Primary Sclerosing Cholangitis
Conditions
Keywords
Primary Sclerosing Cholangitis
Brief summary
This is an open label, proof of concept (PoC) study of Cenicriviroc (CVC) in adult participants with Primary Sclerosing Cholangitis (PSC). The main objective of this PoC study is to assess changes in alkaline phosphatase (ALP) both individually and as a group, over 24 weeks of treatment with CVC.
Interventions
One tablet of CVC 150 mg once daily taken with food in the morning.
Sponsors
Tobira Therapeutics, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Participants with chronic cholestatic liver disease for at least 6 months * Clinical diagnosis of Primary Sclerosing Cholangitis (PSC) as evident by chronic cholestasis of more than six months duration with either a consistent magnetic resonance cholangiopancreatography (MRCP)/endoscopic retrograde cholangiopancreatography (ERCP) showing sclerosing cholangitis, or a liver biopsy taken at any time consistent with PSC in the absence of a documented alternative etiology for sclerosing cholangitis. If diagnosis of PSC was made by histology alone, it must require the presence of fibro-obliterative lesions (i.e., onion skin lesions) * Participants with or without Inflammatory Bowel Disease (IBD) are allowed. If participant has IBD, documented evidence of IBD either by prior endoscopy or in previous medical records, for ≥ 6 months. In addition, participants will be required to enter the study with a Partial Mayo Risk score of 0-3, inclusively * In participants receiving treatment with ursodeoxycholic acid (UDCA), therapy must be stable for at least 3 months, and at a dose not greater than 20 mg/kg/day * Serum ALP greater than 1.5 × upper limit of normal (ULN) * Ability to understand and sign a written informed consent form (ICF) * Participants receiving allowed concomitant medications need to be on stable therapy for 28 days prior to the Baseline Visit with the exception of UDCA in which participants need to be on stable therapy for ≥ 3 months
Exclusion criteria
* Presence of documented secondary sclerosing cholangitis (such as ischemic cholangitis, recurrent pancreatitis, intraductal stone disease, severe bacterial cholangitis, surgical or blunt abdominal trauma, recurrent pyogenic cholangitis, choledocholithiasis, toxic sclerosing cholangitis due to chemical agents, or any other cause of secondary sclerosing cholangitis) on prior clinical investigations * Small duct PSC * Presence of percutaneous drain or bile duct stent * History of cholangiocarcinoma or high clinical suspicion over dominant stricture within 1 year by MRCP/ERCP or clinical judgment * Ascending cholangitis within 60 days prior to Screening * Alcohol consumption greater than 21 units/week for males or 14 units/week for females (one unit of alcohol is ½ pint of beer \[285 mL\], 1 glass of spirits \[25 mL\] or 1 glass of wine \[125 mL\]) * Prior or planned liver transplantation * Presence of alternative causes of chronic liver disease, including alcoholic liver disease, non-alcoholic steatohepatitis, primary biliary cirrhosis, autoimmune hepatitis * History of cirrhosis and/or hepatic impairment (Child-Pugh classes A, B and C) and/or hepatic decompensation including ascites, encephalopathy or variceal bleeding. Participants who show evidence of significant worsening of hepatic function will be excluded * Participants with fibrosis evidence of cirrhosis, as determined by local transient elastography (TE, e.g., Fibroscan) values of ≥ 13.0 kPa, taken within the last 6 months. If TE has not been conducted within the 6 months prior to screening, then one will be conducted during the screening period and can be used as the Baseline value. * Moderate to Severe active IBD or flare in colitis activity within the last 90 days requiring intensification of therapy beyond Baseline treatment. Participants with stable mild to moderate IBD, who are on treatment, are allowed provided they are stable for 3 months with 5-amino salicylic acid drugs or Azathioprine (allowed dose of azathioprine is 50-200 mg/day) * Use of oral prednisolone \> 10 mg/day, biologics and/or hospitalization for colitis within 90 days are disallowed * Aspartate aminotransferase (AST) and alanine aminotransferase (ALT); above the allowed cut-offs, as determined by Screening values: * AST \> 200 IU/L males and females * ALT: males \> 250 IU/L and females \> 200 IU/L * Total Bilirubin and Direct Bilirubin; above the allowed cut-offs, as determined by Screening values: * Total Bilirubin \> 2.0 mg/dL * Direct Bilirubin \> 0.8 mg/dL * International normalized ratio \> 1.3 in the absence of anticoagulants * Immunoglobulin G4 (IgG4) \> 4 × ULN at Screening or evidence of IgG4-related sclerosing cholangitis * Females who are pregnant or breastfeeding * Any other clinically significant disorders or prior therapy that, in the opinion of the investigator, would make the participant unsuitable for the study or unable to comply with the dosing and protocol requirements
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change From Baseline Through Week 24 in Serum Alkaline Phosphatase (ALP) | Baseline (Day 1) to Week 24 | ALP was used as a primary surrogate marker for measuring Primary Sclerosing Cholangitis disease. The percent change from Baseline was defined as 100\*(value at each visit - Baseline value)/Baseline value. The Baseline value was defined as the last non-missing value on or before the Baseline visit (Day 1). A negative percentage change from baseline indicates an improvement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Normalized ALP at Week 24 | Week 24 | ALP was used as a primary surrogate marker for measuring Primary Sclerosing Cholangitis disease. Normalization was defined as ALP values outside of the central laboratory reference range at baseline, but within the central laboratory reference range at Week 24. |
| Percentage of Participants Who Achieved Serum ALP of Less Than 1.5 Times Upper Limit of Normal (ULN) in Serum ALP at Week 24 | Week 24 | ALP was used as a primary surrogate marker for measuring Primary Sclerosing Cholangitis disease. The upper limit of normal ALP was defined according to the central laboratory reference ranges. |
