vincent, Acharya, Subrat, Chowdhury, Abhijit, Duseja, Ajay, Kapoor, Dharmesh, Mukewar, Shrikant, Sarin, Shiv, Shah, Samir, Shalimar, Sood, Ajit, Tantry, BV, Ben-Ari, Ziv, Katchman, Helena, Safadi, Rifaat, Veitsman, Ella, Zuckerman, Eli, Brunetto, Maurizia, Lampertico, Pietro, Mangia, Alessandra, Akahane, Takemi, Akuta, Norio, Eguchi, Yuichiro, Fujiyama, Shigetoshi, Genda, Takuya, Hiasa, Yoichi, Ido, Akio, Ikeda, Fusao, Ikegami, Tadashi, Imajo, Kento, Itoh, Yoshito, Iwasa, Motoh, Karino, Yoshiyasu, Kato, Naoya, Kawaguchi, Takumi, Kawanaka, Miwa, Kido, Masahiro, Kobayashi, Tomoo, Kurosaki, Masayuki, Matsuzaki, Yasushi, Mita, Eiji, Mizukoshi, Eishiro, Nakahara, Takashi, Nomura, Hideyuki, Notsumata, Kazuo, Okanoue, Takeshi, Saito, Satoshi, Sakugawa, Hiroshi, Suzuki, Yoshiyuki, Takaguchi, Koichi, Takaki, Akinobu, Takashima, Tomoyuki, Tanaka, Saiyu, Tsuji, Keiji, Ueno, Yoshiyuki, Umemura, Takeji, Uto, Hirofumi, Yamashita, Nobuyuki, Yanase, Mikio, Yatsuhashi, Hiroshi, Yoneda, Masashi, Chan, Wah Kheong, Tan, Soek Siam, Garza, Laura Cisneros, Ladron De Guevara Cetina, Alma, Angeles, Rocio Guadalupe Vargas, Silva, Francisca Martinez, Van Erpecum, Karel, Orr, David, Jabłkowski, Maciej, Jaroszewicz, Jerzy, Ramos, Jose, Ahmed, Taufique, Ang, Tiing, Dan, Yock young, Goh, Boon Bee, Kaliyaperumal, Kalaiyarasi, Yip, Cherng Hann, Baik, Soon Koo, Jang, Byoung Kuk, Jun, Dae Won, Kim, Won, Kim, Hyung Joon, Kim, Ji Hoon, Lee, Kwan Sik, Lee, Chun Kyon, Lim, Young-Suk, Park, Jun Yong, Tak, Won Young, Augustin, Salvador, Perez, Salvador Benlloch, Caballeria, Juan, Luis, Jose, Panero, Calleja, Rodríguez, Jose Carrión, Garcia, Javier Crespo, Samaniego, Javier Garcia, Gibert, Pere Ginès, Prieto, Martin, Gomez, Manuel Romero, Turnes, Juan, Dufour, Jean-Francois, Moriggia, Alberto, Sheen, I-Shyan, Kao, Jia-Horng, Cheng, Pin-Nan, Huang, Jee-Fu, Yang, Sheng-Shun, Su, Wei-Wen, Chen, Chi-Yi, Chien, Rong-Nan, Lo, Gin-Ho, Chu, Chi-Jen, Wang, Horng-Yuan, Hu, Jui-Ting, Huang, Yi Wen, Agarwal, Kosh, Allison, Michael, Anstee, Quentin, Austin, Andrew, Fowell, Andrew, Ch'ng, Chin Lye, Manousou, Pinelopi, Newsome, Philip, Ryder, Stephen, Shankar, Arun, Abdelmalek, Manal, Abrams, Gary, Aguilar, Humberto, Alam, Imtiaz, Alba, Laura, Alkhouri, Naim, Allen, Alina, Aqel, Bashar, Balart, Luis, Barritt, A. Sidney, IV, Behari, Jaideep, Bennett, Michael, Bernstein, David, Bhandari, Bal Raj, Bonacini, Maurizio, Borg, Brian, Brown, Kimberly, Bzowej, Natalie, Caldwell, Stephen, Chami, Tawfik, Coates, Allan, Cueli, Adolfo, Davis, Mitchell, deLemos, Andrew, Desai, Archita, Dunn, Winston, Ferreira, Nelson, Fine, Michael, Firpi-Morell, Roberto, Freedland, Curtis, Freilich, Bradley, Fuchs, Michael, Galambos, Michael, Gallegos-Orozco, Juan, Galler, Greg, Ghali, Maged, Ghalib, Reem, Gill, Satinder, Gillis, Marcum, Gilroy, Richard, Gordon, Stuart, Gunn, Nadege, Halegoua-DeMarzio, Dina, Hassan, Mohamed, Hassanein, Tarek, Herring, Robert, Jr., Hong, John, Huang, Jonathan, Kabler, Heidi, Kayali, Zeid, Knapple, Whitfield, Kolli, Geetha, Kowdley, Kris, Krause, Richard, Lawitz, Eric, Lidofsky, Steven, Lim, Joseph, Lipkis, Donald, Loomba, Rohit, Mahgoub, Amar, Malespin, Miguel, Manch, Richard, Mannis, Steven, Manos, Paul, McDonald, Thomas, McKenzie, Mark, Mena, Edward, Merriman, Raphael, Moehlen, Martin William, Montgomery, Richard, Murphy, Robert, Natarajan, Yamini, Neff, Guy, Noureddin, Mazen, Ortiz-Lasanta, Grisell, Pagadala, Mangesh, Patel, Keyur, Patton, Heather, Peyton, Adam, Pimstone, Neville, Poulos, John, Pound, David, Pyrsopoulos, Nikolaos, Rafiq, Nila, Ravendhran, Natarajan, Ravinuthala, Ravi, Reddy, K. Rajendar, Reindollar, Robert, Reynolds, Justin, Rinella, Mary, Rizvi, Syed, Rockey, Don, Rodriguez-Perez, Federico, Ruane, Peter, Rubin, Raymond, Ryan, Michael, Saeian, Kia, Sanyal, Arun, Sarkar, Souvik, Scanga, Andrew, Schiff, Eugene, Schmidt, Warren, Schneider, Jeffrey, Sepe, Thomas, Shah, Dhiren, Shaikh, Obaid, Shankar, Uday, Sheikh, Aasim, Sheikh, Muhammad, Sherman, Kenneth, Shiffman, Mitchell, Siddique, Asma, Smith, Matthew, Suarez, Rosa, Talal, Andrew, Te, Helen, Tekola, Bezawit, Tetri, Brent, Thuluvath, Paul, Toro, Doris, Torres, Dawn, Trinh, Huy, Trotter, James, Vento, Angel, Vierling, John, Vuppalanchi, Raj, Waters, Michael, Weisberg, Ilan, Wieland, Amanda, Williams, Alonzo, Younes, Ziad, Adams, Leon, Harding, Damian, Hodge, Alex, Kontorinis, Nick, Strasser, Simone, Thompson, Alex, Horsmans, Yves, Steenkiste, Christophe Van, Bailey, Robert, Giard, Jeanne-Marie, Montano-Loza, Aldo, Puglia, Marco, Tsoi, Keith, Larrey, Dominique, Nguyen-Khac, Eric, Ratziu, Vlad, Spengler, Ulrich, Wiegand, Johannes, Hui, Aric Josun, Acharya, Subrat Kumar, Sarin, Shiv Kumar, Tantry, Vishwanath, Braun, Marius, Hazzan, Rawi, Lurie, Yoav, Colombo, Massimo, Fujii, Hideki, Hashimoto, Etsuko, Kato, Masaki, Ogawa, Koji, Takehara, Tetsuo, Tokushige, Katsutoshi, Garza, Laura Esthela Cisneros, Ladrón De Guevara, Alma Laura, Schultz, Michael, Janczewska, Ewa, Toro, Doris H., Jeong, Sook-Hyang, Kim, Yoon Jun, Lee, Jin-Woo, Ang, Tiing Leong, Bee, George Goh Boon, Benlloch, Salvador, Caballería, Juan, Calleja, José Luis, Rodríguez, Jose A. Carrión, Crespo, Javier, Diago, Moises, Fernandez-Rodriguez, Conrado, García-Samaniego, Javier, Ginès, Pere, Romero, Manuel, Dufour, Jean-François, Alazawi, William, Ch'ng, Chin-Lye, Forton, Daniel, Priest, Matthew, Sheridan, David, Ankoma-Sey, Victor, Balakrishnan, Maya, Bambha, Kiran, Barritt, A. Sidney, Bhandari, Bal, Brandman, Danielle, Chang, Charissa, Corey, Kathleen, Feldman, Michael, Gholam, Pierre, Goff, John, Marzio, Dina Halegoua-De, Harrison, Stephen, Hellstern, Paul, Jr., Herring, Robert, Iyer, Rajalakshmi, Jakiche, Antoine, Kohli, Anita, Krok, Karen, Kugelmas, Marcelo, Kumar, Sonal, Lai, Michelle, Mahmoud, Mitchell, Mantry, Parvez, Marsano, Luis, Nguyen, Tuan, Park, James, Patton, Heather M., Pockros, Paul, Reddy, Rajender, Rodriguez, Miguel, Sarles, Harry, Satapathy, Sanjaya, Sedghi, Shahriar, Shah, Nikunj, Sheikh, Muhammad Yasin, Sigal, Samuel, Stanca, Carmen, Steinbook, Michael, Szabo, Gyongyi, Terrault, Norah, Tong, Myron, Victor, David, Zervos, Xaralambos, Harrison, Stephen A., Wong, Vincent Wai-Sun, Caldwell, Stephen H., Shiffman, Mitchell L., Camargo, Marianne, Li, Georgia, Kersey, Kathryn, Jia, Catherine, Zhu, Yanni, Djedjos, C. Stephen, Subramanian, G. Mani, Myers, Robert P., Anstee, Quentin M., Romero-Gomez, Manuel, Goodman, Zachary, Lawitz, Eric J., and Younossi, Zobair

