Volixibat (SHP626) in the Treatment of Adults With Nonalcoholic Steatohepatitis (NASH)

A Phase 2 Double-blind, Randomized, Placebo-controlled, Dose-finding Study to Evaluate the Safety, Tolerability and Efficacy of Volixibat Potassium, an Apical Sodium-Dependent Bile Acid Transporter Inhibitor (ASBTi) in Adults With Nonalcoholic Steatohepatitis (NASH)

The purpose of this study is to determine if the investigational treatment volixibat (SHP626) is safe, tolerable and effective in adults with nonalcoholic steatohepatitis (NASH).

Study Overview

• Status: Terminated
• Conditions: Non-Alcoholic Steatohepatitis
• Intervention / Treatment: Drug: Placebo; Drug: SHP626

• Study Type: Interventional
• Enrollment (Actual): 197
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4Z5
      • University of Calgary Liver Unit
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 1H2
      • Lair Centre
    • Vancouver, British Columbia, Canada, V6Z 2C7
      • Vancouver ID Research and Care Centre Society
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3HJ 2Y9
      • Nova Scotia Heath Authority
  • Ontario
    • Toronto, Ontario, Canada, M6H 3M1
      • Toronto Liver Centre
  • Quebec
    • Montreal, Quebec, Canada, H2X 0A9
      • CRCHUM
• Puerto Rico
  • San Juan, Puerto Rico, 00935
    • UPR: Medical Sciences Campus
• United Kingdom
  • London, United Kingdom, E1 1BB
    • Royal London Hospital
  • Nottingham, United Kingdom, NG7 2UH
    • Nottingham Digestive Diseases Centre and Biomedical Research Unit
  • Swansea, United Kingdom, SA2 8QA
    • Abertawe Bro Morgannwg University
  • York, United Kingdom, YO31 8HE
    • York Clinical Research Facility
  • London
    • Hampstead, London, United Kingdom, NW3 2QG
      • Royal Free Hospital
  • Norfolk
    • Norwich, Norfolk, United Kingdom, NR4 7UY
      • Norfolk & Norwich University Hospital
  • Oxfordshire
    • Oxford, Oxfordshire, United Kingdom, OX3 9DU
      • John Radcliffe Hospital
  • Tayside
    • Dundee, Tayside, United Kingdom, DD1 9SY
      • NHS Tayside
  • West Midlands
    • Birmingham, West Midlands, United Kingdom, B15 2TH
      • University Hospital Birmingham
• United States
  • California
    • Coronado, California, United States, 92118
      • Southern California Research Center
    • Fresno, California, United States, 93720
      • Fresno Clinical Research Center
    • Los Angeles, California, United States, 90048
      • Ceders-Sinai Medical Center
    • Pasadena, California, United States, 91105
      • California Liver Research Institute
    • Rialto, California, United States, 92377
      • Inland Empire Liver Foundation
  • Colorado
    • Englewood, Colorado, United States, 80113
      • South Denver Gastroenterology, PC
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • MedStar Georgetown University Hospital
    • Washington, District of Columbia, United States, 20037
      • George Washington (GW) Medical Faculty Associates
  • Florida
    • Miami, Florida, United States, 33136
      • Schiff Center for Liver Diseases
    • Wellington, Florida, United States, 33414
      • South Florida Center of Gastroenterology
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
    • Atlanta, Georgia, United States, 30312
      • Internal Medicine Associates of Wellstar Atlanta Medical
    • Marietta, Georgia, United States, 30060
      • Gastrointestinal Specialists of Georgia
  • Hawaii
    • Honolulu, Hawaii, United States, 96813
      • The Queen's Medical Center - Liver Center
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals and Clinics
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • Liver Research Center
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Tulane University Health Sciences Center
    • Shreveport, Louisiana, United States, 71105
      • Louisiana Research Center, LLC
  • Maryland
    • Baltimore, Maryland, United States, 21202
      • Mercy Medical Center
    • Catonsville, Maryland, United States, 21228
      • Digestive Disease Associates
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
    • Worcester, Massachusetts, United States, 01605
      • University of Massachusetts Medical School
  • Michigan
    • Novi, Michigan, United States, 48377
      • Henry Ford Health System
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • University of Mississippi Medical Center
  • Missouri
    • Kansas City, Missouri, United States, 64157
      • Kansas City Research Institute
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth Hitchcock Medical Center
  • New York
    • Manhasset, New York, United States, 11030
      • Northwell Health Inc.
    • New York, New York, United States, 10016
      • Concorde Medical Group PLLC
    • Rochester, New York, United States, 14642
      • University of Rochester Medical Center
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Center for Liver Disease
    • Durham, North Carolina, United States, 27710
      • DUMC-Gastroenterology
    • Fayetteville, North Carolina, United States, 28304
      • Cumberland Research Associates, LLC
    • Statesville, North Carolina, United States, 28677
      • Carolinas Center For Liver Disease
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh Medical Center
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Tennessee
    • Chattanooga, Tennessee, United States, 37421
      • ClinSearch, LLC
    • Memphis, Tennessee, United States, 038104
      • University of TN Health Science Center
    • Nashville, Tennessee, United States, 37211
      • Quality Medical Research
  • Texas
    • Austin, Texas, United States, 78756
      • Austin Center for Clinical Research
    • Dallas, Texas, United States, 75203
      • Methodist Health Systems Clinical
    • Houston, Texas, United States, 77030
      • Texas Children's Hospital
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine - Advanced Liver Therapies
    • Richardson, Texas, United States, 75082
      • DHAT Research Institute
  • Vermont
    • Burlington, Vermont, United States, 05401
      • UVM Medical Center
  • Virginia
    • Norfolk, Virginia, United States, 23502
      • Digestive and Liver Disease Specialists
    • Richmond, Virginia, United States, 23249
      • McGuire VA Medical Center
    • Richmond, Virginia, United States, 23226
      • Bon Secours Liver Institute of Virginia
  • Washington
    • Seattle, Washington, United States, 98101
      • Virginia Mason Medical Center
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • UW Digestive Health Center (DHC)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. An understanding, ability, and willingness to fully comply with study procedures and restrictions.
2. Ability to voluntarily provide written, signed, and dated (personally or via a legally authorized representative, as applicable) informed consent to participate in the study.
3. Age 18-80 years inclusive. This inclusion criterion will only be assessed at the first screening visit.
4. Male, or non-pregnant, non-lactating female, who is sexually active and who agrees to comply with the contraceptive requirements of the protocol, or females of non-childbearing potential. Males and females of child-bearing potential who are sexually active must agree to use acceptable contraception during the study and for 30 days following the last dose of the investigational product (IP).
5. Presence of greater than equals to (>=) 5 percent (%) steatosis on screening magnetic resonance imaging (MRI) from a centrally read radiologist performed either during the screening period or within 6 months prior to the first visit.
6. Histologic confirmation of nonalcoholic steatohepatitis (NASH) without cirrhosis (F0-F3) from a centrally read liver biopsy performed either during the screening period or within 6 months prior to the first visit with a NAS of >=4 with a score of at least 1 in each component (steatosis, lobular inflammation, and hepatocyte ballooning).

