A Nonabsorbable Ileal Apical Sodium-Dependent Bile Acid Transporter Inhibitor for Nonalcoholic Steatohepatitis

Nonalcoholic Steatohepatitis (NASH) Clinical Trial

— BRAVO-1  

Official title:

Use of A4250, a Nonabsorbable Ileal Apical Sodium-Dependent Bile Acid Transporter Inhibitor for Nonalcoholic Steatohepatitis (BRAVO-1)

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT03451279
• Other study ID #: BRAVO-1
• Secondary ID: U01DK061730
• Status: Withdrawn
• Phase: Phase 2
• First received: September 8, 2015
• Last updated: March 12, 2018
• Start date: January 2017
• Est. completion date: July 2019

Study information

• Verified date: February 2018
• Source: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The objective is to determine whether 24 weeks of treatment with A4250 will improve several clinically-relevant features of NASH compared to treatment with placebo.

Description:

BRAVO-1 is a multicenter, randomized, double-masked, placebo controlled trial of 24 weeks of treatment with ABST inhibitor A4250, 3 mg daily or placebo for patients with nonalcoholic fatty liver disease (NAFLD). Screening for eligibility and collection of baseline data will span up to 90 days after obtaining informed consent and registration. Eligible patients will be randomized to receive either ABST inhibitor A4250 (3 mg per day) or placebo for 24 weeks of treatment. The trial will evaluate whether treatment with ABST inhibitor A4250, 3 mg daily for 24 weeks compared to treatment with placebo, improves the severity of nonalcoholic fatty liver disease (NAFLD) as determined by linear regression of change in ALT of treatment group and baseline ALT.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: July 2019
• Est. primary completion date: January 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Age 18 years or older at initial screening

• Serum alanine aminotransferase (ALT) greater than or equal to 40 U/L

• Histological evidence of definite or borderline NASH (as defined by a NASH CRN pathologist) on a liver biopsy obtained no more than 120 days prior to randomization and a NAFLD activity score (NAS) of 4 or greater.

Exclusion Criteria:

• Failure to obtain consent or ability to follow through with protocol

• Intestinal disorders or prior GI tract surgery that interfere with A4250's function presumed mechanism of action; e.g., Crohn's disease, ulcerative colitis, intestinal resection, colectomy; biliary tract surgery other than cholecystectomy

• Significant alcohol consumption (more than 30 grams per day for men or 20 grams per day for women on more than 3 consecutive days within 1 year prior to screening, or inability to reliably quantify alcohol intake

• Use of drugs historically associated with NAFLD (amiodarone, methotrexate, systemic glucocorticoids, tetracycline, tamoxifen, estrogens at doses greater than those used for hormone replacement, anabolic steroids, valproic acid, other known hepatotoxins) for more than 2 weeks in the past year prior to randomization

• Cholestyramine, colesevelam or other bile acid binding resin therapy within 90 days prior to randomization

• Use of ursodeoxycholic acid (Ursodiol, Urso) within 90 days prior to randomization

• Use of fenofibrate; within 90 days prior to randomization

• Use of GLP-1 agonists: exenatide, liraglutide, albiglutide, etc. within 90 days prior to randomization

• Use of gliptins (dipeptidyl peptidase 4 inhibitors): sitagliptin, saxagliptin, linagliptin, alogliptin, etc., within 90 days prior to randomization

• Prior or planned bariatric surgery

• Presence of cirrhosis on liver biopsy

• A platelet count below 100,000 /mm^3

• Clinical evidence of hepatic decompensation (serum albumin < 3.2 g/dL, INR >1.3, direct bilirubin >1.3 mg/dL, history of esophageal varices, ascites, or hepatic encephalopathy)

• Evidence of other forms of chronic liver disease (Hep B/HepC) (evaluated via Standard of care by each PI)

• Serum alanine aminotransferase (ALT) greater than 300 U/L

• Serum creatinine of 2.0 mg/dL or greater

• Type I diabetes

• Uncontrolled diabetes defined as Hemoglobin A1c greater than 8.5% within 60 days prior to enrollment (use of insulin is not exclusionary)

• Known heart failure (Grade III or IV of New York Heart Association classification).

• Known positivity for Human Immunodeficiency Virus (HIV) infection

• Active, serious medical disease with likely life expectancy less than 5 years

• History of malignancy, other than non-melanomatous skin cancer, within 5 years prior to screening

• Active substance abuse including inhaled or injected drugs, in the year prior to screening

• Pregnancy, planned pregnancy, potential for pregnancy and unwillingness to use effective birth control during the trial, breast feeding

• Participation in another study with an experimental agent in the 30 days prior to randomization

• Any other condition which, in the opinion of the investigator, would impede compliance or hinder completion of the study

Related Conditions & MeSH terms

• Fatty Liver
• Liver Diseases
• Non-alcoholic Fatty Liver Disease
• Nonalcoholic Fatty Liver Disease (NAFLD)
• Nonalcoholic Steatohepatitis (NASH)

Intervention

Drug:
• A4250
0.5 mg x 1 week, 1.5 mg x 1 week, 3 mg x 22 weeks
• Placebo
0.5 mg x 1 week, 1.5 mg x 1 week, 3 mg x 22 weeks

Locations

Country	Name	City	State
United States	Indiana University	Bloomington	Indiana
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	Duke University Medical Center	Durham	North Carolina
United States	University of California, San Diego	La Jolla	California
United States	Virginia Commonwealth University	Richmond	Virginia
United States	Saint Louis University	Saint Louis	Missouri
United States	University of California, San Francisco	San Francisco	California
United States	Swedish Medical Center	Seattle	Washington

Sponsors (11)

Lead Sponsor	Collaborator
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)	Duke University, Indiana University, Johns Hopkins Bloomberg School of Public Health, National Cancer Institute (NCI), St. Louis University, Swedish Medical Center, The Cleveland Clinic, University of California, San Diego, University of California, San Francisco, Virginia Commonwealth University

Country where clinical trial is conducted

United States, 

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* Note: There are 76 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in serum alanine aminotransferase (ALT) levels		From baseline to 24 weeks
Secondary	Change in gamma-glutamyl transpeptidase (GGT) levels		From baseline to 24 weeks
Secondary	Change in aspartate aminotransferase (AST) levels		From baseline to 24 weeks
Secondary	Change in HOMA-IR levels		From baseline to 24 weeks
Secondary	Change in fasting serum LDL cholesterol level		From baseline to 24 weeks
Secondary	Change in hepatic steatosis as evaluated by Fibroscan®		From baseline to 24 weeks
Secondary	Change in hepatic stiffness measurements by Fibroscan®		From baseline to 24 weeks
Secondary	Change in fasting serum HDL cholesterol		From baseline to 24 weeks

External Links

•   Nonalcoholic Steatohepatitis Clinical Research Network
•   The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)