Published
2020
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4. Open‐label, clinical trial extension: Two‐year safety and efficacy results of seladelpar in patients with primary biliary cholangitis.

Author

Mayo, Marlyn J., Vierling, John M., Bowlus, Christopher L., Levy, Cynthia, Hirschfield, Gideon M., Neff, Guy W., Galambos, Michael R., Gordon, Stuart C., Borg, Brian B., Harrison, Stephen A., Thuluvath, Paul J., Goel, Aparna, Shiffman, Mitchell L., Swain, Mark G., Jones, David E. J., Trivedi, Palak, Kremer, Andreas E., Aspinall, Richard J., Sheridan, David A., and Dörffel, Yvonne

Subjects
CHOLANGITIS, CLINICAL trials, ADVERSE health care events, NON-alcoholic fatty liver disease, BIOMARKERS
Abstract

Summary: Background: Seladelpar is a potent and selective peroxisome proliferator‐activated receptor‐δ agonist that targets multiple cell types involved in primary biliary cholangitis (PBC), leading to anti‐cholestatic, anti‐inflammatory and anti‐pruritic effects. Aims: To evaluate the long‐term safety and efficacy of seladelpar in patients with PBC. Methods: In an open‐label, international, long‐term extension study, patients with PBC completing seladelpar lead‐in studies continued treatment. Seladelpar was taken orally once daily at doses of 5 or 10 mg with dose adjustment permitted for safety or tolerability. The primary analysis was for safety and the secondary efficacy analysis examined biochemical markers of cholestasis and liver injury. The study was terminated early due to the unexpected histological findings in a concurrent study for non‐alcoholic steatohepatitis, which were subsequently found to predate treatment. Safety and efficacy data were analysed through 2 years. Results: There were no serious treatment‐related adverse events observed among 106 patients treated with seladelpar for up to 2 years. There were four discontinuations for safety, one possibly related to seladelpar. Among 53 patients who completed 2 years of seladelpar, response rates increased from years 1 to 2 for the composite endpoint (alkaline phosphatase [ALP] <1.67 × ULN, ≥15% decrease in ALP, and total bilirubin ≤ULN) and ALP normalisation from 66% to 79% and from 26% to 42%, respectively. In those with elevated bilirubin at baseline, 43% achieved normalisation at year 2. Conclusions: Seladelpar was safe, and markedly improved biochemical markers of cholestasis and liver injury in patients with PBC. These effects were maintained or improved throughout the second year. Clinicaltrials.gov: NCT03301506; Clinicaltrialsregister.eu: 2017‐003910‐16. [ABSTRACT FROM AUTHOR]

Published
2024
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5. Efficacy and Safety of Sofosbuvir/Velpatasvir Plus Ribavirin in Patients with Hepatitis C Virus-Related Decompensated Cirrhosis.

Author

Flamm, Steven, Lawitz, Eric, Borg, Brian, Charlton, Michael, Landis, Charles, Reddy, K. Rajender, Shiffman, Mitchell, Alsina, Angel, Chang, Charissa, Ravendhran, Natarajan, Hernandez, Candido, Hézode, Christophe, Scherbakovsky, Stacey, Mercier, Renee-Claude, and Samuel, Didier

Subjects
HEPATITIS C, RIBAVIRIN, HEPATITIS C virus, END of treatment, CIRRHOSIS of the liver
Abstract

A fixed-dose combination of sofosbuvir/velpatasvir (SOF/VEL) plus weight-based ribavirin (RBV) for 12 weeks is recommended for the treatment of patients with hepatitis C virus (HCV)-associated decompensated cirrhosis. However, large global studies, while confirming the effectiveness of SOF/VEL in a broad range of patients, often exclude these patients. This Phase 2, single-arm, open-label study in adult patients with HCV-associated decompensated cirrhosis in France and the USA aimed to provide further data on the safety and efficacy of SOF/VEL plus RBV for 12 weeks in this population. Patients were treated with a fixed-dose combination of SOF 400 mg/VEL 100 mg plus weight-based RBV once daily for 12 weeks. The inclusion criteria were chronic HCV infection (≥6 months), quantifiable HCV RNA at screening, Child–Turcotte–Pugh class B or C cirrhosis, and liver imaging within 6 months of Day 1 to exclude hepatocellular carcinoma. Among 32 patients who initiated treatment, 78.1% achieved sustained virologic response 12 weeks after the end of treatment (SVR12). Failure to achieve SVR12 was due to non-virologic reasons (investigator discretion, n = 1; death, n = 6). All 25 patients in the per-protocol population achieved SVR12 and all but one achieved sustained virologic response 24 weeks after the end of treatment. Adverse events (AEs) were as expected for a patient population with advanced liver disease. All Grade 3–4 and serious AEs and deaths were deemed unrelated to treatment. In patients with HCV-associated decompensated cirrhosis, SOF/VEL plus RBV achieved high SVR12 rates and was generally well tolerated. [ABSTRACT FROM AUTHOR]

Published
2023
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7. Extracorporeal cellular therapy (ELAD) in severe alcoholic hepatitis: A multinational, prospective, controlled, randomized trial

Author

Thompson, Julie, Jones, Natasha, Al‐Khafaji, Ali, Malik, Shahid, Reich, David, Munoz, Santiago, MacNicholas, Ross, Hassanein, Tarek, Teperman, Lewis, Stein, Lance, Duarte‐Rojo, Andrés, Malik, Raza, Adhami, Talal, Asrani, Sumeet, Shah, Nikunj, Gaglio, Paul, Duddempudi, Anupama, Borg, Brian, Jalan, Rajiv, Brown, Robert, Patton, Heather, Satoskar, Rohit, Rossi, Simona, Parikh, Amay, ElSharkawy, Ahmed, Mantry, Parvez, Sher, Linda, Wolf, David, Hart, Marquis, Landis, Charles, Wigg, Alan, Habib, Shahid, McCaughan, Geoffrey, Colquhoun, Steven, Henry, Alyssa, Bedard, Patricia, Landeen, Lee, Millis, Michael, Ashley, Robert, Frank, William, Henry, Andrew, Stange, Jan, and Subramanian, Ram

Published
2018
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9. Impact of Pruritus on Quality of Life and Current Treatment Patterns in Patients with Primary Biliary Cholangitis.

