Rationale and design of a randomised, double-blind, placebo-controlled, parallel-group, investigator-initiated phase 2a study to investigate the efficacy and safety of elobixibat in combination with cholestyramine for non-alcoholic fatty liver disease
Introduction Non-alcoholic fatty liver disease (NAFLD) pathogenesis involves abnormal metabolism of cholesterol and hepatic accumulation of toxic free-cholesterol. Elobixibat (EXB) inhibits the ileal bile acid (BA) transporter. EXB and cholestyramine (CTM) facilitate the removal of free cholesterol...
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2020-09-01
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| Series: | BMJ Open |
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| author | Atsushi Nakajima Takeharu Yamanaka Koji Yamamoto Yasushi Honda Kento Imajo Masato Yoneda Yuji Ogawa Takaomi Kessoku Takashi Kobayashi Anna Ozaki Satoru Saito Michihiro Iwaki Yusuke Saigusa Haruki Usuda Koichiro Wada |
| author_facet | Atsushi Nakajima Takeharu Yamanaka Koji Yamamoto Yasushi Honda Kento Imajo Masato Yoneda Yuji Ogawa Takaomi Kessoku Takashi Kobayashi Anna Ozaki Satoru Saito Michihiro Iwaki Yusuke Saigusa Haruki Usuda Koichiro Wada |
| author_sort | Atsushi Nakajima |
| collection | DOAJ |
| description | Introduction Non-alcoholic fatty liver disease (NAFLD) pathogenesis involves abnormal metabolism of cholesterol and hepatic accumulation of toxic free-cholesterol. Elobixibat (EXB) inhibits the ileal bile acid (BA) transporter. EXB and cholestyramine (CTM) facilitate the removal of free cholesterol from the liver by decreasing BA recirculation to the liver, thereby stimulating novel BA synthesis from cholesterol. In this randomised, double-blind, placebo-controlled, parallel-group, phase IIa study, we aim to provide a proof-of-concept assessment by evaluating the efficacy and safety of EXB in combination with CTM in patients with NAFLD.Methods and analysis A total of 100 adult patients with NAFLD, diagnosed based on low-density lipoprotein cholesterol (LDL-C) level of >120 mg/dL and liver fat content of ≥8% by MRI-based proton density fat fraction (MRI-PDFF), who meet the inclusion/exclusion criteria will be enrolled. The patients will be randomly assigned to receive the combination therapy of 10 mg EXB and 9 g CTM powder (4 g CTM), 10 mg EXB monotherapy, 9 g CTM powder monotherapy or a placebo treatment (n=25 per group). Blood tests and MRIs will be performed 16 weeks following treatment initiation. The primary study endpoint will be the absolute LDL-C level change at week 16 after treatment initiation. The exploratory endpoint will include absolute changes in the liver fat fraction as measured by MRI-PDFF. This proof-of-concept study will determine whether the combination therapy of EXB and CTM is effective and safe for patients with NAFLD.Ethics and dissemination Ethics approval was obtained from the Ethics Committee of Yokohama City University Hospital before participant enrolment. The results of this study will be submitted for publication in international peer-reviewed journals and the key findings will be presented at international scientific conferences.Trial registration number NCT04235205 |
| format | Article |
| id | doaj-art-c3f9def2e0b54a23b84c11b95309d3a5 |
| institution | Kabale University |
| issn | 2044-6055 |
| language | English |
| publishDate | 2020-09-01 |
| publisher | BMJ Publishing Group |
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| series | BMJ Open |
| spelling | doaj-art-c3f9def2e0b54a23b84c11b95309d3a52025-01-08T14:15:11ZengBMJ Publishing GroupBMJ Open2044-60552020-09-0110910.1136/bmjopen-2020-037961Rationale and design of a randomised, double-blind, placebo-controlled, parallel-group, investigator-initiated phase 2a study to investigate the efficacy and safety of elobixibat in combination with cholestyramine for non-alcoholic fatty liver diseaseAtsushi Nakajima0Takeharu Yamanaka1Koji Yamamoto2Yasushi Honda3Kento Imajo4Masato Yoneda5Yuji Ogawa6Takaomi Kessoku7Takashi Kobayashi8Anna Ozaki9Satoru Saito10Michihiro Iwaki11Yusuke Saigusa12Haruki Usuda13Koichiro Wada14Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, JapanDepartment of Biostatics, Yokohama City University, Yokohama, Kanagawa, Japan9 General Medicine, Sumitomo Hospital, Osaka, JapanDepartment of Palliative Medicine, Yokohama City University Hospital, Yokohama, Japan3 Department of Gastroenterology, Shin Yurigaoka General Hospital, Kawasaki, Kanagawa, Japan6 Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan2 Department of Gastroenterology, National Hospital Organisation Yokohama Medical Center, Yokohama, JapanDepartment of Palliative Medicine, Yokohama City University Hospital, Yokohama, Japan1 Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine Graduate School of Medicine, Yokohama, Kanagawa, JapanDepartment of