Efficacy and Safety of Elobixibat in Combination With Cholestyramine for Patients With Nonalcoholic Fatty Liver Disease: a Single Center, Double-blind, Randomized, Placebo-Controlled, Phase 2a Trial.
Efficacy and Safety of Elobixibat in Combination With Cholestyramine for Nonalcoholic Fatty Liver Disease
Sept. 30, 2021
No
version:
date:
Yokohama city university
3-9, Fukuura, Kanazawa-ku, Yokohama city
+81-45-787-2640
kessoku-tho@umin.ac.jp
Yokohama city university
3-9, Fukuura, Kanazawa-ku, Yokohama city
+81-45-787-2640
takaomi0027@gmail.com
completed
Jan. 30, 2020
100
Interventional
Single-center, randomized, double-blind, placebo-controlled, parallel-group comparison study
treatment purpose
2
Inclusion Criteria
1.Patients who received adequate explanation about this study and provided written informed consent
2.Patients who are 20 and older and under 75 years of age at the time of informed consent
3.Patients who have a current biopsy-confirmed NASH within 8 months of screening or a suspected diagnosis of NAFLD/NASH based on the criteria outlined below:
(1)Biopsy-confirmed NASH is defined as histological NASH diagnosis with fibrosis stage F1 through F3 and a NAFLD activity score (NAS) of 4 point and more with a score of 1 point and more in each of the NAS components below as assessed by a pathologist using the NASH Clinical Research Network criteria:
1)Steatosis (scored 0 to 3)
2)Ballooning degeneration (scored 0 to 2)
3)Lobular inflammation (scored 0 to 3)
(2)The suspected diagnosis of NAFLD/NASH is based on the following criteria:
1)Serum aspartate aminotransferase (AST) 20 and more U/L and alanine aminotransferase (ALT) 40 and more U/L in males or 28 and more U/L in females
2)Waist circumference 85 and more cm in males or 90 and more cm in females
3)Diagnosis of metabolic syndrome having 2 or more of the following 3 risk factors at Screening:
a)Fasting plasma glucose 110 and more mg/dL or undergoing drug treatment for elevated glucose
b)Systolic blood pressure 130 and more mmHg and/or diastolic blood pressure 85 and more mmHg or undergoing drug treatment for hypertension, or antihypertensive drug treatment in a patient with a history of hypertension
c)Triglycerides (TGs) 150 and more mg/dL or undergoing drug treatment for elevated triglycerides, and/or high-density lipoprotein-cholesterol (HDL-C) less than 40 mg/dL or undergoing drug treatment for reduced HDL-C
4.Screening Magnetic Resonance Imaging (MRI) -Proton Density Fat Fraction (PDFF) with 8 and more % liver steatosis
5.Fasting serum low density lipoprotein-cholesterol (LDL-C) 120 and more mg/dL or undergoing antidyslipidemic drugs
6.Be willing to maintain a stable diet and physical activity throughout the course of the study
1.Women who are pregnant, breastfeeding, possibly pregnant or do not agree to use birth control during the study
2.Body mass index (BMI) less than 23 kg/m2
3.Magnetic Resonance Elastography (MRE) value more than 6.7 kPa
4.Any of the following laboratory abnormalities:
(1)ALT more than 5 times upper limit normal (ULN) or AST more than 5 times ULN
(2)Prothrombin time - international normalized ratio (PT-INR) 1.3 and more unless on anticoagulant therapy
(3)Total bilirubin more than ULN, except with an established diagnosis of Gilberts syndrome
(4)Platelet count less than 80000/microL
(5)eGFR less than 45 as calculated by the body surface area (BSA) adjustment (normalized eGFR)
5.Acute or chronic liver disease other than NAFLD/NASH including but not limited to the following:
(1)Hepatitis B (as defined by the presence of hepatitis B surface [HBs] antigen at Screening) or hepatitis C (as defined by the presence of hepatitis C virus [HCV] antibody [anti-HCV])
Patients with positive anti-HCV who test negative for HCV ribonucleic acid (HCV-RNA) at Screening will be allowed to participate in the study as long as there is evidence of viral negativity for a minimum of 12 months prior to Screening
(2)Evidence of autoimmune hepatitis
(3)History of primary biliary cholangitis, primary sclerosing cholangitis, Wilsons disease, alpha-1-anti-trypsin deficiency, hemochromatosis or iron overload, drug-induced or alcoholic liver disease, or known bile duct obstruction
(4)Suspected or proven hepatocellular carcinoma
6.Known history of human immunodeficiency virus (HIV)
7.Medical history of liver cirrhosis
8.Clinical evidence of portal hypertension to include any history of ascites, hepatic encephalopathy, or presence of esophageal varices
9.Use of drugs historically associated with NAFLD (amiodarone, methotrexate, systemic glucocorticoids, tetracyclines, tamoxifen, estrogens at doses greater than those used for hormone replacement, anabolic steroids, or valproic acid) or other known hepatotoxins for 2 and more weeks in the year prior to Screening
10.Use of the following medications:
(1)Glucagon-like peptide-1 (GLP-1) agonists unless on a stable dose 3 months prior to Screening or liver biopsy
