Primary Biliary Cholangitis
Conditions
Brief summary
The primary objective of this study is to evaluate the safety and tolerability of cilofexor in adults with primary biliary cholangitis (PBC).
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: * Meets all of the following conditions * Definite or probable PBC as defined by at least 2 of the 3 following criteria: * Serum alkaline phosphatase (ALP) \> the upper limit of normal (ULN) * Presence of anti-mitochondrial antibodies (AMA) in serum (≥ 1:40 on immunofluorescence) * Liver histological findings consistent with PBC including nonsuppurative, destructive cholangitis affecting mainly the interlobular bile and septal bile ducts * Serum ALP \> 1.67 x ULN and/or total bilirubin \>ULN but ≤ 2 x ULN * Ursodeoxycholic acid (UDCA) use at a stable dose for at least 12 months or intolerant of UDCA with no UDCA use for at least 12 months before screening * 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) \> 5 x ULN * Total bilirubin \> 2 x ULN * International normalized ratio (INR) \> 1.2 unless on anticoagulant therapy * Other causes of liver disease including viral, metabolic, alcoholic, and other autoimmune conditions. Participants 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. * 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) * History of decompensated liver disease, including ascites, hepatic encephalopathy or variceal bleeding * Liver stiffness \> 16.9 kPa by FibroScan® Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) in the Blinded Study Phase | First dose date up to Week 12 + 30 days | — |
| Percentage of Participants Experiencing TEAEs and TESAEs in the Open-Label Extension (OLE) Phase | First dose date in the OLE phase up to last dose date (Maximum: 97.4 weeks) + 30 days | — |
| Percentage of Participants Who Experienced Graded Laboratory Abnormalities in the Blinded Study Phase | First dose date up to Week 12 + 30 days | Treatment-emergent laboratory abnormalities were defined as values that increase at least one toxicity grade from baseline. The most severe graded abnormality from all tests was counted for each participant. |
| Percentage of Participants Who Experienced Graded Laboratory Abnormalities in the OLE Phase | First dose date in the OLE phase up to last dose date (Maximum: 97.4 weeks) + 30 days | Treatment-emergent laboratory abnormalities were defined as values that increase at least one toxicity grade from baseline. The most severe graded abnormality from all tests was counted for each participant. |
Countries
Austria, Canada, United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled at study sites in United States, Canada, United Kingdom, and Austria. The first participant was screened on 01 December 2016. The last study visit occurred on 4 September 2019.
Pre-assignment details
130 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| Cilofexor 100 mg Blinded Study Phase: Cilofexor 100 mg tablet + placebo to match cilofexor 30 mg tablet orally once daily for 12 weeks.
Open Label Extension (OLE) Phase: Following Blinded Study Phase, participants willing to enter OLE phase received open-label cilofexor 100 mg tablet orally once daily for 97.4 weeks. | 28 |
| Cilofexor 30 mg Blinded Study Phase: Cilofexor 30 mg tablet + placebo to match cilofexor 100 mg tablet orally once daily for 12 weeks.
OLE Phase: Following Blinded Study Phase, participants willing to enter OLE Phase received open-label cilofexor 100 mg tablet orally once daily for 96.1 weeks. | 30 |
| Placebo Blinded Study Phase: Placebo to match cilofexor 100 mg tablet + placebo to match cilofexor 30 mg tablet orally once daily for 12 weeks.
