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

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ClinicalTrials.gov Identifier: NCT02787304
Recruitment Status : Terminated
First Posted : June 1, 2016
Last Update Posted : March 18, 2019
Sponsor:
Information provided by (Responsible Party):
Mirum Pharmaceuticals, Inc.

Tracking Information
First Submitted Date  ICMJE May 11, 2016
First Posted Date  ICMJE June 1, 2016
Last Update Posted Date March 18, 2019
Actual Study Start Date  ICMJE October 24, 2016
Actual Primary Completion Date July 27, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 8, 2017)
Number of Subjects Achieving Binary Response on Liver Histology Between Volixibat (SHP626) and Placebo at Week 48 [ Time Frame: Baseline, 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).
Original Primary Outcome Measures  ICMJE
 (submitted: May 25, 2016)
The effect of volixibat compared to placebo on liver histology as assessed by a reduction of at least 2 points without worsening of fibrosis from Baseline nonalcoholic fatty liver disease (NAFLD) activity score (NAS) [ Time Frame: Baseline to Week 48 ]
Change History Complete list of historical versions of study NCT02787304 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: May 8, 2017)
  • Change From Baseline to Week 48 on Liver Histology [ Time Frame: Baseline, Week 48 ]
    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).
  • Change From Baseline to Week 48 on Hepatic Steatosis [ Time Frame: Baseline, Week 48 ]
    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.
  • Change from baseline to Week 48 on liver histology [ Time Frame: Baseline, Week 48 ]
    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).
  • Resolution of NASH at Week 48 [ Time Frame: 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.
  • Change from baseline to Week 48 on Serum Liver-related Biochemistry [ Time Frame: Baseline, Week 48 ]
    Serum liver-related biochemistry will be analysed by measuring alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), and total bilirubin (TB).
  • Change From Baseline to Week 48 on Metabolic Indicators [ Time Frame: Baseline, Week 48 ]
    Metabolic indicators will be assessed by measuring fasting serum glucose levels, insulin levels and hemoglobin A1c (HbA1c).
  • Change From Baseline to Week 48 on Serum Lipids [ Time Frame: Baseline, Week 48 ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: May 25, 2016)
  • Safety and tolerability of volixibat compared to placebo as measured by the number of subjects discontinuing treatment due to any one treatment-emergent adverse event (TEAE) [ Time Frame: Baseline to Week 48 ]
  • Effect of volixibat compared to placebo on hepatic steatosis as measured by MRI-PDFF (proton density fat fraction centrally read on a subset of subjects) [ Time Frame: Baseline to Week 48 ]
  • Effect of volixibat compared to placebo on liver histology as measured by individual NAS components [ Time Frame: Baseline to Week 48 ]
  • Effect of volixibat compared to placebo on serum liver-related biochemistry as measured by alkaline phosphatase (ALP) in blood sample [ Time Frame: Baseline to Week 48 ]
  • Effect of volixibat compared to placebo on metabolic indicators as measured by insulin levels in blood sample [ Time Frame: Baseline to Week 48 ]
  • Effect of volixibat compared to placebo on serum lipids as measured by cholesterol levels in blood sample [ Time Frame: Baseline to Week 48 ]
  • Effect of volixibat compared to placebo on liver histology as measured by NASH resolution without worsening fibrosis using NAS [ Time Frame: Baseline to Week 48 ]
  • Effect of volixibat compared to placebo on serum liver-related biochemistry as measured by alanine aminotransferase (ALT) in blood sample [ Time Frame: Baseline to Week 48 ]
  • Effect of volixibat compared to placebo on serum liver-related biochemistry as measured by aspartate aminotransferase (AST) in blood sample [ Time Frame: Baseline to Week 48 ]
  • Effect of volixibat compared to placebo on serum liver-related biochemistry as measured by gamma glutamyl transferase (GGT) in blood sample [ Time Frame: Baseline to Week 48 ]
  • Effect of volixibat compared to placebo on serum liver-related biochemistry as measured by total bilirubin (TB) in blood sample [ Time Frame: Baseline to Week 48 ]
  • Effect of volixibat compared to placebo on metabolic indicators as measured by blood glucose levels [ Time Frame: Baseline to Week 48 ]
  • Effect of volixibat compared to placebo on metabolic indicators as measured by hemoglobin A1c [HbA1c] in blood sample [ Time Frame: Baseline to Week 48 ]
  • Effect of volixibat compared to placebo on serum lipids as measured by levels of HDL-C in blood sample [ Time Frame: Baseline to Week 48 ]
  • Effect of volixibat compared to placebo on serum lipids as measured by levels of LDL-C in blood sample [ Time Frame: Baseline to Week 48 ]
  • Effect of volixibat compared to placebo on serum lipids as measured by levels of blood sample triglyceride levels [ Time Frame: Baseline to Week 48 ]
  • Effect of volixibat compared to placebo on liver histology as measured by fibrosis stage [ Time Frame: Baseline to Week 48 ]
  • Effect of volixibat compared to placebo on liver histology as measured by NASH resolution without worsening fibrosis using Fibrosis score [ Time Frame: Baseline to Week 48 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Volixibat (SHP626) in the Treatment of Adults With Nonalcoholic Steatohepatitis (NASH)
Official Title  ICMJE 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)
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).
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Non-Alcoholic Steatohepatitis
Intervention  ICMJE
  • Drug: SHP626
    5 mg, 10 mg, and 20 mg of SHP626 capsule by orally once daily in a double-blinded fashion
    Other Name: Volixibat (SHP626)
  • Drug: Placebo
    Matching placebo
Study Arms  ICMJE
  • Experimental: SHP626 5 Milligram (mg)
    Subject will be administered 5 mg SHP626 capsule by orally once daily in a double-blinded fashion
    Intervention: Drug: SHP626
  • Experimental: SHP626 10 Milligram (mg)
    Subject will be administered 10 mg SHP626 capsule by orally once daily in a double-blinded fashion
    Intervention: Drug: SHP626
  • Experimental: SHP626 20 Milligram (mg)
    Subject will be administered 20 mg SHP626 capsule by orally once daily in a double-blinded fashion
    Intervention: Drug: SHP626
  • Placebo Comparator: Placebo (PBO)
    Subject will be administered SHP626 matching PBO capsule by orally once daily in a double-blinded fashion
    Intervention: Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: June 13, 2018)
197
Original Estimated Enrollment  ICMJE
 (submitted: May 25, 2016)
266
Actual Study Completion Date  ICMJE July 27, 2018
Actual Primary Completion Date July 27, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada,   Puerto Rico,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02787304
Other Study ID Numbers  ICMJE SHP626-201
2016-000203-82 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Mirum Pharmaceuticals, Inc.
Study Sponsor  ICMJE Mirum Pharmaceuticals, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Study Director Mirum
PRS Account Mirum Pharmaceuticals, Inc.
Verification Date March 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP