Study of Cilofexor in Adults With Primary Sclerosing Cholangitis

Study Overview
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Brief Summary
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The primary objective of this study is to evaluate whether cilofexor reduces the risk of fibrosis progression among non-cirrhotic adults with primary sclerosing cholangitis (PSC).

Official Title
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A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety, Tolerability, and Efficacy of Cilofexor in Non-Cirrhotic Subjects With Primary Sclerosing Cholangitis

Conditions
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Primary Sclerosing Cholangitis

Intervention / Treatment
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* Drug: Cilofexor
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Diagnosis of large duct PSC Liver biopsy at screening that is deemed acceptable for interpretation and demonstrates stage F0 - F3 fibrosis in the opinion of the central reader Individual has the following laboratory parameters at the screening visit, as determined by the central laboratory: Platelet count ≥ 150,000/mm^3 Estimated glomerular filtration rate (eGFR) ≥ 30 milliliter/minute (mL/min), as calculated by the Cockcroft-Gault equation Alanine transaminase (ALT) ≤ 8 x upper limit of the normal range (ULN) Total bilirubin < 2 mg/dL, unless the individual is known to have Gilbert's syndrome or hemolytic anemia International normalized ratio (INR) ≤ 1.4, unless due to therapeutic anticoagulation Negative anti-mitochondrial antibody Key Exclusion Criteria: Current or prior history of any of the following: Cirrhosis Liver transplantation Cholangiocarcinoma or hepatocellular carcinoma (HCC) Ascending cholangitis within 30 days of screening Presence of a percutaneous drain or biliary stent Other causes of liver disease Current or prior history of unstable cardiovascular disease Current moderate to severe inflammatory bowel disease (IBD) (including ulcerative colitis, Crohn's disease, and indeterminate colitis) Note: Other protocol defined Inclusion/Exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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 Phase)<br>Participants received cilofexor 100 mg tablet, orally, once daily for up to 100.3 weeks. | Drug: Cilofexor<br>* 100 mg tablet administered orally once daily<br>* Other names: GS-9674;|
| Placebo Comparator: Placebo (Blinded Phase)<br>Participants received placebo to match cilofexor 100 mg tablet, orally, once daily for up to 98.1 weeks. | Drug: Placebo<br>* Tablet administered orally once daily<br>|
| Experimental: Cilofexor From Cilofexor 100 mg (OLE Phase)<br>Participants who received cilofexor in blinded phase and had entered the open-label extension (OLE) phase received open-label cilofexor 100 mg tablet, orally, once daily for up to 44.7 weeks. | Drug: Cilofexor<br>* 100 mg tablet administered orally once daily<br>* Other names: GS-9674;|
| Experimental: Cilofexor From Placebo (OLE Phase)<br>Participants who received placebo in blinded phase and had entered the OLE phase received open-label cilofexor 100 mg tablet, orally, once daily for up to 45.0 weeks. | Drug: Cilofexor<br>* 100 mg tablet administered orally once daily<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 With Progression of Liver Fibrosis at Blinded Phase Week 96 | Progression of liver fibrosis was defined as having a ≥ 1-stage increase from baseline in fibrosis according to the Ludwig classification at Blinded Phase Week 96. The stages of fibrosis was assessed according to Ludwig classification. Ludwig classification fibrosis stages range from 0 to 4, with higher scores indicating greater fibrosis (0=no fibrosis, 4=cirrhosis). | Blinded Phase Week 96 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) in The Blinded Phase | An AE was any untoward medical occurrence in a clinical study participant administered a study drug that does not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or disease temporally associated with the use of a study drug, whether or not the AE is considered related to the study drug. For Blinded Study Phase and OLE Phase, TEAEs were defined as 1 or both of the following: Any 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 and/or any AEs leading to premature discontinuation of study drug. | First dose date in the Blinded Phase up to 100.3 weeks plus 30 days | 