Author

Mayo, Marlyn J., Carey, Elizabeth, Smith, Helen T., Mospan, Andrea R., McLaughlin, Megan, Thompson, April, Morris, Heather L., Sandefur, Robert, Kim, W. Ray, Bowlus, Christopher, the TARGET-PBC Investigators, Ankoma-Sey, Victor, Bernstein, David, Borg, Brian, Brown, Robert, Clark, Virginia, Darling, Jama, Dranoff, Jonathan, Elbeshbeshy, Hany, and Forman, Lisa

Subjects
ITCHING, QUALITY of life, CHOLANGITIS, FATIGUE (Physiology), KRUSKAL-Wallis Test, MEDICAL records
Abstract

Background and Aims : Patients with primary biliary cholangitis (PBC) often suffer with pruritus. We describe the impact of pruritus on quality of life and how it is managed in a real-world cohort. Methods : TARGET-PBC is a longitudinal observational cohort of patients with PBC across the USA. Data include information from medical records for three years prior to the date of consent up to 5 years of follow-up. Enrolled patients were asked to complete patient-reported outcome surveys: PBC-40, 5-D itch, and the PROMIS fatigue survey. Kruskal–Wallis tests were used to compare differences in symptoms between groups. Results : A total of 211 patients with completed PRO surveys were included in the current study. PRO respondents were compared with non-respondents in the TARGET-PBC population and were broadly similar. Pruritus was reported in 170 patients (81%), with those reporting clinically significant pruritus (30%) scoring worse across each domain of the PBC-40 and 5-D itch, more frequently having cirrhosis, and having significantly greater levels of fatigue. Patients reporting clinically significant pruritus were more likely to receive treatment, but 33% had never received treatment (no itch = 43.9%, mild itch = 38.3%). Conclusions : The prevalence of pruritus was high in this population, and those reporting clinically significant pruritus had a higher likelihood of having advanced disease and worse quality of life. However, this study found that pruritus in PBC is under-treated. This may be due in part to ineffectiveness of current treatments, poor tolerance, or the lack of FDA-approved medications for pruritus. [ABSTRACT FROM AUTHOR]

Published
2023
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14. A functional SNP of interferon-[gamma], gene is important for interferon-[alpha]-induced and spontaneous recovery from hepatitis C virus infection

Author

Huang, Ying, Yang, Huiying, Borg, Brian B., Su, Xiaowen, Rhodes, Shannon L., Yang, Kai, Tong, Xiaomei, Tang, George, Howell, Charles D., Rosen, Hugo R., Thio, Chloe L., Thomas, David L., Alter, Harvey J., Sapp, Ronda K., and Liang, T. Jake

Subjects
Hepatitis C virus -- Drug therapy, Hepatitis C virus -- Research, Hepatitis C virus -- Genetic aspects, Genetic polymorphisms -- Research, Cytokines -- Genetic aspects, Cytokines -- Research, Science and technology
Abstract

Cytokine polymorphisms are associated with disease outcome and interferon (IFN) treatment response in hepatitis C virus (HCV) infection. We genotyped eight SNPs spanning the entire IFN-[gamma] gene in two cohorts and assessed the association between those polymorphisms and treatment response or spontaneous viral clearance. The first cohort was composed of 284 chronically HCV-infected patients who had received IFN-[alpha]-based therapy and the second was 251 i.v. drug users who had either spontaneously cleared HCV or become chronically infected. A SNP variant located in the proximal IFN-[gamma], promoter region next to the binding motif of heat shock transcription factor (HSF), -764G, was significantly associated with sustained virological response [P = 0.04, odds ratio (OR) = 3.51 (confidence interval 1.0-12.5)]. The association was independently significant in multiple logistic regression (P = 0.04) along with race, viral titer, and genotype. This variant was also significantly associated with spontaneous recovery [P = 0.04, OR = 3.51 (1.0-12.5)] in the second cohort. Functional analyses show that the G allele confers a two- to three-fold higher promoter activity and stronger binding affinity to HSF1 than the C allele. Our study suggests that the IFN-[gamma] promoter SNP -764G/C is functionally important in determining viral clearance and treatment response in HCV-infected patients and may be used as a genetic marker to predict sustained virological response in HCV-infected patients. genetics | human study | cytokine | viral clearance | antiviral treatment

Published
2007

21. Emergent realities for social wellbeing : environmental, spatial and social pathways

Author

Borg, Brian

Subjects
Water utilities -- Malta, Malta. Water Services Corporation, Spatial analysis (Statistics), Geographic information systems -- Malta
Abstract

Making sure that water continues to flow irrespective of population growth, increases in tourism numbers and other seasonal demands, requires a large infrastructure, sophisticated technology, and a dedicated organisation behind it. The Water Services Corporation (WSC) in Malta has evolved over the past two decades into a modern corporation adopting innovative technological solutions and sophisticated technology that has helped deliver the best-quality service to customers. One way is by using geographic information system (GIS) based applications. Adopting this “spatial” strategy has enabled the WSC to determine how core business can exploit location data to improve decision-making, reduce risks, and optimise operations. The WSC is, as far as is known, the first large local organisation to adopt GIS to manage, control, and plan internal projects. Over the years the corporation has built up a very comprehensive GIS capacity that includes the geo-located points of all water meters, valves, taps, and pipes that exist on the Islands. Since the WSC is also responsible for Malta’s wastewater, the company also has the same facilities in this sector too, complete with slope angle and elevation data., peer-reviewed

Published
2017

22. Featured Cover.

Author

Mayo, Marlyn J., Vierling, John M., Bowlus, Christopher L., Levy, Cynthia, Hirschfield, Gideon M., Neff, Guy W., Galambos, Michael R., Gordon, Stuart C., Borg, Brian B., Harrison, Stephen A., Thuluvath, Paul J., Goel, Aparna, Shiffman, Mitchell L., Swain, Mark G., Jones, David E. J., Trivedi, Palak, Kremer, Andreas E., Aspinall, Richard J., Sheridan, David A., and Dörffel, Yvonne

Subjects
CHOLANGITIS, CLINICAL trials, PHARMACOLOGY
Abstract

This document is a featured cover image for the journal Alimentary Pharmacology & Therapeutics. The image is based on a clinical trial extension study on the safety and efficacy of seladelpar in patients with primary biliary cholangitis. The study was conducted by a team of authors and provides two-year results. The document does not provide any specific details or findings from the study, but it serves as a visual representation of the research. [Extracted from the article]

Published
2024
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23. 686 EFFECTS ON PRURITUS AND SLEEP DISTURBANCE IN PATIENTS WITH PRIMARY BILIARY CHOLANGITIS (PBC) AFTER 1 YEAR OF TREATMENT WITH SELADELPAR, A PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR DELTA AGONIST: RESULTS OF AN OPEN-LABEL PHASE 2 STUDY

Author

Kremer, Andreas E., Mayo, Marlyn J., Bowlus, Christopher L., Neff, Guy, Swain, Mark G., Galambos, Michael, Goel, Aparna, Trivedi, Palak, Hirschfield, Gideon, Aspinall, Richard, Gordon, Stuart C., Borg, Brian B., Harrison, Stephen, Thuluvath, Paul, Jones, David E., Doerffel, Yvonne, Levy, Cynthia, Stanca, Carmen, Sheridan, David, Vierling, John M., Shiffman, Mitchell L., Odin, Joseph, Bacon, Bruce, Hassanein, Tarek, Thorburn, Douglas, Berg, Christoph, Bernstein, David, Gulamhusein, Aliya, Landis, Charles, Peyton, Adam, Corless, Lynsey, Buggisch, Peter, Wörns, Marcus-Alexander, Bergheanu, Sandrin, Varga, Monika, Li, Yu, Yang, Ke, Dickinson, Klara, Boudes, Pol, McWherter, Charles A., Steinberg, Alexandra, and Choi, Yun-Jung

Published
2020
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24. Interleukin-6 (IL-6) haplotypes and the response to therapy of chronic hepatitis C virus infection

Author

Yee, Leland J., Im, KyungAh, Borg, Brian, Yang, Huiying, and Liang, T. Jake

Subjects
Adult, Male, Genotype, Interleukin-6, Interferon-alpha, Hepacivirus, Hepatitis C, Chronic, Interferon alpha-2, Middle Aged, Polymorphism, Single Nucleotide, Article, Recombinant Proteins, Polyethylene Glycols, Cohort Studies, Gene Expression Regulation, Gene Frequency, Haplotypes, Multivariate Analysis, Humans, Female, Alleles
Abstract

Chronic hepatitis C virus (HCV) infection affects nearly 170 million individuals worldwide. Treatment of HCV with pegylated interferon-alpha-2a is successful in eradicating virus from only 30 to 80% of those treated. Interleukin-6 (IL-6) is an important cytokine involved in the immune response to infectious agents and in vitro studies suggest that host genetic variation, particularly haplotypes, may affect IL-6 expression. We examined the contribution of haplotypes in the IL-6 gene on sustained viral response (SVR) to the therapy for chronic HCV infection. We observed the IL-6 T-T-G-G-G-G-C-A-G-A haplotype to be associated with a lower risk of achieving SVR among Caucasian Americans (CAs) ((relative risk) RR=0.80; 95% CI: 0.66-0.98; P=0.0261). Using a sliding window approach, the rs1800797-(G)-rs1800796-(G)-rs1800795-(G) haplotype was associated with a reduced chance of SVR (RR=0.79; 95% CI: 0.66-0.94; P=0.0081), as was the rs1800796-(G)-rs1800795-(G)-rs2069830-(C) haplotype (RR=0.78; 95% CI: 0.66-0.94; P=0.0065) among CAs. Overall, the rs1800797-(G)-rs1800796-(G)-rs1800795-(G) haplotype was independently associated with a reduced chance of SVR (RR=0.78; 95% CI: 0.62-1.0; P=0.0489) after adjustment for potential confounding factors. Our findings further illustrate the complexity of IL-6 genetic regulation and the potential importance of haplotypes on IL-6 expression. Our findings provide additional support for the potential importance of genetic variation in the IL-6 gene and the response to HCV therapy.

