Primary Sclerosing Cholangitis
Conditions
Brief summary
The primary objective of this study is to evaluate the safety and tolerability of cilofexor in adults with primary sclerosing cholangitis (PSC).
Interventions
DRUGCilofexor
Tablet(s) administered orally once daily with food
Tablet(s) administered orally once daily with food
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Experiencing Treatment-Emergent Adverse Events During the Blinded Phase | First dose date up to last dose date plus 30 days (Up to 17 weeks) | 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. |
| Percentage of Participants Experiencing Treatment-Emergent Serious Adverse Events During the Blinded Phase | First dose date up to last dose date plus 30 days (Up to 17 weeks) | 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. |
| Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities During the Blinded Phase | First dose date up to last dose date plus 30 days (Up to 17 weeks) | 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). |
Countries
Austria, Canada, United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled at study sites in North America and Europe. The first participant was screened on 29 November 2016. The last study visit occurred on 18 May 2020.
Pre-assignment details
105 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| Cilofexor 100 mg Cilofexor 100 mg tablet + placebo to match cilofexor 30 mg tablet orally once daily with food for up to 12.6 weeks | 22 |
| Cilofexor 30 mg Cilofexor 30 mg tablet + placebo to match cilofexor 100 mg tablet orally once daily with food for up to 12.7 weeks | 20 |
| Placebo Placebo to match cilofexor 30 mg tablet + placebo to match cilofexor 100 mg tablet orally once daily with food for up to 12.3 weeks | 10 |
| Total | 52 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Blinded Study Phase | Adverse Event | 3 | 0 | 0 |
| Blinded Study Phase | Withdrew Consent | 0 | 1 | 0 |
| Open Label Extension (OLE) Phase | Adverse Event | 2 | 5 | 2 |
| Open Label Extension (OLE) Phase | Investigator's Discretion | 1 | 1 | 0 |
| Open Label Extension (OLE) Phase | Withdrew Consent | 2 | 1 | 0 |
Baseline characteristics
| Characteristic | Total | Cilofexor 30 mg | Cilofexor 100 mg | Placebo |
|---|---|---|---|---|
| Age, Continuous | 43 years STANDARD_DEVIATION 10.4 | 46 years STANDARD_DEVIATION 12.1 | 42 years STANDARD_DEVIATION 8.6 | 42 years STANDARD_DEVIATION 10.9 |
| Race/Ethnicity, Customized Ethnicity Hispanic or Latino | 3 Participants | 3 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Ethnicity Not Hispanic or Latino | 47 Participants | 17 Participants | 21 Participants | 9 Participants |
| Race/Ethnicity, Customized Ethnicity Not Permitted | 2 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Asian | 3 Participants | 2 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Black or African American | 8 Participants | 3 Participants | 4 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Not Permitted | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Other | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Race White | 39 Participants | 15 Participants | 17 Participants | 7 Participants |
| Region of Enrollment Austria | 1 participants | 0 participants | 1 participants | 0 participants |
| Region of Enrollment Canada | 8 participants | 2 participants | 4 participants | 2 participants |
| Region of Enrollment United Kingdom | 7 participants | 1 participants | 5 participants | 1 participants |
| Region of Enrollment United States | 36 participants | 17 participants | 12 participants | 7 participants |
| Sex: Female, Male Female | 22 Participants | 6 Participants | 11 Participants | 5 Participants |
| Sex: Female, Male Male | 30 Participants | 14 Participants | 11 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 22 | 0 / 20 | 0 / 10 | 0 / 47 |
| other Total, other adverse events | 18 / 22 | 14 / 20 | 10 / 10 | 41 / 47 |
| serious Total, serious adverse events | 3 / 22 | 0 / 20 | 0 / 10 | 10 / 47 |
Outcome results
Primary
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.
Time frame: First dose date up to last dose date plus 30 days (Up to 17 weeks)
Population: Safety Analysis Set included all participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cilofexor 100 mg | Percentage of Participants Experiencing Treatment-Emergent Adverse Events During the Blinded Phase | 81.8 percentage of participants |
| Cilofexor 30 mg | Percentage of Participants Experiencing Treatment-Emergent Adverse Events During the Blinded Phase | 70.0 percentage of participants |
| Placebo | Percentage of Participants Experiencing Treatment-Emergent Adverse Events During the Blinded Phase | 100.0 percentage of participants |
Primary
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).
Time frame: First dose date up to last dose date plus 30 days (Up to 17 weeks)
Population: Participants in the Safety Analysis Set were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cilofexor 100 mg | Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities During the Blinded Phase | Grade 3 | 27.3 percentage of participants |
| Cilofexor 100 mg | Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities During the Blinded Phase | Grade 2 | 36.4 percentage of participants |
| Cilofexor 100 mg | Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities During the Blinded Phase | Any Grade 1 or Higher | 90.9 percentage of participants |
| Cilofexor 100 mg | Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities During the Blinded Phase | Grade 1 | 22.7 percentage of participants |
| Cilofexor 100 mg | Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities During the Blinded Phase | Grade 4 | 4.5 percentage of participants |
| Cilofexor 30 mg | Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities During the Blinded Phase | Grade 2 | 35.0 percentage of participants |
| Cilofexor 30 mg | Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities During the Blinded Phase | Any Grade 1 or Higher | 85.0 percentage of participants |
| Cilofexor 30 mg | Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities During the Blinded Phase | Grade 1 | 25.0 percentage of participants |
| Cilofexor 30 mg | Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities During the Blinded Phase | Grade 3 | 20.0 percentage of participants |
| Cilofexor 30 mg | Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities During the Blinded Phase | Grade 4 | 5.0 percentage of participants |
| Placebo | Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities During the Blinded Phase | Grade 4 | 0 percentage of participants |
| Placebo | Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities During the Blinded Phase | Grade 3 | 30.0 percentage of participants |
| Placebo | Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities During the Blinded Phase | Any Grade 1 or Higher | 100.0 percentage of participants |
| Placebo | Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities During the Blinded Phase | Grade 2 | 60.0 percentage of participants |
| Placebo | Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities During the Blinded Phase | Grade 1 | 10.0 percentage of participants |
Primary
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.
Time frame: First dose date up to last dose date plus 30 days (Up to 17 weeks)
Population: Participants in the Safety Analysis Set were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cilofexor 100 mg | Percentage of Participants Experiencing Treatment-Emergent Serious Adverse Events During the Blinded Phase | 13.6 percentage of participants |
| Cilofexor 30 mg | Percentage of Participants Experiencing Treatment-Emergent Serious Adverse Events During the Blinded Phase | 0 percentage of participants |
| Placebo | Percentage of Participants Experiencing Treatment-Emergent Serious Adverse Events During the Blinded Phase | 0 percentage of participants |