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

Study Overview
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Brief Summary
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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).

Official Title
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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)

Conditions
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Non-Alcoholic Steatohepatitis

Intervention / Treatment
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* Drug: SHP626
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: An understanding, ability, and willingness to fully comply with study procedures and restrictions. Ability to voluntarily provide written, signed, and dated (personally or via a legally authorized representative, as applicable) informed consent to participate in the study. Age 18-80 years inclusive. This inclusion criterion will only be assessed at the first screening visit. 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). 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. 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: Presence of or history of cirrhosis or evidence of decompensated liver disease (example: ascites, variceal bleeding, etc.) or hepatocellular carcinoma. 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. 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. 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. 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. 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. 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. Uncontrolled diabetes defined as HbA1c of >=9.5% within 60 days prior to enrollment. 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%. 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). Serum aspartate aminotransferase (AST) greater than (>) 7 times upper limit of normal (ULN) at screening. Serum alanine aminotransferase (ALT) >7 times ULN at screening. Elevated serum creatinine >=2.0 milligram/deciliter (mg/dL). International normalized ratio (INR) >1.3 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). Platelet count <130 × 10^9/liter (L) 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). Uncontrolled thyroid disease. Type 1 diabetes mellitus. Known or suspected intolerance or hypersensitivity to the IP, closely-related compounds, or any of the stated ingredients. 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. 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. Inability to safely obtain a liver biopsy. Females who are pregnant, planning to become pregnant, or are breastfeeding, or males who are planning to father a child during study participation. The anticipated need for a surgical procedure during the study that could interfere with the treatment. Known positivity for human immunodeficiency virus (HIV) infection. 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. 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. 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. 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). Subjects who are employees at the unit of the investigational site that is conducting the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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