Published
2009

26. Mo1473 – Seladelpar for the Treatment of Primary Biliary Cholangitis: Experience with 26 Cirrhotic Patients

Author

Mayo, Marlyn J., Bowlus, Christopher L., Galambos, Michael, Neff, Guy, Trivedi, Palak, Goel, Aparna, Odin, Joseph, Bacon, Bruce R., Borg, Brian B., Gordon, Stuart C., Gulamhusein, Aliya, Harrison, Stephen, Levy, Cynthia, stanca, carmen, Vierling, John M., Steinberg, Alexandra, Varga, Monika, Nguyen, Jaidyn, Bergheanu, Sandrin, Choi, Yun-Jung, Standen, Mary, and Boudes, Pol

Published
2019
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27. 953 – High Efficacy and Improvement in Cpt Class with Sofosbuvir/Velpatasvir Plus Ribavirin for 12 Weeks in Patients with Cpt C Decompensated Cirrhosis

Author

Flamm, Steven L., Lawitz, Eric, Borg, Brian, Charlton, Michael, Landis, Charles, Reddy, K. Rajender, Shiffman, Mitchell L., Samuel, Didier, Alsina, Angel, Chang, Charissa Y., Ravendhran, Natarajan, Zhang, Gulan, Cheinquer, Nelson, Moon, Scott, Spellman, James, Stamm, Luisa, Gaggar, Anuj, and Hezode, Christophe

Published
2019
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29. PS-122-Seladelpar for the treatment of primary biliary cholangitis: Experience with 26 cirrhotic patients

Author

Mayo, Marlyn J., Bowlus, Christopher, Michael, Galambos, Neff, Guy, Trivedi, Palak, Goel, Aparna, Odin, Joseph, Bacon, Bruce, Borg, Brian, Gordon, Stuart C, Gulamhusein, Aliya, Harrison, Stephen, LEVY, Cynthia, Stanca, Carmen, Vierling, John, Steinberg, Alexandra (Sasha), Varga, Monika, Nguyen, Jaidyn, Bergheanu, Sandrin, Choi, Yun-Jung, Standen, Mary, and Boudes, Pol

Published
2019
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30. GS-02-Efficacy of GKT831 in patients with primary biliary cholangitis and inadequate response to ursodeoxycholic acid: Interim efficacy results of a phase 2 clinical trial

Author

Dalekos, George, Invernizzi, Pietro, Nevens, Frederik, Hans, Van Vlierberghe, Zigmond, Ehud, Andrade, Raul J., Ari, Ziv Ben, Heneghan, Michael, Huang, Jonathan, Harrison, Stephen, Minuk, Gerald, JörnPD Dr., Schattenberg, Moreno, Christophe, Vierling, John, Vincent, Catherine, Bowlus, Christopher, Lurie, Yoav, Muratori, Luigi, Niro, Grazia, Hirschfield, Gideon, Post, Anthony, Zeuzem, Stefan, Welzel, Tania, Ch’ng, Chin Lye, Levy, Cynthia, Miller, Michael, Albillos, Agustin, Collier, Jane D., Corless, Lynsey, Dieterich, Douglas, Kremer, Andreas E, Papatheodoridis, George, Romeo, David, Silveira, Marina, Bernstein, David, Cohen-Naftaly, Michal, Floreani, Annarosa, Borg, Brian, Carey, Elizabeth, Hollywood, Coral, Maliakkal, Benedict, Marzioni, Marco, Rabinovitz, Mordechai, Rupp, Christian, Sheridan, David, Stanca, Carmen, Swain, Mark G, Veitsman, Ella, Spyridon Dourakis, P, and Wiese, Philippe

Published
2019
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31. Sa1450 - Hepatoprotective Biomarkers, Amphiregulin and Soluble FAS, Increase During ELAD Treatment in Alcoholic Hepatitis Subjects

Author

Lapetoda, Jason, Anderson, Samantha, Landeen, Lee K., Al-Khafaji, Ali, Parikh, Amay, Duarte-Rojo, Andres, Borg, Brian B., McCaughan, Geoff, Stein, Lance, Allison, Michael, Shah, Nikunj, Subramanian, Ram, Malik, Raza, Brown, Robert S., MacNicholas, Ross, Asrani, Sumeet K., Adhami, Talal, Reich, David, Thompson, Julie, Chacko, Kristina, Teperman, Lewis, Hassanein, Tarek I., and Bedard, Patty W.

Published
2018
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33. Fatal Acute Sickle Cell Intrahepatic Cholestasis Despite Exchange Transfusion: A Case Report and Literature Review.

Author

CAPRA, CARTER, WESLEY ALDRED, L., PATNANA, SRIKRISHNA, BORG, BRIAN, and HERRIN, VINCENT

Subjects
CHOLESTASIS, LIVER biopsy, CLINICAL pathology, INTENSIVE care units, OBSTRUCTIVE jaundice
Abstract

The article presents the case of a 19-year old African American with fatal acute sickle cell intrahepatic cholestasis despite exchange transfusion. He was admitted to the intensive care unit for hypovolemic shock and started on veno-venous hemodialysis. He was treated and then sent for liver biopsy.

Published
2018

34. Management of Ameboma Presenting as a Large Ulcerated Cecal Mass.

Author

SHAH, NIRAJ JAMES, BASU, PATRICK, FORTUZI, KED, ALOYSIUS, MARK M., SHEHI, ELONA, BORG, BRIAN B., and GUPTA, NITIN K.

Subjects
MEDICAL societies
Abstract

The article presents a case study of a 45-year-old woman presented with diarrhea, abdominal discomfort and significant weight loss. It mentions diagnosis of colonic amebiasis presenting as an ameboma or an inflammatory mass which mimicked a colonic tumor; and also mentions treatment with Nitazoxanide.

Published
2019

35. Hepatitis E in post-liver transplantation: is it time to routinely consider it?

Author

Borg, Brian B., Feng, Zongdi, Earl, Truman M., and Anderson, Christopher D.

Subjects
*LIVER transplantation, *LIVER function tests, *HEPATITIS E, *DIAGNOSIS, *THERAPEUTICS
Abstract

Hepatitis E, although commonly recognized in the Eastern Hemisphere, is less well recognized in the West. Particularly owing to this disease's grave impact on outcomes after liver transplantation, greater consideration of hepatitis E is necessary in the context of abnormal liver tests. Here, we review the most recent data on detecting and managing hepatitis E, both pre- and post-liver transplantation, discuss major detection assay limitations, consider future directions, and propose an algorithm for the diagnosis and management of pre-and post-transplantation hepatitis E. [ABSTRACT FROM AUTHOR]

Published
2016
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37. Queue Position in the Endoscopic Schedule Impacts Effectiveness of Colonoscopy.

Author

Lee, Alexander, Iskander, John M., Gupta, Nitin, Borg, Brian B., Zuckerman, Gary, Banerjee, Bhaskar, and Gyawali, C Prakash

Subjects
COLONOSCOPY, FATIGUE (Physiology), POLYPS, ENDOSCOPY, MULTIVARIATE analysis, DIAGNOSIS
Abstract

OBJECTIVES:Endoscopist fatigue potentially impacts colonoscopy. Fatigue is difficult to quantitate, but polyp detection rates between non-fatigued and fatigued time periods could represent a surrogate marker. We assessed whether timing variables impacted polyp detection rates at a busy tertiary care endoscopy suite.METHODS:Consecutive patients undergoing colonoscopy were retrospectively identified. Indications, clinical demographics, pre-procedural, and procedural variables were extracted from chart review; colonoscopy findings were determined from the procedure reports. Three separate timing variables were assessed as surrogate markers for endoscopist fatigue: morning vs. afternoon procedures, start times throughout the day, and queue position, a unique variable that takes into account the number of procedures performed before the colonoscopy of interest. Univariate and multivariate analyses were performed to determine whether timing variables and other clinical, pre-procedural, and procedural variables predicted polyp detection.RESULTS:During the 4-month study period, 1,083 outpatient colonoscopy procedures (57.5±0.5 years, 59.5% female) were identified, performed by 28 endoscopists (mean 38.7 procedures/endoscopist), with a mean polyp detection rate of 0.851/colonoscopy. At least, one adenoma was detected in 297 procedures (27.4%). A 12.4% reduction in mean detected polyps was detected between morning and afternoon procedures (0.90±0.06 vs. 0.76±0.06, P=0.15). Using start time on a continuous scale, however, each elapsed hour in the day was associated with a 4.6% reduction in polyp detection (P=0.005). When queue position was assessed, a 5.4% reduction in polyp detection was noted with each increase in queue position (P=0.016). These results remained significant when controlled for each individual endoscopist.CONCLUSIONS:Polyp detection rates decline as time passes during an endoscopist's schedule, potentially from endoscopist fatigue. Queue position may be a novel surrogate measure for operator fatigue. [ABSTRACT FROM AUTHOR]

Published
2011
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38. A functional SNP of interferon-γ gene is important for interferon-α-induced and spontaneous recovery from hepatitis C virus infection.