(2)Ursodeoxycholic acid or thiazolidinediones within 3 months prior to Screening
(3)Antidyslipidemic drugs have been stable for 3 and more months prior to Screening
(4)Oral antidiabetic drugs have been stable for 3 and more months prior to Screening
(5)Agents (including herbal over-the-counter weight loss preparations) or medications known to significantly impact body weight within 3 months prior to Screening
11.History of significant alcohol consumption, defined as an average of 20 and more g/day in female patients and 30 and more g/day in male patients, for a period of more than 3 consecutive months within 1 year prior to Screening, hazardous alcohol use (Alcohol Use Disorders Identification Test score 8 and more), or an inability to reliably quantify alcohol consumption but determined as alcohol polydipsia based upon judgment of the Investigator or subinvestigator
12.Weight change 10 and more % within the 6 months prior to Screening or 5 and more % within the 3 months prior to Screening
13.Surgery planned during the study period or after bariatric surgery (e.g., gastroplasty and roux-en-Y gastric bypass)
14.Type 1 diabetes by medical history
15.Uncontrolled Type 2 diabetes defined as hemoglobin A1c (HbA1c) more than 9.5% at Screening (patients with HbA1c more than 9.5% may be rescreened) or requiring insulin dose adjustment more than 10% within 2 months prior to Screening
16.Clinical hyperthyroidism or hypothyroidism or Screening hormone results pointing to thyroid dysfunction.
Patients receiving dose-stable thyroid replacement therapy for 3 and more months prior to Screening will be allowed to participate in this study as long as thyroid tests show that the patient is euthyroid and stable
17.History of any condition causing malabsorption such as chronic pancreatitis, extensive bowel/small intestine surgery, celiac disease, or bile flow obstruction
18.History of any condition associated with acute or chronic diarrhea such as inflammatory bowel disease (IBD), functional diarrhea, irritable bowel syndrome (IBS) with predominant diarrhea, IBS with mixed bowel habits, or unclassified IBS
19.Uncontrolled hypertension (either treated or untreated) defined as systolic blood pressure more than 160 mmHg or a diastolic blood pressure more than 100 mmHg at Screening
20.History of New York Heart Association (NYHA) Class III or IV heart failure, or known left ventricular ejection fraction less than 30%
21.History of myocardial infarction, unstable angina, percutaneous coronary intervention, coronary artery bypass graft, or stroke or major surgery within 6 months prior to Screening
22.Active substance abuse, within 1 year prior to Screening
23.Participation in an investigational new drug trial in the 30 days prior to Screening or within 5 half-lives of an investigational agent, whichever is longer
24.Complication with malignancy
Patients with a history of malignancies that have been treated with curative intent or completed chemotherapy may be eligible. Patients under evaluation for malignancy are not eligible
25.Known intolerance to MRI or conditions contraindicated for MRI procedures
26.Any other condition which is considered to be inappropriate for the study by the Investigator or subin
20age old over
75age old under
Both
Nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH)
investigational material(s)
Generic name etc : Elobixibat
INN of investigational material : Elobixibat
Therapeutic category code : 239 Other agents affecting digestive organs
Dosage and Administration for Investigational material : Elobixibat 10mg once a day for 16 weeks
Generic name etc : cholestylamine
INN of investigational material : cholestylamine
Therapeutic category code : 239 Other agents affecting digestive organs
Dosage and Administration for Investigational material : Cholestyramine powder 9g once a day for 16 weeks
control material(s)
Generic name etc : Placebo
INN of investigational material : -
Therapeutic category code : --- Other
Dosage and Administration for Investigational material : Placebo once a day for 16 weeks
efficacy
Absolute change from baseline in serum LDL-C at Week 16
safety
efficacy
exploratory
Efficacy:
1, Absolute change from baseline to Week 16 in the liver fat fraction
2, Absolute change from baseline to Week 16 in hepatic fibrosis as measured by MRE
3, Change from baseline to Week 16 in the following:
ALT, AST, gammma-glutamyl transpeptidase (GGT), HDL-C, non-HDL-C, LDL-C/HDL-C ratio and TG
Safety:
1, Incidence of adverse events in the active drug groups compared with the placebo groups
2, Change from baseline in the daily score of the Bristol Stool Form Scale , the number of bowel movements and the Patient Assessment of Constipation Quality of Life (PAC-QOL) at every visit
3, Change from baseline in the Chronic Liver Disease Questionnaire (CLDQ) scale at every visit
Takaomi Kessoku
-
EA Pharma Co., Ltd.
-
IRB of Yokohama city university
3-9, Fukuura, Kanazawa-ku, Yokohama city, Kanagawa prefecture