Gastroenterology and Hepatology, Yokohama City University, Yokohama, JapanDepartment of Gastroenterology and Hepatology, Yokohama City University School of Medicine Graduate School of Medicine, Yokohama, Japan1 Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine Graduate School of Medicine, Yokohama, Kanagawa, JapanDepartment of Biostatistics, Yokohama City University School of Medicine Graduate School of Medicine, Yokohama, JapanDepartment of Pharmacology, Shimane University Faculty of Medicine Graduate School of Medicine, Izumo, Shimane, JapanDepartment of Pharmacology, Shimane University Faculty of Medicine Graduate School of Medicine, Izumo, Shimane, JapanIntroduction Non-alcoholic fatty liver disease (NAFLD) pathogenesis involves abnormal metabolism of cholesterol and hepatic accumulation of toxic free-cholesterol. Elobixibat (EXB) inhibits the ileal bile acid (BA) transporter. EXB and cholestyramine (CTM) facilitate the removal of free cholesterol from the liver by decreasing BA recirculation to the liver, thereby stimulating novel BA synthesis from cholesterol. In this randomised, double-blind, placebo-controlled, parallel-group, phase IIa study, we aim to provide a proof-of-concept assessment by evaluating the efficacy and safety of EXB in combination with CTM in patients with NAFLD.Methods and analysis A total of 100 adult patients with NAFLD, diagnosed based on low-density lipoprotein cholesterol (LDL-C) level of >120 mg/dL and liver fat content of ≥8% by MRI-based proton density fat fraction (MRI-PDFF), who meet the inclusion/exclusion criteria will be enrolled. The patients will be randomly assigned to receive the combination therapy of 10 mg EXB and 9 g CTM powder (4 g CTM), 10 mg EXB monotherapy, 9 g CTM powder monotherapy or a placebo treatment (n=25 per group). Blood tests and MRIs will be performed 16 weeks following treatment initiation. The primary study endpoint will be the absolute LDL-C level change at week 16 after treatment initiation. The exploratory endpoint will include absolute changes in the liver fat fraction as measured by MRI-PDFF. This proof-of-concept study will determine whether the combination therapy of EXB and CTM is effective and safe for patients with NAFLD.Ethics and dissemination Ethics approval was obtained from the Ethics Committee of Yokohama City University Hospital before participant enrolment. The results of this study will be submitted for publication in international peer-reviewed journals and the key findings will be presented at international scientific conferences.Trial registration number NCT04235205https://bmjopen.bmj.com/content/10/9/e037961.full |
| spellingShingle | Atsushi Nakajima Takeharu Yamanaka Koji Yamamoto Yasushi Honda Kento Imajo Masato Yoneda Yuji Ogawa Takaomi Kessoku Takashi Kobayashi Anna Ozaki Satoru Saito Michihiro Iwaki Yusuke Saigusa Haruki Usuda Koichiro Wada Rationale and design of a randomised, double-blind, placebo-controlled, parallel-group, investigator-initiated phase 2a study to investigate the efficacy and safety of elobixibat in combination with cholestyramine for non-alcoholic fatty liver disease BMJ Open |
| title | Rationale and design of a randomised, double-blind, placebo-controlled, parallel-group, investigator-initiated phase 2a study to investigate the efficacy and safety of elobixibat in combination with cholestyramine for non-alcoholic fatty liver disease |
| title_full | Rationale and design of a randomised, double-blind, placebo-controlled, parallel-group, investigator-initiated phase 2a study to investigate the efficacy and safety of elobixibat in combination with cholestyramine for non-alcoholic fatty liver disease |
| title_fullStr | Rationale and design of a randomised, double-blind, placebo-controlled, parallel-group, investigator-initiated phase 2a study to investigate the efficacy and safety of elobixibat in combination with cholestyramine for non-alcoholic fatty liver disease |
| title_full_unstemmed | Rationale and design of a randomised, double-blind, placebo-controlled, parallel-group, investigator-initiated phase 2a study to investigate the efficacy and safety of elobixibat in combination with cholestyramine for non-alcoholic fatty liver disease |
| title_short | Rationale and design of a randomised, double-blind, placebo-controlled, parallel-group, investigator-initiated phase 2a study to investigate the efficacy and safety of elobixibat in combination with cholestyramine for non-alcoholic fatty liver disease |
| title_sort | rationale and design of a randomised double blind placebo controlled parallel group investigator initiated phase 2a study to investigate the efficacy and safety of elobixibat in combination with cholestyramine for non alcoholic fatty liver disease |
| url | https://bmjopen.bmj.com/content/10/9/e037961.full |
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