OLE Phase: Following Blinded Study Phase, participants willing to enter OLE Phase received open-label cilofexor 100 mg tablet orally once daily for 97.3 weeks. | 13 |
| Total | 71 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Blinded Study Phase | Adverse Event | 3 | 0 | 0 |
| Blinded Study Phase | Investigator's discretion | 1 | 0 | 0 |
| Blinded Study Phase | Withdrew Consent | 1 | 2 | 1 |
| Open-Label Extension Phase | Adverse Event | 4 | 7 | 3 |
| Open-Label Extension Phase | Lack of Efficacy | 3 | 4 | 0 |
| Open-Label Extension Phase | Lost to Follow-up | 0 | 1 | 0 |
| Open-Label Extension Phase | Study terminated by sponsor | 10 | 12 | 6 |
| Open-Label Extension Phase | Withdrew consent | 1 | 1 | 1 |
Baseline characteristics
| Characteristic | Total | Cilofexor 30 mg | Cilofexor 100 mg | Placebo |
|---|---|---|---|---|
| Age, Continuous | 56 years STANDARD_DEVIATION 7.9 | 57 years STANDARD_DEVIATION 6.3 | 54 years STANDARD_DEVIATION 9.8 | 58 years STANDARD_DEVIATION 5.9 |
| Race/Ethnicity, Customized Ethnicity Hispanic or Latino | 4 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Ethnicity Not Hispanic or Latino | 65 Participants | 28 Participants | 26 Participants | 11 Participants |
| Race/Ethnicity, Customized Ethnicity Not Permitted | 2 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Asian | 2 Participants | 0 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Black or African American | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Not Permitted | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Other | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race White | 66 Participants | 27 Participants | 26 Participants | 13 Participants |
| Region of Enrollment Austria | 7 participants | 2 participants | 4 participants | 1 participants |
| Region of Enrollment Canada | 21 participants | 9 participants | 9 participants | 3 participants |
| Region of Enrollment United Kingdom | 8 participants | 3 participants | 3 participants | 2 participants |
| Region of Enrollment United States | 35 participants | 16 participants | 12 participants | 7 participants |
| Sex: Female, Male Female | 66 Participants | 26 Participants | 28 Participants | 12 Participants |
| Sex: Female, Male Male | 5 Participants | 4 Participants | 0 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 28 | 0 / 30 | 0 / 13 | 0 / 23 | 0 / 28 | 0 / 12 |
| other Total, other adverse events | 21 / 28 | 18 / 30 | 11 / 13 | 20 / 23 | 25 / 28 | 12 / 12 |
| serious Total, serious adverse events | 0 / 28 | 1 / 30 | 0 / 13 | 1 / 23 | 0 / 28 | 0 / 12 |
Outcome results
Primary
Percentage of Participants Experiencing TEAEs and TESAEs in the Open-Label Extension (OLE) Phase
Time frame: First dose date in the OLE phase up to last dose date (Maximum: 97.4 weeks) + 30 days
Population: The OLE Analysis Set included all participants who took at least 1 dose of study drug in the OLE Phase.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Blinded Study Phase: Cilofexor 100 mg | Percentage of Participants Experiencing TEAEs and TESAEs in the Open-Label Extension (OLE) Phase | TEAEs | 95.7 percentage of participants |
| Blinded Study Phase: Cilofexor 100 mg | Percentage of Participants Experiencing TEAEs and TESAEs in the Open-Label Extension (OLE) Phase | TESAEs | 4.3 percentage of participants |
| Blinded Study Phase: Cilofexor 30 mg | Percentage of Participants Experiencing TEAEs and TESAEs in the Open-Label Extension (OLE) Phase | TEAEs | 89.3 percentage of participants |
| Blinded Study Phase: Cilofexor 30 mg | Percentage of Participants Experiencing TEAEs and TESAEs in the Open-Label Extension (OLE) Phase | TESAEs | 0 percentage of participants |
| Blinded Study Phase: Placebo | Percentage of Participants Experiencing TEAEs and TESAEs in the Open-Label Extension (OLE) Phase | TESAEs | 0 percentage of participants |
| Blinded Study Phase: Placebo | Percentage of Participants Experiencing TEAEs and TESAEs in the Open-Label Extension (OLE) Phase | TEAEs | 100.0 percentage of participants |
Primary
Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) in the Blinded Study Phase
Time frame: First dose date up to Week 12 + 30 days
Population: The Safety Analysis Set included all participants who took at least 1 dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Blinded Study Phase: Cilofexor 100 mg | Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) in the Blinded Study Phase | TESAEs | 0 percentage of participants |
| Blinded Study Phase: Cilofexor 100 mg | Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) in the Blinded Study Phase | TEAEs | 89.3 percentage of participants |
| Blinded Study Phase: Cilofexor 30 mg | Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) in the Blinded Study Phase | TESAEs | 3.3 percentage of participants |
| Blinded Study Phase: Cilofexor 30 mg | Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) in the Blinded Study Phase | TEAEs | 76.7 percentage of participants |
| Blinded Study Phase: Placebo | Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) in the Blinded Study Phase | TEAEs | 84.6 percentage of participants |
| Blinded Study Phase: Placebo | Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) in the Blinded Study Phase | TESAEs | 0 percentage of participants |
Primary
Percentage of Participants Who Experienced Graded Laboratory Abnormalities in the Blinded Study Phase
Treatment-emergent laboratory abnormalities were defined as values that increase at least one toxicity grade from baseline. The most severe graded abnormality from all tests was counted for each participant.