Author

Ying Huang, Huiying Yang, Borg, Brian B., Xiaowen Su, Rhodes, Shannon L., Kai Yang, Xiaomei Tong, Tang, George, Howell, Charles D., Rosen, Hugo R., Thio, Chloe L., Thomas, David L., Alter, Harvey J., Sapp, Ronda K., and Liang, T. Jake

Subjects
GENETIC polymorphisms, INTERFERONS, HEPATITIS C, HEPATITIS C virus, VIRAL hepatitis
Abstract

Cytokine polymorphisms are associated with disease outcome and interferon (IFN) treatment response in hepatitis C virus (HCV) infection. We genotyped eight SNPs spanning the entire IFN-γ gene in two cohorts and assessed the association between those polymorphisms and treatment response or spontaneous viral clearance. The first cohort was composed of 284 chronically HCV-infected patients who had received lFN-α-based therapy and the second was 251 i.v. drug users who had either spontaneously cleared HCV or become chronically infected. A SNP variant located in the proximal IFN-γ promoter region next to the binding motif of heat shock transcription factor (HSF), -764G. was significantly associated with sustained virological response [P = 0.04, odds ratio (OR) = 3.51 (confidence interval 1.0-12.5)]. The association was independently significant in multiple logistic regression (P = 0.04) along with race, viral titer, and genotype. This variant was also significantly associated with spontaneous recovery [P = 0.04, OR = 3.51 (1.0-12.5)] in the second cohort. Functional analyses show that the G allele confers a two- to three-fold higher promoter activity and stronger binding affinity to HSF1 than the C allele. Our study suggests that the IFN-γ promoter SNP-764G/C is functionally important in determining viral clearance and treatment response in HCV-infected patients and may be used as a genetic marker to predict sustained virological response in HCV-infected patients. [ABSTRACT FROM AUTHOR]

Published
2007
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44. FRI133 - Durability of treatment response after 1 year of therapy with seladelpar in patients with primary biliary cholangitis (PBC): final results of an international phase 2 study.

Author

Levy, Cynthia, Bowlus, Christopher, Neff, Guy, Swain, Mark G., Michael, Galambos, Mayo, Marlyn J., Goel, Aparna, Trivedi, Palak, Hirschfield, Gideon, Aspinall, Richard, Kremer, Andreas E., Gordon, Stuart C., Borg, Brian, Harrison, Stephen, Jones, David, Thuluvath, Paul, Doerffel, Yvonne, Stanca, Carmen, Sheridan, David, and Bacon, Bruce

Subjects
*CHOLANGITIS, *DURABILITY, *LIVER diseases
Published
2020
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45. Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial

Author

Zobair M Younossi, Vlad Ratziu, Rohit Loomba, Mary Rinella, Quentin M Anstee, Zachary Goodman, Pierre Bedossa, Andreas Geier, Susanne Beckebaum, Philip N Newsome, David Sheridan, Muhammad Y Sheikh, James Trotter, Whitfield Knapple, Eric Lawitz, Manal F Abdelmalek, Kris V Kowdley, Aldo J Montano-Loza, Jerome Boursier, Philippe Mathurin, Elisabetta Bugianesi, Giuseppe Mazzella, Antonio Olveira, Helena Cortez-Pinto, Isabel Graupera, David Orr, Lise Lotte Gluud, Jean-Francois Dufour, David Shapiro, Jason Campagna, Luna Zaru, Leigh MacConell, Reshma Shringarpure, Stephen Harrison, Arun J Sanyal, 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, 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, William Bowman, David Bradley, Marija Brankovic, Marius Braun, Jean-Pierre Bronowicki, Savino Bruno, Cindy Cai, Amy Calderon, José Luis Calleja Panero, Elizabeth Carey, Michal Carmiel, Jose Antonio Carrión, Matthew Cave, Cristina Chagas, Tawfik Chami, Alan Chang, Allan Coates, Jeremy Cobbold, Charlote Costentin, Kathleen Corey, Lynsey Corless, Javier Crespo, Oscar Cruz Pereira, Victor de Ledinghen, Andrew deLemos, Moises Diago, Mamie Dong, Jean-François 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, Jacob George, Maged Ghali, Reem Ghalib, Pierre Gholam, Pere Gines, Norman Gitlin, 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, Marek Hartleb, Tarek Hassanein, Dieter Häussinger, Paul Hellstern, Robert Herring, Eva Heurich, Christophe Hezode, Holger Hinrichsen, Peter Holland Fischer, Yves Horsmans, Jonathan Huang, Hyder Hussaini, Antoine Jakiche, Lennox Jeffers, Blake Jones, Rosa Jorge, Francisco Jorquera, Shoba Joshi, Alisan Kahraman, Kelly Kaita, Nicholas Karyotakis, Zeid Kayali, Stergios Kechagias, Thomas Kepczyk, Mandana Khalili, Hicham Khallafi, Johannes Kluwe, Anita Kohli, Kevin Korenblat, Kris Kowdley, Aleksander Krag, Richard Krause, Andreas Kremer, Karen Krok, Miodrag Krstic, Marcelo Kugelmas, Sonal Kumar, Scott Kuwada, Damien Labarriere, Michelle Lai, Wim Laleman, Pietro Lampertico, Alice Lee, Vincent Leroy, Steven Lidofsky, Tina Huey Lim, Joseph Lim, Donald Lipkis, Ester Little, Amadeo Lonardo, Michelle Long, Velimir Anthony Christopher Luketic, Yoav Lurie, Guilherme Macedo, Joana Magalhaes, Mihály Makara, Benedict Maliakkal, Michael Manns, Pinelopi Manousou, Parvez Mantry, Giulio Marchesini, Carla Marinho, Paul Marotta, Hanns-Ulrich Marschall, Linda Martinez, Marlyn Mayo, Mark McCullen, William McLaughlin, Uta Merle, Raphael Merriman, Apurva Modi, Esther Molina, Aldo Montano-Loza, Carlos Monteverde, Amilcar Morales Cardona, Sulleman Moreea, Christophe Moreno, Filomena Morisco, Abdullah Mubarak, Beat Muellhaupt, Sandeep Mukherjee, Tobias Müller, Aleksandar Nagorni, Jahnavi Naik, Guy Neff, Moises Nevah, Philip Newsome, Eric Nguyen-Khac, Mazen Noureddin, Jude Oben, Hans Orlent, James Orr, Grisell Ortiz-Lasanta, Violaine Ozenne, Prashant Pandya, Angelo Paredes, James Park, Joykumar Patel, Keyur Patel, Sonali Paul, Heather Patton, Markus Peck-Radosavljevic, Salvatore Petta, Stephen Pianko, Anna Piekarska, Neville Pimstone, Joseph Pisegna, Paul Pockros, Stanislas Pol, Michael Porayko, John Poulos, David Pound, Joe Pouzar, Jose Presa Ramos, Nikolaos Pyrsopoulos, Nila Rafiq, Kate Muller, Alnoor Ramji, Ravi Ravinuthala, Chakradhar Reddy, Gautham Reddy K G, K. Rajender Reddy K R, Frederic Regenstein, Robert Reindollar, Justin Reynolds, Andres Riera, Jose Rivera Acosta, Geert Robaeys, Stuart Roberts, Federico Rodriguez-Perez, Sandor Romero, 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, Jörn Schattenberg, Ingolf Schiefke, Eugene Schiff, Wolfgang Schmidt, Jeffrey Schneider, Jeoffrey Schouten, Michael Schultz, Giada Sebastiani, David Semela, Thomas Sepe, Aasim Sheikh, Muhammad Sheikh, 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, Albert Tran, Michael Trauner, Christian Trautwein, 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, Julia Wattacheril, 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, Younossi Z.M., Ratziu V., Loomba R., Rinella M., Anstee Q.M., Goodman Z., Bedossa P., Geier A., Beckebaum S., Newsome P.N., Sheridan D., Sheikh M.Y., Trotter J., Knapple W., Lawitz E., Abdelmalek M.F., Kowdley K.V., Montano-Loza A.J., Boursier J., Mathurin P., Bugianesi E., Mazzella G., Olveira A., Cortez-Pinto H., Graupera I., Orr D., Gluud L.L., Dufour J.-F., Shapiro D., Campagna J., Zaru L., MacConell L., Shringarpure R., Harrison S., Sanyal A.J., Abdelmalek M., Abrams G., Aguilar H., Ahmed A., Aigner E., Aithal G., Ala A., Alazawi W., Albillos A., Allison M., Al-Shamma S., Andrade R., Andreone P., Angelico M., Ankoma-Sey V., Anstee Q., Anty R., Araya V., Arenas Ruiz J.I., Arkkila P., Arora M., Asselah T., Au J., Ayonrinde O., Bailey R.J., Balakrishnan M., Bambha K., Bansal M., Barritt S., Bate J., Beato J., Behari J., Bellot P., Ben Ari Z., Bennett M., Berenguer M., Beretta-Piccoli B.T., Berg T., Bonacini M., Bonet L., Borg B., Bourliere M., Bowman W., Bradley D., Brankovic M., Braun M., Bronowicki J.-P., Bruno S., Cai C., Calleja Panero J.L., Carey E., Carmiel M., Carrion J.A., Cave M., Chagas C., Chami T., Chang A., Coates A., Cobbold J., Corey K., Corless L., Crespo J., Cruz Pereira O., de Ledinghen V., deLemos A., Diago M., Dugalic P., Dunn W., Elkhashab M., Epstein M., Escudero-Garcia M.D., Etzion O., Evans L., Falcone R., Fernandez C., Ferreira J., Fink S., Finnegan K., Firpi-Morell R., Floreani A., Fontanges T., Ford R., Forrest E., Fowell A., Fracanzani A.L., Francque S., Freilich B., Frias J., Fuchs M., Fuentes J., Galambos M., Gallegos J., Geerts A., George J., Ghali M., Ghalib R., Gholam P., Gines P., Gitlin N., Goeser T., Goff J., Gordon S., Gordon F., Goria O., Greer S., Grigorian A., Gronbaek H., Guillaume M., Gunaratnam N., Halegoua-De Marzio D., Hameed B., Hametner S., Hamilton J., Hartleb M., Hassanein T., Haussinger D., Hellstern P., Herring R., Heurich E., Hezode C., Hinrichsen H., Holland Fischer P., Horsmans Y., Huang J., Jakiche A., Jeffers L., Jones B., Jorge R., Jorquera F., Kahraman A., Kaita K., Karyotakis N., Kayali Z., Kechagias S., Kepczyk T., Khalili M., Khallafi H., Kluwe J., Kohli A., Korenblat K., Kowdley K., Krag A., Krause R., Kremer A., Krok K., Krstic M., Kugelmas M., Kumar S., Labarriere D., Lai M., Lampertico P., Lee A., Leroy V., Lidofsky S., Lim T.H., Lim J., Lipkis D., Little E., Lonardo A., Long M., Lurie Y., Macedo G., Makara M., Maliakkal B., Manns M., Manousou P., Mantry P., Marchesini G., Marinho C., Marotta P., Marschall H.-U., Mayo M., McCullen M., McLaughlin W., Merriman R., Modi A., Molina E., Montano-Loza A., Monteverde C., Moreea S., Moreno C., Morisco F., Mubarak A., Muellhaupt B., Mukherjee S., Muller T., Nagorni A., Naik J., Neff G., Nevah M., Newsome P., Nguyen-Khac E., Noureddin M., Oben J., Orlent H., Orr J., Ortiz-Lasanta G., Ozenne V., Pandya P., Paredes A., Park J., Patel J., Patel K., Uta M., Patton H., Peck-Radosavljevic M., Petta S., Pianko S., Piekarska A., Pimstone N., Pockros P., Pol S., Porayko M., Poulos J., Pound D., Pouzar J., Presa Ramos J., Pyrsopoulos N., Rafiq N., Muller K., Ramji A., Ravinuthala R., Reddy C., Reddy K G G., Reddy K R K.R., Regenstein F., Reindollar R., Riera A., Rivera Acosta J., Robaeys G., Roberts S., Rodriguez-Perez F., Romero-Gomez M., Rubin R., Rumi M., Rushbrook S., Rust C., Ryan M., Safadi R., Said A., Salminen K., Samuel D., Santoro J., Sanyal A., Sarkar S., Schaeffer C., Schattenberg J., Schiefke I., Schiff E., Schmidt W., Schneider J., Schouten J., Schultz M., Sebastiani G., Semela D., Sepe T., Sheikh A., Sheikh M., Sherman K., Shibolet O., Shiffman M., Siddique A., Sieberhagen C., Sigal S., Sikorska K., Simon K., Sinclair M., Skoien R., Solis J., Sood S., Souder B., Spivey J., Stal P., Stinton L., Strasser S., Svorcan P., Szabo G., Talal A., Tam E., Tetri B., Thuluvath P., Tobias H., Tomasiewicz K., Torres D., Trauner M., Trautwein C., Tsochatzis E., Unitt E., Vargas V., Varkonyi I., Veitsman E., Vespasiani Gentilucci U., Victor D., Vierling J., Vincent C., Vincze A., von der Ohe M., Von Roenn N., Vuppalanchi R., Waters M., Watt K., Weltman M., Wieland A., Wiener G., Williams A A., Williams J J., Wilson J., Yataco M., Yoshida E., Younes Z., Yuan L., Zivony A., Zogg D., Zoller H., Zoulim F., Zuckerman E., Zuin M., Repositório da Universidade de Lisboa, Younossi, Z. M., Ratziu, V., Loomba, R., Rinella, M., Anstee, Q. M., Goodman, Z., Bedossa, P., Geier, A., Beckebaum, S., Newsome, P. N., Sheridan, D., Sheikh, M. Y., Trotter, J., Knapple, W., Lawitz, E., Abdelmalek, M. F., Kowdley, K. V., Montano-Loza, A. J., Boursier, J., Mathurin, P., Bugianesi, E., Mazzella, G., Olveira, A., Cortez-Pinto, H., Graupera, I., Orr, D., Gluud, L. L., Dufour, J. -F., Shapiro, D., Campagna, J., Zaru, L., Macconell, L., Shringarpure, R., Harrison, S., Sanyal, A. J., Abdelmalek, M., Abrams, G., Aguilar, H., Ahmed, A., Aigner, E., Aithal, G., Ala, A., Alazawi, W., Albillos, A., Allison, M., Al-Shamma, S., Andrade, R., Andreone, P., Angelico, M., Ankoma-Sey, V., Anstee, Q., Anty, R., Araya, V., Arenas Ruiz, J. I., Arkkila, P., Arora, M., Asselah, T., Au, J., Ayonrinde, O., Bailey, R. J., Balakrishnan, M., Bambha, K., Bansal, M., Barritt, S., Bate, J., Beato, J., Behari, J., Bellot, P., Ben Ari, Z., Bennett, M., Berenguer, M., Beretta-Piccoli, B. T., Berg, T., Bonacini, M., Bonet, L., Borg, B., Bourliere, M., Bowman, W., Bradley, D., Brankovic, M., Braun, M., Bronowicki, J. -P., Bruno, S., Cai, C., Calleja Panero, J. L., Carey, E., Carmiel, M., Carrion, J. A., Cave, M., Chagas, C., Chami, T., Chang, A., Coates, A., Cobbold, J., Corey, K., Corless, L., Crespo, J., Cruz Pereira, O., de Ledinghen, V., Delemos, A., Diago, M., Dugalic, P., Dunn, W., Elkhashab, M., Epstein, M., Escudero-Garcia, M. D., Etzion, O., Evans, L., Falcone, R., Fernandez, C., Ferreira, J., Fink, S., Finnegan, K., Firpi-Morell, R., Floreani, A., Fontanges, T., Ford, R., Forrest, E., Fowell, A., Fracanzani, A. L., Francque, S., Freilich, B., Frias, J., Fuchs, M., Fuentes, J., Galambos, M., Gallegos, J., Geerts, A., George, J., Ghali, M., Ghalib, R., Gholam, P., Gines, P., Gitlin, N., Goeser, T., Goff, J., Gordon, S., Gordon, F., Goria, O., Greer, S., Grigorian, A., Gronbaek, H., Guillaume, M., Gunaratnam, N., Halegoua-De Marzio, D., Hameed, B., Hametner, S., Hamilton, J., Hartleb, M., Hassanein, T., Haussinger, D., Hellstern, P., Herring, R., Heurich, E., Hezode, C., Hinrichsen, H., Holland Fischer, P., Horsmans, Y., Huang, J., Jakiche, A., Jeffers, L., Jones, B., Jorge, R., Jorquera, F., Kahraman, A., Kaita, K., Karyotakis, N., Kayali, Z., Kechagias, S., Kepczyk, T., Khalili, M., Khallafi, H., Kluwe, J., Kohli, A., Korenblat, K., Kowdley, K., Krag, A., Krause, R., Kremer, A., Krok, K., Krstic, M., Kugelmas, M., Kumar, S., Labarriere, D., Lai, M., Lampertico, P., Lee, A., Leroy, V., Lidofsky, S., Lim, T. H., Lim, J., Lipkis, D., Little, E., Lonardo, A., Long, M., Lurie, Y., Macedo, G., Makara, M., Maliakkal, B., Manns, M., Manousou, P., Mantry, P., Marchesini, G., Marinho, C., Marotta, P., Marschall, H. -U., Mayo, M., Mccullen, M., Mclaughlin, W., Merriman, R., Modi, A., Molina, E., Montano-Loza, A., Monteverde, C., Moreea, S., Moreno, C., Morisco, F., Mubarak, A., Muellhaupt, B., Mukherjee, S., Muller, T., Nagorni, A., Naik, J., Neff, G., Nevah, M., Newsome, P., Nguyen-Khac, E., Noureddin, M., Oben, J., Orlent, H., Orr, J., Ortiz-Lasanta, G., Ozenne, V., Pandya, P., Paredes, A., Park, J., Patel, J., Patel, K., Uta, M., Patton, H., Peck-Radosavljevic, M., Petta, S., Pianko, S., Piekarska, A., Pimstone, N., Pockros, P., Pol, S., Porayko, M., Poulos, J., Pound, D., Pouzar, J., Presa Ramos, J., Pyrsopoulos, N., Rafiq, N., Muller, K., Ramji, A., Ravinuthala, R., Reddy, C., Reddy K G, G., Reddy K R, K. R., Regenstein, F., Reindollar, R., Riera, A., Rivera Acosta, J., Robaeys, G., Roberts, S., Rodriguez-Perez, F., Romero-Gomez, M., Rubin, R., Rumi, M., Rushbrook, S., Rust, C., Ryan, M., Safadi, R., Said, A., Salminen, K., Samuel, D., Santoro, J., Sanyal, A., Sarkar, S., Schaeffer, C., Schattenberg, J., Schiefke, I., Schiff, E., Schmidt, W., Schneider, J., Schouten, J., Schultz, M., Sebastiani, G., Semela, D., Sepe, T., Sheikh, A., Sheikh, M., Sherman, K., Shibolet, O., Shiffman, M., Siddique, A., Sieberhagen, C., Sigal, S., Sikorska, K., Simon, K., Sinclair, M., Skoien, R., Solis, J., Sood, S., Souder, B., Spivey, J., Stal, P., Stinton, L., Strasser, S., Svorcan, P., Szabo, G., Talal, A., Tam, E., Tetri, B., Thuluvath, P., Tobias, H., Tomasiewicz, K., Torres, D., Trauner, M., Trautwein, C., Tsochatzis, E., Unitt, E., Vargas, V., Varkonyi, I., Veitsman, E., Vespasiani Gentilucci, U., Victor, D., Vierling, J., Vincent, C., Vincze, A., von der Ohe, M., Von Roenn, N., Vuppalanchi, R., Waters, M., Watt, K., Weltman, M., Wieland, A., Wiener, G., Williams A, A., Williams J, J., Wilson, J., Yataco, M., Yoshida, E., Younes, Z., Yuan, L., Zivony, A., Zogg, D., Zoller, H., Zoulim, F., Zuckerman, E., Zuin, M., Younossi, Zobair M, Ratziu, Vlad, Loomba, Rohit, Rinella, Mary, Anstee, Quentin M, Goodman, Zachary, Bedossa, Pierre, Geier, Andrea, Beckebaum, Susanne, Newsome, Philip N, Sheridan, David, Sheikh, Muhammad Y, Trotter, Jame, Knapple, Whitfield, Lawitz, Eric, Abdelmalek, Manal F, Kowdley, Kris V, Montano-Loza, Aldo J, Boursier, Jerome, Mathurin, Philippe, Bugianesi, Elisabetta, Mazzella, Giuseppe, Olveira, Antonio, Cortez-Pinto, Helena, Graupera, Isabel, Orr, David, Gluud, Lise Lotte, Dufour, Jean-Francoi, Shapiro, David, Campagna, Jason, Zaru, Luna, MacConell, Leigh, Shringarpure, Reshma, Harrison, Stephen, Sanyal, Arun J, Abdelmalek, Manal, Abrams, Gary, Aguilar, Humberto, Ahmed, Aijaz, Aigner, Elmar, Aithal, Guruprasad, Ala, Aftab, Alazawi, William, Albillos, Agustin, Allison, Michael, Al-Shamma, Sfa, Andrade, Raul, Andreone, Pietro, Angelico, Mario, Ankoma-Sey, Victor, Anstee, Quentin, Anty, Rodolphe, Araya, Victor, Arenas Ruiz, Juan Ignacio, Arkkila, Perttu, Arora, Marty, Asselah, Tarik, Au, Jennifer, Ayonrinde, Oyekoya, Bailey, Robert Jame, Balakrishnan, Maya, Bambha, Kiran, Bansal, Meena, Barritt, Sidney, Bate, John, Beato, Jorge, Behari, Jaideep, Bellot, Pablo, Ben Ari, Ziv, Bennett, Michael, Berenguer, Marina, Beretta-Piccoli, Benedetta Terziroli, Berg, Thoma, Bonacini, Maurizio, Bonet, Lucia, Borg, Brian, Bourliere, Marc, Bowman, William, Bradley, David, Brankovic, Marija, Braun, Mariu, Bronowicki, Jean-Pierre, Bruno, Savino, Cai, Cindy, Calleja Panero, José Lui, Carey, Elizabeth, Carmiel, Michal, Carrión, Jose Antonio, Cave, Matthew, Chagas, Cristina, Chami, Tawfik, Chang, Alan, Coates, Allan, Cobbold, Jeremy, Corey, Kathleen, Corless, Lynsey, Crespo, Javier, Cruz Pereira, Oscar, de Ledinghen, Victor, deLemos, Andrew, Diago, Moise, Dufour, Jean-Françoi, Dugalic, Predrag, Dunn, Winston, Elkhashab, Magby, Epstein, Michael, Escudero-Garcia, Maria Desamparado, Etzion, Ohad, Evans, Larry, Falcone, Robert, Fernandez, Conrado, Ferreira, Jose, Fink, Scott, Finnegan, Kevin, Firpi-Morell, Roberto, Floreani, Annarosa, Fontanges, Thierry, Ford, Ryan, Forrest, Ewan, Fowell, Andrew, Fracanzani, Anna Ludovica, Francque, Sven, Freilich, Bradley, Frias, Juan, Fuchs, Michael, Fuentes, Javier, Galambos, Michael, Gallegos, Juan, Geerts, Anja, George, Jacob, Ghali, Maged, Ghalib, Reem, Gholam, Pierre, Gines, Pere, Gitlin, Norman, Goeser, Tobia, Goff, John, Gordon, Stuart, Gordon, Frederic, Goria, Odile, Greer, Shaun, Grigorian, Alla, Gronbaek, Henning, Guillaume, Maeva, Gunaratnam, Naresh, Halegoua-De Marzio, Dina, Hameed, Bilal, Hametner, Stephanie, Hamilton, Jame, Hartleb, Marek, Hassanein, Tarek, Häussinger, Dieter, Hellstern, Paul, Herring, Robert, Heurich, Eva, Hezode, Christophe, Hinrichsen, Holger, Holland Fischer, Peter, Horsmans, Yve, Huang, Jonathan, Jakiche, Antoine, Jeffers, Lennox, Jones, Blake, Jorge, Rosa, Jorquera, Francisco, Kahraman, Alisan, Kaita, Kelly, Karyotakis, Nichola, Kayali, Zeid, Kechagias, Stergio, Kepczyk, Thoma, Khalili, Mandana, Khallafi, Hicham, Kluwe, Johanne, Kohli, Anita, Korenblat, Kevin, Kowdley, Kri, Krag, Aleksander, Krause, Richard, Kremer, Andrea, Krok, Karen, Krstic, Miodrag, Kugelmas, Marcelo, Kumar, Sonal, Labarriere, Damien, Lai, Michelle, Lampertico, Pietro, Lee, Alice, Leroy, Vincent, Lidofsky, Steven, Lim, Tina Huey, Lim, Joseph, Lipkis, Donald, Little, Ester, Lonardo, Amadeo, Long, Michelle, Lurie, Yoav, Macedo, Guilherme, Makara, Mihály, Maliakkal, Benedict, Manns, Michael, Manousou, Pinelopi, Mantry, Parvez, Marchesini, Giulio, Marinho, Carla, Marotta, Paul, Marschall, Hanns-Ulrich, Mayo, Marlyn, McCullen, Mark, McLaughlin, William, Merriman, Raphael, Modi, Apurva, Molina, Esther, Montano-Loza, Aldo, Monteverde, Carlo, Moreea, Sulleman, Moreno, Christophe, Morisco, Filomena, Mubarak, Abdullah, Muellhaupt, Beat, Mukherjee, Sandeep, Müller, Tobia, Nagorni, Aleksandar, Naik, Jahnavi, Neff, Guy, Nevah, Moise, Newsome, Philip, Nguyen-Khac, Eric, Noureddin, Mazen, Oben, Jude, Orlent, Han, Orr, Jame, Ortiz-Lasanta, Grisell, Ozenne, Violaine, Pandya, Prashant, Paredes, Angelo, Park, Jame, Patel, Joykumar, Patel, Keyur, Uta, Merle, Patton, Heather, Peck-Radosavljevic, Marku, Petta, Salvatore, Pianko, Stephen, Piekarska, Anna, Pimstone, Neville, Pockros, Paul, Pol, Stanisla, Porayko, Michael, Poulos, John, Pound, David, Pouzar, Joe, Presa Ramos, Jose, Pyrsopoulos, Nikolao, Rafiq, Nila, Muller, Kate, Ramji, Alnoor, Ravinuthala, Ravi, Reddy, Chakradhar, Reddy K G, Gautham, Reddy K R, K. Rajender, Regenstein, Frederic, Reindollar, Robert, Riera, Andre, Rivera Acosta, Jose, Robaeys, Geert, Roberts, Stuart, Rodriguez-Perez, Federico, Romero-Gomez, Manuel, Rubin, Raymond, Rumi, Mariagrazia, Rushbrook, Simon, Rust, Christian, Ryan, Michael, Safadi, Rifaat, Said, Adnan, Salminen, Kimmo, Samuel, Didier, Santoro, John, Sanyal, Arun, Sarkar, Souvik, Schaeffer, Cynthia, Schattenberg, Jörn, Schiefke, Ingolf, Schiff, Eugene, Schmidt, Wolfgang, Schneider, Jeffrey, Schouten, Jeoffrey, Schultz, Michael, Sebastiani, Giada, Semela, David, Sepe, Thoma, Sheikh, Aasim, Sheikh, Muhammad, Sherman, Kenneth, Shibolet, Oren, Shiffman, Mitchell, Siddique, Asma, Sieberhagen, Cyril, Sigal, Samuel, Sikorska, Katarzyna, Simon, Krzysztof, Sinclair, Marie, Skoien, Richard, Solis, Joel, Sood, Siddharth, Souder, Bob, Spivey, Jame, Stal, Per, Stinton, Laura, Strasser, Simone, Svorcan, Petar, Szabo, Gyongzi, Talal, Andrew, Tam, Edward, Tetri, Brent, Thuluvath, Paul, Tobias, Hillel, Tomasiewicz, Krzysztof, Torres, Dawn, Trauner, Michael, Trautwein, Christian, Tsochatzis, Emanuel, Unitt, Esther, Vargas, Victor, Varkonyi, Istvan, Veitsman, Ella, Vespasiani Gentilucci, Umberto, Victor, David, Vierling, John, Vincent, Catherine, Vincze, Aron, von der Ohe, Manfred, Von Roenn, Natasha, Vuppalanchi, Raj, Waters, Michael, Watt, Kymberly, Weltman, Martin, Wieland, Amanda, Wiener, Gregory, Williams A, Alonzo, Williams J, Jeffrey, Wilson, Jason, Yataco, Maria, Yoshida, Eric, Younes, Ziad, Yuan, Liyun, Zivony, Adam, Zogg, Donald, Zoller, Heinz, Zoulim, Fabien, Zuckerman, Eli, Zuin, Massimo, and REGENERATE Study Investigators

