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

Non-Alcoholic Steatohepatitis Clinical Trial

Official title:

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)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02787304
• Other study ID #: SHP626-201
• Secondary ID: 2016-000203-82
• Status: Terminated
• Phase: Phase 2
• Start date: October 24, 2016
• Est. completion date: July 27, 2018

Study information

• Verified date: November 2019
• Source: Mirum Pharmaceuticals, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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).

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 197
• Est. completion date: July 27, 2018
• Est. primary completion date: July 27, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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.

Related Conditions & MeSH terms

• Fatty Liver
• Non-alcoholic Fatty Liver Disease
• Non-Alcoholic Steatohepatitis

Intervention

Drug:
• SHP626
5 mg, 10 mg, and 20 mg of SHP626 capsule by orally once daily in a double-blinded fashion
• Placebo
Matching placebo

Locations

Country	Name	City	State
Canada	University of Calgary Liver Unit	Calgary	Alberta
Canada	Nova Scotia Heath Authority	Halifax	Nova Scotia
Canada	CRCHUM	Montreal	Quebec
Canada	Toronto Liver Centre	Toronto	Ontario
Canada	LAIR Centre	Vancouver	British Columbia
Canada	Vancouver ID Research and Care Centre Society	Vancouver	British Columbia
Puerto Rico	UPR: Medical Sciences Campus	San Juan
United Kingdom	University Hospital Birmingham	Birmingham	West Midlands
United Kingdom	NHS Tayside	Dundee	Tayside
United Kingdom	Royal Free Hospital	Hampstead	London
United Kingdom	Royal London Hospital	London
United Kingdom	Norfolk & Norwich University Hospital	Norwich	Norfolk
United Kingdom	Nottingham Digestive Diseases Centre and Biomedical Research Unit	Nottingham
United Kingdom	John Radcliffe Hospital	Oxford	Oxfordshire
United Kingdom	Abertawe Bro Morgannwg University	Swansea
United Kingdom	York Clinical Research Facility	York
United States	Emory University	Atlanta	Georgia
United States	Internal Medicine Associates of Wellstar Atlanta Medical	Atlanta	Georgia
United States	Austin Center for Clinical Research	Austin	Texas
United States	Mercy Medical Center	Baltimore	Maryland
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	UVM Medical Center	Burlington	Vermont
United States	Digestive Disease Associates	Catonsville	Maryland
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Center for Liver Disease	Charlotte	North Carolina
United States	Clinsearch, LLC	Chattanooga	Tennessee
United States	Southern California Research Center	Coronado	California
United States	Methodist Health Systems Clinical	Dallas	Texas
United States	DUMC-Gastroenterology	Durham	North Carolina
United States	South Denver Gastroenterology, PC	Englewood	Colorado
United States	Cumberland Research Associates, LLC	Fayetteville	North Carolina
United States	Fresno Clinical Research Center	Fresno	California
United States	The Queen's Medical Center - Liver Center	Honolulu	Hawaii
United States	Baylor College of Medicine - Advanced Liver Therapies	Houston	Texas
United States	Texas Children's Hospital	Houston	Texas
United States	University of Iowa Hospitals and Clinics	Iowa City	Iowa
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Kansas City Research Institute	Kansas City	Missouri
United States	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire
United States	Ceders-Sinai Medical Center	Los Angeles	California
United States	Liver Research Center	Louisville	Kentucky
United States	UW Digestive Health Center (DHC)	Madison	Wisconsin
United States	Northwell Health Inc.	Manhasset	New York
United States	Gastrointestinal Specialists of Georgia	Marietta	Georgia
United States	University of TN Health Science Center	Memphis	Tennessee
United States	Schiff Center for Liver Diseases	Miami	Florida
United States	Quality Medical Research	Nashville	Tennessee
United States	Tulane University Health Sciences Center	New Orleans	Louisiana
United States	Concorde Medical Group PLLC	New York	New York
United States	Digestive and Liver Disease Specialists	Norfolk	Virginia
United States	Henry Ford Health System	Novi	Michigan
United States	California Liver Research Institute	Pasadena	California
United States	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania
United States	Inland Empire Liver Foundation	Rialto	California
United States	DHAT Research Institute	Richardson	Texas
United States	Bon Secours Liver Institute of Virginia	Richmond	Virginia
United States	McGuire VA Medical Center	Richmond	Virginia
United States	University of Rochester Medical Center	Rochester	New York
United States	Virginia Mason Medical Center	Seattle	Washington
United States	Louisiana Research Center, LLC	Shreveport	Louisiana
United States	Carolinas Center for Liver Disease	Statesville	North Carolina
United States	George Washington (GW) Medical Faculty Associates	Washington	District of Columbia
United States	Medstar Georgetown University Hospital	Washington	District of Columbia
United States	South Florida Center of Gastroenterology	Wellington	Florida
United States	University of Massachusetts Medical School	Worcester	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
Mirum Pharmaceuticals, Inc.

Countries where clinical trial is conducted

United States,  Canada,  Puerto Rico,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Change From Baseline to Week 48 on Metabolic Indicators	Metabolic indicators will be assessed by measuring hemoglobin A1c (HbA1c).	Baseline, Week 48
Secondary	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