Time frame: First dose date up to Week 12 + 30 days
Population: Participants in the Safety Analysis Set were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Blinded Study Phase: Cilofexor 100 mg | Percentage of Participants Who Experienced Graded Laboratory Abnormalities in the Blinded Study Phase | Any Graded Laboratory Abnormality | 85.7 percentage of participants |
| Blinded Study Phase: Cilofexor 100 mg | Percentage of Participants Who Experienced Graded Laboratory Abnormalities in the Blinded Study Phase | Grade 4 or above Laboratory Abnormalities | 0 percentage of participants |
| Blinded Study Phase: Cilofexor 30 mg | Percentage of Participants Who Experienced Graded Laboratory Abnormalities in the Blinded Study Phase | Any Graded Laboratory Abnormality | 86.7 percentage of participants |
| Blinded Study Phase: Cilofexor 30 mg | Percentage of Participants Who Experienced Graded Laboratory Abnormalities in the Blinded Study Phase | Grade 4 or above Laboratory Abnormalities | 3.3 percentage of participants |
| Blinded Study Phase: Placebo | Percentage of Participants Who Experienced Graded Laboratory Abnormalities in the Blinded Study Phase | Any Graded Laboratory Abnormality | 92.3 percentage of participants |
| Blinded Study Phase: Placebo | Percentage of Participants Who Experienced Graded Laboratory Abnormalities in the Blinded Study Phase | Grade 4 or above Laboratory Abnormalities | 0 percentage of participants |
Primary
Percentage of Participants Who Experienced Graded Laboratory Abnormalities in the OLE Phase
Treatment-emergent laboratory abnormalities were defined as values that increase at least one toxicity grade from baseline. The most severe graded abnormality from all tests was counted for each participant.
Time frame: First dose date in the OLE phase up to last dose date (Maximum: 97.4 weeks) + 30 days
Population: Participants in the OLE Analysis Set were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Blinded Study Phase: Cilofexor 100 mg | Percentage of Participants Who Experienced Graded Laboratory Abnormalities in the OLE Phase | Any Graded Laboratory Abnormality | 91.3 percentage of participants |
| Blinded Study Phase: Cilofexor 100 mg | Percentage of Participants Who Experienced Graded Laboratory Abnormalities in the OLE Phase | Grade 4 or above Laboratory Abnormalities | 0 percentage of participants |
| Blinded Study Phase: Cilofexor 30 mg | Percentage of Participants Who Experienced Graded Laboratory Abnormalities in the OLE Phase | Any Graded Laboratory Abnormality | 96.4 percentage of participants |
| Blinded Study Phase: Cilofexor 30 mg | Percentage of Participants Who Experienced Graded Laboratory Abnormalities in the OLE Phase | Grade 4 or above Laboratory Abnormalities | 0 percentage of participants |
| Blinded Study Phase: Placebo | Percentage of Participants Who Experienced Graded Laboratory Abnormalities in the OLE Phase | Any Graded Laboratory Abnormality | 100.0 percentage of participants |
| Blinded Study Phase: Placebo | Percentage of Participants Who Experienced Graded Laboratory Abnormalities in the OLE Phase | Grade 4 or above Laboratory Abnormalities | 0 percentage of participants |