| Percentage of Participants Who Experienced TEAEs in The OLE Phase | An AE was any untoward medical occurrence in a clinical study participant administered a study drug that does not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or disease temporally associated with the use of a study drug, whether or not the AE is considered related to the study drug. For Blinded Study Phase and OLE Phase, TEAEs were defined as 1 or both of the following: Any 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 and/or any AEs leading to premature discontinuation of study drug. | First dose date in the OLE Phase up to 45 weeks plus 30 days | 
| Percentage of Participants Who Experienced Treatment-emergent Serious Adverse Events (SAEs) in the Blinded Phase | An SAE was defined as an event that, at any dose, results in the following: death, a life-threatening situation; 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 in the Blinded Phase up to 100.3 weeks plus 30 days | 
| Percentage of Participants Who Experienced Treatment-emergent SAEs in the OLE Phase | An SAE was defined as an event that, at any dose, results in the following: death, a life-threatening situation; 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 in the OLE Phase up to 45 weeks plus 30 days | 
| Change From Baseline in Serum Concentrations of Alkaline Phosphatase (ALP) at Blinded Phase Week 96 |  | Baseline, Blinded Phase Week 96 | 
| Change From Baseline in Serum Concentrations of Alanine Aminotransferase (ALT) at Blinded Phase Week 96 |  | Baseline, Blinded Phase Week 96 | 
| Change From Baseline in Serum Concentrations of Fasting Total Bile Acids at Blinded Phase Week 96 |  | Baseline, Blinded Phase Week 96 | 
| Percentage of Participants With ≥ 25% Relative Reduction in Serum ALP Concentration From Baseline and No Worsening of Fibrosis According to the Ludwig Classification at Blinded Phase Week 96 | The stages of fibrosis was assessed according to Ludwig classification. Ludwig classification fibrosis stages range from 0 to 4, with higher scores indicating greater fibrosis (0=no fibrosis, 4=cirrhosis).The percentage of participants with ≥ 25% reduction in serum ALP Concentration from baseline and no increase in fibrosis according to the Ludwig Classification at Blinded Phase Week 96 was analyzed. | Baseline, Blinded Phase Week 96 | 
| Percentage of Participants With Fibrosis Improvement According to the Ludwig Classification at Blinded Phase Week 96 | Fibrosis improvement was defined as having ≥ 1-stage decrease from baseline in fibrosis according to the Ludwig classification score at Blinded Study Phase Week 96. The stages of fibrosis was assessed according to Ludwig classification. Ludwig classification fibrosis stages range from 0 to 4, with higher scores indicating greater fibrosis (0=no fibrosis, 4=cirrhosis). | Blinded Phase Week 96 | 
| Change From Baseline in Primary Sclerosing Cholangitis (PSC) Symptoms - Module 1 Based on Disease-specific Patient Reported Outcome (PSC-PRO) at Blinded Phase Week 96 | The PSC-PRO addressed the severity of common everyday symptoms of PSC (eg, pruritus, fatigue, and right upper quadrant abdominal discomfort); and their functional impact (eg, on physical function, activities of daily living, and work productivity, etc). PSC-PRO module 1 - PSC symptoms contains a total of 12 questions asking about the severity of specific PSC symptoms on a scale of 0 (no symptoms) to 10 (symptoms as bad as you could imagine) with a 24-hour recall period. The total score, which is computed as 12 times the average of nonmissing scores of the 12 questions, can potentially range between 0 and 120, with higher scores indicating more severe symptoms. A positive change from baseline indicates worsening of symptoms. | Baseline, Blinded Phase Week 96 | 
| Change From Baseline in Enhanced Liver Fibrosis (ELF™ ) Test Score at Blinded Phase Week 96 | The Enhanced Liver Fibrosis (ELF™) test is a composite of three serum biomarkers of hepatobiliary fibrosis: hyaluronic acid, procollagen III amino-terminal peptide, and tissue inhibitor of metalloproteinase. A typical range for ELF™ test scores in PSC is between 6 and 14. Higher ELF™ test scores are associated with more severe liver disease. A positive change from baseline indicated worsening of fibrosis. | Baseline, Blinded Phase Week 96 | 
| Change From Baseline in Liver Stiffness by FibroScan® at Blinded Phase Week 96 | Change in liver stiffness was measured by FibroScan® scores. FibroScan measures liver scarring by measuring the stiffness of the liver. It's normally between 2 and 6 kPa. Many people with liver disease(s) have a result that's higher than the normal range. Higher scores indicate increased scarring of the liver. A positive change from baseline indicates severe liver disease(s). | Baseline, Blinded Phase Week 96 |