Study to Evaluate the Safety, Tolerability, and Efficacy of Cilofexor in Adults With Primary Sclerosing Cholangitis Without Cirrhosis

Study Overview
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Brief Summary
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The primary objective of this study is to evaluate the safety and tolerability of cilofexor in adults with primary sclerosing cholangitis (PSC).

Official Title
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A Phase 2, Randomized, Double-Blind, Placebo Controlled Study Evaluating the Safety, Tolerability, and Efficacy of GS-9674 in Subjects With Primary Sclerosing Cholangitis Without Cirrhosis

Conditions
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Primary Sclerosing Cholangitis

Intervention / Treatment
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* Drug: Cilofexor
* Drug: Placebo to match cilofexor


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Diagnosis of PSC based on cholangiogram (magnetic resonance cholangiopancreatography (MRCP), endoscopic retrograde cholangiopancreatography (ERCP), or percutaneous transhepatic cholangiogram (PTC)) within the previous 12 months Serum alkaline phosphatase (ALP) > 1.67 x upper limit of the normal range (ULN) For individuals on ursodeoxycholic acid (UDCA), the dose of UDCA must have been stable for at least 12 months prior to screening through the end of treatment. For individuals not on UDCA, no UDCA use for at least 12 months before screening through the end of treatment For individuals being administered biologic treatments (eg, antitumor necrosis factor (TNF) or anti-integrin monoclonal antibodies), immunosuppressants or systemic corticosteroids, the dose must have been stable at least 3 months prior to screening and anticipated to remain stable throughout the trial Screening FibroSURE/FibroTest® <0.75 unless a historical liver biopsy within 12 months of screening does not reveal cirrhosis. In adults with Gilbert's syndrome or hemolysis, FibroSURE/FibroTest® will be calculated using direct bilirubin instead of total bilirubin. Key Exclusion Criteria: Alanine aminotransferase (ALT) > 10 x ULN Total bilirubin > 2 x ULN International normalized ratio (INR) > 1.2 unless on anticoagulant therapy Small-duct PSC (histologic evidence of PSC with normal bile ducts on cholangiography) Other causes of liver disease including secondary sclerosing cholangitis and viral, metabolic, alcoholic, and other autoimmune conditions. Individuals with hepatic steatosis may be included if there is no evidence of nonalcoholic steatohepatitis (NASH) in the opinion of the investigator or on liver biopsy; Ascending cholangitis within 60 days of screening Presence of a percutaneous drain or bile duct stent Use of fibrates or obeticholic acid within 3 months prior to screening through the end of treatment Cirrhosis of the liver as defined by any of the following: Historical liver biopsy demonstrating cirrhosis (eg, Ludwig stage 4 or Ishak stage ≥ 5) Prior history of decompensated liver disease, including ascites, hepatic encephalopathy or variceal bleeding Liver stiffness > 14.4 kilopascal (kPa) by FibroScan Current, active inflammatory bowel disease (IBD) defined as a partial Mayo score of > 1 and/or a score on the Rectal Bleeding domain > 0. Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Cilofexor 100 mg (Blinded Study Phase)<br>Cilofexor 100 mg + placebo to match cilofexor 30 mg for up to 12.6 weeks | Drug: Cilofexor<br>* Tablet(s) administered orally once daily with food<br>* Other names: GS-9674;Drug: Placebo to match cilofexor<br>* Tablet(s) administered orally once daily with food<br>|
| Experimental: Cilofexor 30 mg (Blinded Study Phase)<br>Cilofexor 30 mg + placebo to match cilofexor 100 mg for up to 12.7 weeks | Drug: Cilofexor<br>* Tablet(s) administered orally once daily with food<br>* Other names: GS-9674;Drug: Placebo to match cilofexor<br>* Tablet(s) administered orally once daily with food<br>|
| Placebo Comparator: Placebo (Blinded Study Phase)<br>Placebo to match cilofexor 30 mg + placebo to match cilofexor 100 mg for up to 12.3 weeks | Drug: Placebo to match cilofexor<br>* Tablet(s) administered orally once daily with food<br>|
| Experimental: Cilofexor (Open Label Extension Phase)<br>Following the Blinded Study Phase, eligible participants received cilofexor for an additional up to 97.4 weeks. | Drug: Cilofexor<br>* Tablet(s) administered orally once daily with food<br>* Other names: GS-9674;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Experiencing Treatment-Emergent Adverse Events During the Blinded Phase | Treatment-emergent adverse events occurring during the Blinded Phase were defined as 1 or both of the following: 1) Any adverse events (AEs) with an onset date on or after the study drug start date and no later than 30 days after permanent discontinuation of study drug in the Blinded Phase (and before the first dosing date in the Open Label Extension (OLE) Phase), or 2) Any AEs leading to premature discontinuation of study drug in the Blinded Phase. | First dose date up to last dose date plus 30 days (Up to 17 weeks) | 
| Percentage of Participants Experiencing Treatment-Emergent Serious Adverse Events During the Blinded Phase | A serious adverse event was defined as an event that, at any dose, resulted in any of the following: death, life-threatening, in-patient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, a congenital anomaly/birth defect, or a medically important event or reaction. | First dose date up to last dose date plus 30 days (Up to 17 weeks) | 
| Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities During the Blinded Phase | Treatment-emergent laboratory abnormalities occurring during the Blinded Phase were defined as values that increase at least 1 toxicity grade from baseline at any postbaseline time point, up to and including the date of last dose of study drug in the Blinded Phase plus 30 days (and prior to or on the first dose date of the OLE phase). The Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 was used for assigning toxicity grades (0 to 4, with higher grades indicating more severity). | First dose date up to last dose date plus 30 days (Up to 17 weeks) |