Exclusion Criteria:

1. Presence of or history of cirrhosis or evidence of decompensated liver disease (example: ascites, variceal bleeding, etc.) or hepatocellular carcinoma.
2. History or presence of other concomitant liver disease as assessed by the investigator or determined by laboratory findings including, but not limited to: active hepatitis B virus (HBV) infection (hepatitis B surface antigen [HBsAg] positive and/or hepatitis B virus deoxyribonucleic acid (HBVDNA) positive; subjects who are hepatitis B core antibody [HBcAb] positive may be eligible as long as HBsAg is negative and HBVDNA is non detectable), active hepatitis C virus (HCV) infection (prior exposure to HCV [defined as HCVAb positive] without a current or prior history of a detectable HCVRNA) may be eligible, alcoholic liver disease, proven autoimmune hepatitis, primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), hemochromatosis, Wilson's disease, alpha-1 antitrypsin deficiency, bile duct obstruction, liver primary or metastatic cancer.
3. Current or recurrent disease that could affect the action, absorption, disposition, or laboratory assessment of the IP (including bile salt metabolism in the intestine) example (e.g,) uncontrolled inflammatory bowel disease, uncontrolled celiac disease, gastric bypass procedures (gastric lap band or gastric sleeve is acceptable), ileal or ileocecal resection, uncontrolled irritable bowel syndrome with predominant diarrhea, or history of chronic diarrhea or loose stools of any etiology.
4. Weight change >=5% after qualifying liver biopsy and/or MRI performed. If the subject had a liver biopsy and/or MRI within 6 months of screening, but experienced a weight change of >=5% since the date of liver biopsy and/or MRI, the liver biopsy and/or MRI must be repeated at screening.
5. Contraindications to MRI (e.g, claustrophobia, coronary stents, coronary implantable devices, girth, etc.). Stents or other devices may be allowed, at the investigator's discretion, if they do not interfere with the functioning of the MRI machine.
6. Current or relevant history of physical or psychiatric illness, any medical disorder that may require treatment or make the subject unlikely to complete the study.
7. Treatment with Vitamin E, thiazolidinediones (TZD), or glucagon-like peptide-1 receptor agonists (GLP-1 RA) unless subject on a stable dose for 6 months prior to qualifying liver biopsy and not initiated after qualifying liver biopsy and will continue the same dosing regimen throughout study participation.
8. Uncontrolled diabetes defined as HbA1c of >=9.5% within 60 days prior to enrollment.
9. Current use of any medication (including over-the-counter, herbal, or homeopathic preparations) that could affect the action, absorption, or disposition of the IP, or clinical or laboratory assessment. (Current use is defined as use within 14 days of screening). Subjects currently taking insulin will not be excluded; however, they must be on a stable dose for at least 30 days prior to screening, or a sliding scale of insulin is allowed as long as the subject's HbA1c remains less than (<) 9.5%.
10. Use of drugs, herbs or supplements historically associated with causing or worsening NAFLD/NASH for less than 6 months prior to liver biopsy, or initiated any time after liver biopsy performed, including the use of total parenteral nutrition (TPN).
11. Serum aspartate aminotransferase (AST) greater than (>) 7 times upper limit of normal (ULN) at screening.
12. Serum alanine aminotransferase (ALT) >7 times ULN at screening.
13. Elevated serum creatinine >=2.0 milligram/deciliter (mg/dL).
14. International normalized ratio (INR) >1.3
15. Total bilirubin (TB) >2.0 times ULN at screening (Except for documented Gilbert's syndrome with bilirubin levels 20 micromole per liter (mcmol/L) to 90 mcmol/L (1.2 to 5.3 mg/dL) and with a ratio of unconjugated/conjugated bilirubin that is commensurately higher).
16. Platelet count <130 × 10^9/liter (L)
17. Medical history of impaired hemostasis or use of anticoagulant medication (use of antiplatelet medications, such as low-dose, that is 81 mg, aspirin [ASA] or clopidogrel [Plavix] will be allowed).
18. Uncontrolled thyroid disease.
19. Type 1 diabetes mellitus.
20. Known or suspected intolerance or hypersensitivity to the IP, closely-related compounds, or any of the stated ingredients.
21. Known history of alcohol or other substance abuse within the last year or at any time during the study based on investigator's discretion. Weekly alcohol intake greater than 21 grams/day for males and 14 grams/day for females on average or inability to reliably quantify alcohol consumption based on investigator's judgment.

22. Within 6 months of MRI and liver biopsy:

    • Have used any IP.
    • Have been enrolled in a clinical study (including vaccine studies) that, in the investigator's opinion, may impact this Shire-sponsored study.
23. Inability to safely obtain a liver biopsy.
24. Females who are pregnant, planning to become pregnant, or are breastfeeding, or males who are planning to father a child during study participation.
25. The anticipated need for a surgical procedure during the study that could interfere with the treatment.
26. Known positivity for human immunodeficiency virus (HIV) infection.
27. Cancer within 5 years of screening, except for basal or squamous cell carcinoma of the skin or in situ cervical carcinoma that has been treated with no evidence of recurrence.
28. History of noncompliance with medical regimens, unreliability, mental instability or incompetence that could compromise the validity of informed consent or lead to noncompliance with the study protocol.
29. Any other conditions or abnormalities which, in the opinion of the investigator, may compromise the safety of the subject, or interfere with the subject participating.
30. Subject is currently enrolled in this study at any study site (unless the subject is transferring to another qualified study site with prior sponsor approval).
31. Subjects who are employees at the unit of the investigational site that is conducting the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: SHP626 5 Milligram (mg); Subject will be administered 5 mg SHP626 capsule by orally once daily in a double-blinded fashion	Drug: SHP626; 5 mg, 10 mg, and 20 mg of SHP626 capsule by orally once daily in a double-blinded fashion; Other Names: Volixibat (SHP626)
Experimental: SHP626 10 Milligram (mg); Subject will be administered 10 mg SHP626 capsule by orally once daily in a double-blinded fashion	Drug: SHP626; 5 mg, 10 mg, and 20 mg of SHP626 capsule by orally once daily in a double-blinded fashion; Other Names: Volixibat (SHP626)
Experimental: SHP626 20 Milligram (mg); Subject will be administered 20 mg SHP626 capsule by orally once daily in a double-blinded fashion	Drug: SHP626; 5 mg, 10 mg, and 20 mg of SHP626 capsule by orally once daily in a double-blinded fashion; Other Names: Volixibat (SHP626)
Placebo Comparator: Placebo (PBO); Subject will be administered SHP626 matching PBO capsule by orally once daily in a double-blinded fashion	Drug: Placebo; Matching placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Subjects Achieving Binary Response on Liver Histology Between Volixibat (SHP626) and Placebo at Week 48	Binary response indicating (yes/no) whether a subject responded at week 48 with a reduction of at least 2 points, without worsening of fibrosis, from baseline nonalcoholic fatty liver disease (NAFLD) activity score (NAS). The NAS grades NAFLD on liver biopsy based on the individual scoring of steatosis, inflammation and ballooning. The NAS is assessed on a scale of 0 to 8 with higher scores indicating more severe disease and lower scores indicating less severe disease. NAS is obtained by adding steatosis(assessed on a scale of 0 to 3), inflammation (assessed on a scale of 0 to 3) and ballooning (assessed on a scale of 0 to 2).	Baseline, Week 48