Subjects
Male, Biopsy, Clinical Trial, Phase III, Administration, Oral, 030204 cardiovascular system & hematology, Chronic liver disease, Settore MED/04, Biomarkers/analysis, Gastroenterology, chemistry.chemical_compound, 0302 clinical medicine, Liver Function Tests, Non-alcoholic Fatty Liver Disease, Clinical endpoint, Medicine, 030212 general & internal medicine, 610 Medicine & health, Chenodeoxycholic Acid/administration & dosage, education.field_of_study, Liver Function Test, Research Support, Non-U.S. Gov't, Fatty liver, Obeticholic acid, NASH, OBETICHOLIC ACID, General Medicine, Middle Aged, Multicenter Study, Randomized Controlled Trial, Administration, Female, Biomarkers, Chenodeoxycholic Acid, Double-Blind Method, Humans, Human, Oral, medicine.medical_specialty, Population, Placebo, 03 medical and health sciences, Research Support, N.I.H., Extramural, Internal medicine, Journal Article, education, Intention-to-treat analysis, business.industry, Biomarker, Interim analysis, medicine.disease, Non-alcoholic Fatty Liver Disease/drug therapy, chemistry, Human medicine, business
Abstract

© 2019 Elsevier Ltd. All rights reserved., 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 (≥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.

Published
2019
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46. Combination Therapies Including Cilofexor and Firsocostat for Bridging Fibrosis and Cirrhosis Attributable to NASH.

Author

Loomba R, Noureddin M, Kowdley KV, Kohli A, Sheikh A, Neff G, Bhandari BR, Gunn N, Caldwell SH, Goodman Z, Wapinski I, Resnick M, Beck AH, Ding D, Jia C, Chuang JC, Huss RS, Chung C, Subramanian GM, Myers RP, Patel K, Borg BB, Ghalib R, Kabler H, Poulos J, Younes Z, Elkhashab M, Hassanein T, Iyer R, Ruane P, Shiffman ML, Strasser S, Wong VW, and Alkhouri N

Subjects
Aged, Azetidines adverse effects, Benzamides administration & dosage, Benzamides adverse effects, Biomarkers blood, Biopsy, Drug Administration Schedule, Drug Therapy, Combination adverse effects, Drug Therapy, Combination methods, End Stage Liver Disease pathology, Female, Humans, Imidazoles administration & dosage, Imidazoles adverse effects, Isobutyrates adverse effects, Isonicotinic Acids adverse effects, Liver drug effects, Liver pathology, Liver Cirrhosis complications, Liver Cirrhosis diagnosis, Liver Cirrhosis pathology, Liver Function Tests, Male, Middle Aged, Non-alcoholic Fatty Liver Disease diagnosis, Non-alcoholic Fatty Liver Disease etiology, Non-alcoholic Fatty Liver Disease pathology, Oxazoles adverse effects, Pyridines administration & dosage, Pyridines adverse effects, Pyrimidines adverse effects, Severity of Illness Index, Treatment Outcome, Azetidines administration & dosage, End Stage Liver Disease prevention & control, Isobutyrates administration & dosage, Isonicotinic Acids administration & dosage, Liver Cirrhosis drug therapy, Non-alcoholic Fatty Liver Disease drug therapy, Oxazoles administration & dosage, Pyrimidines administration & dosage
Abstract

Background and Aims: Advanced fibrosis attributable to NASH is a leading cause of end-stage liver disease., Approach and Results: In this phase 2b trial, 392 patients with bridging fibrosis or compensated cirrhosis (F3-F4) were randomized to receive placebo, selonsertib 18 mg, cilofexor 30 mg, or firsocostat 20 mg, alone or in two-drug combinations, once-daily for 48 weeks. The primary endpoint was a ≥1-stage improvement in fibrosis without worsening of NASH between baseline and 48 weeks based on central pathologist review. Exploratory endpoints included changes in NAFLD Activity Score (NAS), liver histology assessed using a machine learning (ML) approach, liver biochemistry, and noninvasive markers. The majority had cirrhosis (56%) and NAS ≥5 (83%). The primary endpoint was achieved in 11% of placebo-treated patients versus cilofexor/firsocostat (21%; P = 0.17), cilofexor/selonsertib (19%; P = 0.26), firsocostat/selonsertib (15%; P = 0.62), firsocostat (12%; P = 0.94), and cilofexor (12%; P = 0.96). Changes in hepatic collagen by morphometry were not significant, but cilofexor/firsocostat led to a significant decrease in ML NASH CRN fibrosis score (P = 0.040) and a shift in biopsy area from F3-F4 to ≤F2 fibrosis patterns. Compared to placebo, significantly higher proportions of cilofexor/firsocostat patients had a ≥2-point NAS reduction; reductions in steatosis, lobular inflammation, and ballooning; and significant improvements in alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, bile acids, cytokeratin-18, insulin, estimated glomerular filtration rate, ELF score, and liver stiffness by transient elastography (all P ≤ 0.05). Pruritus occurred in 20%-29% of cilofexor versus 15% of placebo-treated patients., Conclusions: In patients with bridging fibrosis and cirrhosis, 48 weeks of cilofexor/firsocostat was well tolerated, led to improvements in NASH activity, and may have an antifibrotic effect. This combination offers potential for fibrosis regression with longer-term therapy in patients with advanced fibrosis attributable to NASH., (© 2020 by the American Association for the Study of Liver Diseases.)

Published
2021
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