Clinical trial NCT02787304: Volixibat (SHP626) in the Treatment of Adults With Nonalcoholic Steatohepatitis (NASH)
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)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Non-Alcoholic Steatohepatitis
Keywords: NAFLD activity score
ASBTi
MRI PDFF
NAS
NAFLD
liver disease
ASBT
MRI proton density fat fraction
nonalcoholic steatohepatitis
apical sodium dependent bile acid transporter inhibitor
fatty liver
NASH
Lead sponsor: Mirum Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2016-06-01
Enrollment: 197
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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).


Eligibility criteria: 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.

Primary outcomes:
measure: Number of Subjects Achieving Binary Response on Liver Histology Between Volixibat (SHP626) and Placebo at Week 48
timeFrame: Baseline, Week 48
Secondary outcomes:
measure: Change From Baseline to Week 48 on Liver Histology
timeFrame: Baseline, Week 48
measure: Change From Baseline to Week 48 on Hepatic Steatosis
timeFrame: Baseline, Week 48
measure: Change From Baseline to Week 48 on Liver Histology
timeFrame: Baseline, Week 48
measure: Number of Participants With Resolution of NASH at Week 48
timeFrame: Week 48
measure: Change From Baseline to Week 48 on Serum Liver-related Biochemistry
timeFrame: Baseline, Week 48
measure: Change From Baseline to Week 48 on Serum Liver-related Biochemistry
timeFrame: Baseline, Week 48
measure: Change From Baseline to Week 48 on Metabolic Indicators
timeFrame: Baseline, Week 48
measure: Change From Baseline to Week 48 on Metabolic Indicators
timeFrame: Baseline, Week 48
measure: Change From Baseline to Week 48 on Serum Lipids
timeFrame: Baseline, Week 48
Other outcomes:
Locations:
city: Coronado
country: United States
facility: Southern California Research Center
state: California
city: Fresno
country: United States
facility: Fresno Clinical Research Center
state: California
city: Los Angeles
country: United States
facility: Ceders-Sinai Medical Center
state: California
city: Pasadena
country: United States
facility: California Liver Research Institute
state: California
city: Rialto
country: United States
facility: Inland Empire Liver Foundation
state: California
city: Englewood
country: United States
facility: South Denver Gastroenterology, PC
state: Colorado
city: Washington
country: United States
facility: Medstar Georgetown University Hospital
state: District of Columbia
city: Washington
country: United States
facility: George Washington (GW) Medical Faculty Associates
state: District of Columbia
city: Miami
country: United States
facility: Schiff Center for Liver Diseases
state: Florida
city: Wellington
country: United States
facility: South Florida Center of Gastroenterology
state: Florida
city: Atlanta
country: United States
facility: Internal Medicine Associates of Wellstar Atlanta Medical
state: Georgia
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Marietta
country: United States
facility: Gastrointestinal Specialists of Georgia
state: Georgia
city: Honolulu
country: United States
facility: The Queen's Medical Center - Liver Center
state: Hawaii
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics
state: Iowa
city: Louisville
country: United States
facility: Liver Research Center
state: Kentucky
city: New Orleans
country: United States
facility: Tulane University Health Sciences Center
state: Louisiana
city: Shreveport
country: United States
facility: Louisiana Research Center, LLC
state: Louisiana
city: Baltimore
country: United States
facility: Mercy Medical Center
state: Maryland
city: Catonsville
country: United States
facility: Digestive Disease Associates
state: Maryland
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Worcester
country: United States
facility: University of Massachusetts Medical School
state: Massachusetts
city: Novi
country: United States
facility: Henry Ford Health System
state: Michigan
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Kansas City
country: United States
facility: Kansas City Research Institute
state: Missouri
city: Lebanon
country: United States
facility: Dartmouth Hitchcock Medical Center
state: New Hampshire
city: Manhasset
country: United States
facility: Northwell Health Inc.
state: New York
city: New York
country: United States
facility: Concorde Medical Group PLLC
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
city: Charlotte
country: United States
facility: Center for Liver Disease
state: North Carolina
city: Durham
country: United States
facility: DUMC-Gastroenterology
state: North Carolina
city: Fayetteville
country: United States
facility: Cumberland Research Associates, LLC
state: North Carolina
city: Statesville
country: United States
facility: Carolinas Center for Liver Disease
state: North Carolina
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Chattanooga
country: United States
facility: Clinsearch, LLC
state: Tennessee
city: Memphis
country: United States
facility: University of TN Health Science Center
state: Tennessee
city: Nashville
country: United States
facility: Quality Medical Research
state: Tennessee
city: Austin
country: United States
facility: Austin Center for Clinical Research
state: Texas
city: Dallas
country: United States
facility: Methodist Health Systems Clinical
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine - Advanced Liver Therapies
state: Texas
city: Houston
country: United States
facility: Texas Children's Hospital
state: Texas
city: Richardson
country: United States
facility: DHAT Research Institute
state: Texas
city: Burlington
country: United States
facility: UVM Medical Center
state: Vermont
city: Norfolk
country: United States
facility: Digestive and Liver Disease Specialists
state: Virginia
city: Richmond
country: United States
facility: Bon Secours Liver Institute of Virginia
state: Virginia
city: Richmond
country: United States
facility: McGuire VA Medical Center
state: Virginia
city: Seattle
country: United States
facility: Virginia Mason Medical Center
state: Washington
city: Madison
country: United States
facility: UW Digestive Health Center (DHC)
state: Wisconsin
city: Calgary
country: Canada
facility: University of Calgary Liver Unit
state: Alberta
city: Vancouver
country: Canada
facility: LAIR Centre
state: British Columbia
city: Vancouver
country: Canada
facility: Vancouver ID Research and Care Centre Society
state: British Columbia
city: Halifax
country: Canada
facility: Nova Scotia Heath Authority
state: Nova Scotia
city: Toronto
country: Canada
facility: Toronto Liver Centre
state: Ontario
city: Montreal
country: Canada
facility: CRCHUM
state: Quebec
city: San Juan
country: Puerto Rico
facility: UPR: Medical Sciences Campus
city: Hampstead
country: United Kingdom
facility: Royal Free Hospital
state: London
city: Norwich
country: United Kingdom
facility: Norfolk & Norwich University Hospital
state: Norfolk
city: Oxford
country: United Kingdom
facility: John Radcliffe Hospital
state: Oxfordshire
city: Dundee
country: United Kingdom
facility: NHS Tayside
state: Tayside
city: Birmingham
country: United Kingdom
facility: University Hospital Birmingham
state: West Midlands
city: London
country: United Kingdom
facility: Royal London Hospital
city: Nottingham
country: United Kingdom
facility: Nottingham Digestive Diseases Centre and Biomedical Research Unit
city: Swansea
country: United Kingdom
facility: Abertawe Bro Morgannwg University
city: York
country: United Kingdom
facility: York Clinical Research Facility
Study officials:
affiliation: Mirum
name: Study Director
role: STUDY_DIRECTOR
References:
citation: 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.