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline to Week 48 on Liver Histology	Change in liver histology will be measured by the individual NAS components (ballooning, inflammation, steatosis). The NAS grades NAFLD on liver biopsy based on the individual scoring of steatosis, inflammation and ballooning. The NAS is assessed on a scale of 0 to 8 with higher scores indicating more severe disease and lower scores indicating less severe disease. NAS is obtained by adding steatosis (assessed on a scale of 0 to 3), inflammation (assessed on a scale of 0 to 3) and ballooning (assessed on a scale of 0 to 2).	Baseline, Week 48
Change From Baseline to Week 48 on Hepatic Steatosis	Change in hepatic steatosis will be evaluated by measuring the reduction of liver fat with magnetic resonance imaging-proton density fat-fraction (MRI-PDFF) and stratified by treatment group.	Baseline, Week 48
Change From Baseline to Week 48 on Liver Histology	Change in liver histology will be measured by fibrosis stage. Fibrosis stage is assessed on a scale of 0-4 with higher scores indicating more severe disease and lower scores indicating less severe disease (F0 = no fibrosis, F4 = cirrhosis).	Baseline, Week 48
Number of Participants With Resolution of NASH at Week 48	Resolution of NASH is defined as total absence of ballooning [score = 0], absent or mild inflammation [score 0-1], steatosis can be present [score 0-3]) without worsening of fibrosis as assessed by liver histology at Week 48.	Week 48
Change From Baseline to Week 48 on Serum Liver-related Biochemistry	Serum liver-related biochemistry will be analysed by measuring alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and gamma glutamyl transferase (GGT).	Baseline, Week 48
Change From Baseline to Week 48 on Serum Liver-related Biochemistry	Serum liver-related biochemistry will be analysed by measuring total bilirubin (TB).	Baseline, Week 48
Change From Baseline to Week 48 on Metabolic Indicators	Metabolic indicators will be assessed by measuring fasting serum glucose levels and insulin levels.	Baseline, Week 48
Change From Baseline to Week 48 on Metabolic Indicators	Metabolic indicators will be assessed by measuring hemoglobin A1c (HbA1c).	Baseline, Week 48
Change From Baseline to Week 48 on Serum Lipids	Serum lipids level will be measured by calculating fasting total cholesterol, high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), and triglycerides.	Baseline, Week 48

Collaborators and Investigators

• Sponsor: Mirum Pharmaceuticals, Inc.

Publications and helpful links

General Publications

• Newsome PN, Palmer M, Freilich B, Sheikh MY, Sheikh A, Sarles H, Herring R, Mantry P, Kayali Z, Hassanein T, Lee HM, Aithal GP; Volixibat in Adults study group. Volixibat in adults with non-alcoholic steatohepatitis: 24-week interim analysis from a randomized, phase II study. J Hepatol. 2020 Aug;73(2):231-240. doi: 10.1016/j.jhep.2020.03.024. Epub 2020 Mar 29.

Study record dates

Study Major Dates

• Study Start (Actual): October 24, 2016
• Primary Completion (Actual): July 27, 2018
• Study Completion (Actual): July 27, 2018

Study Registration Dates

• First Submitted: May 11, 2016
• First Submitted That Met QC Criteria: May 25, 2016
• First Posted (Estimate): June 1, 2016

Study Record Updates

• Last Update Posted (Actual): November 25, 2019
• Last Update Submitted That Met QC Criteria: November 6, 2019
• Last Verified: November 1, 2019

More Information

Terms related to this study

• Keywords: NAFLD; NASH; fatty liver; liver disease; nonalcoholic steatohepatitis; NAS; NAFLD activity score; ASBTi; MRI PDFF; ASBT; MRI proton density fat fraction; apical sodium dependent bile acid transporter inhibitor
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Lipid Regulating Agents; Volixibat
• Other Study ID Numbers: SHP626-201; 2016-000203-82 (EudraCT Number)