| Percentage of Participants Who Achieved a 50% Decrease in ALP at Week 24 | Week 24 | ALP was used as a primary surrogate marker for measuring Primary Sclerosing Cholangitis disease. |
| Percentage of Participants With a Treatment-emergent Adverse Event (TEAE) | Baseline (Day 1) to Week 24 | An adverse event (AE) was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, regardless of whether related to the medicinal (investigational) product. A TEAE was defined as an AE with an onset that occurred after receiving treatment. |
| Percentage of Participants Who Discontinued Due to a TEAE | Baseline (Day 1) to Week 24 | An adverse event was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, regardless of whether related to the medicinal (investigational) product. A TEAE was defined as an AE with an onset that occurred after receiving treatment. |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cenicriviroc 150 mg Cenicriviroc 150 mg was administered orally once daily with food in the morning for 24 weeks. | 24 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Non-compliance with Study Drug | 1 |
| Overall Study | Protocol Violation | 1 |
| Overall Study | Suspected Drug Induced Liver Injury | 1 |
Baseline characteristics
| Characteristic | Cenicriviroc 150 mg |
|---|---|
| Age, Continuous | 43.3 years STANDARD_DEVIATION 12.93 |
| Race/Ethnicity, Customized Asian | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants |
| Race/Ethnicity, Customized Hispanic | 2 Participants |
| Race/Ethnicity, Customized Not Hispanic | 22 Participants |
| Race/Ethnicity, Customized Other | 1 Participants |
| Race/Ethnicity, Customized White | 21 Participants |
| Sex: Female, Male Female | 12 Participants |
| Sex: Female, Male Male | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 24 |
| other Total, other adverse events | 20 / 24 |
| serious Total, serious adverse events | 1 / 24 |
Outcome results
Primary
Percentage Change From Baseline Through Week 24 in Serum Alkaline Phosphatase (ALP)
ALP was used as a primary surrogate marker for measuring Primary Sclerosing Cholangitis disease. The percent change from Baseline was defined as 100\*(value at each visit - Baseline value)/Baseline value. The Baseline value was defined as the last non-missing value on or before the Baseline visit (Day 1). A negative percentage change from baseline indicates an improvement.
Time frame: Baseline (Day 1) to Week 24
Population: ITT Population: All enrolled participants who received at least 1 dose of study treatment. Participants who did not return for any post-baseline visits were not included in the efficacy measurements. Number of participants analyzed are the participants with available data at the given time-point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cenicriviroc 150 mg | Percentage Change From Baseline Through Week 24 in Serum Alkaline Phosphatase (ALP) | -4.5 percentage change in ALP | Standard Deviation 34.84 |
Secondary
Percentage of Participants Who Achieved a 50% Decrease in ALP at Week 24
ALP was used as a primary surrogate marker for measuring Primary Sclerosing Cholangitis disease.
Time frame: Week 24
Population: ITT Population: All enrolled participants who received at least 1 dose of study treatment. Participants who did not return for any post-baseline visits were not included in the efficacy measurements. Number of participants analyzed are the participants with available data at the given time-point.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cenicriviroc 150 mg | Percentage of Participants Who Achieved a 50% Decrease in ALP at Week 24 | 0.0 percentage of participants |
Secondary
Percentage of Participants Who Achieved Serum ALP of Less Than 1.5 Times Upper Limit of Normal (ULN) in Serum ALP at Week 24
ALP was used as a primary surrogate marker for measuring Primary Sclerosing Cholangitis disease. The upper limit of normal ALP was defined according to the central laboratory reference ranges.
Time frame: Week 24
Population: ITT Population: All enrolled participants who received at least 1 dose of study treatment. Participants who did not return for any post-baseline visits were not included in the efficacy measurements. Number of participants analyzed are the participants with available data at the given time-point.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cenicriviroc 150 mg | Percentage of Participants Who Achieved Serum ALP of Less Than 1.5 Times Upper Limit of Normal (ULN) in Serum ALP at Week 24 | 10 percentage of participants |
Secondary
Percentage of Participants Who Discontinued Due to a TEAE
An adverse event was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, regardless of whether related to the medicinal (investigational) product. A TEAE was defined as an AE with an onset that occurred after receiving treatment.
Time frame: Baseline (Day 1) to Week 24
Population: Safety Analysis Set: All enrolled participants who received at least 1 dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cenicriviroc 150 mg | Percentage of Participants Who Discontinued Due to a TEAE | 8.3 percentage of participants |
Secondary
Percentage of Participants Who Normalized ALP at Week 24
ALP was used as a primary surrogate marker for measuring Primary Sclerosing Cholangitis disease. Normalization was defined as ALP values outside of the central laboratory reference range at baseline, but within the central laboratory reference range at Week 24.
Time frame: Week 24
Population: ITT Population: All enrolled participants who received at least 1 dose of study treatment. Participants who did not return for any post-baseline visits were not included in the efficacy measurements. Number of participants analyzed are the participants with available data at the given time-point.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cenicriviroc 150 mg | Percentage of Participants Who Normalized ALP at Week 24 | 0.0 percentage of participants |
Secondary
Percentage of Participants With a Treatment-emergent Adverse Event (TEAE)
An adverse event (AE) was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, regardless of whether related to the medicinal (investigational) product. A TEAE was defined as an AE with an onset that occurred after receiving treatment.
Time frame: Baseline (Day 1) to Week 24
Population: Safety Analysis Set: All enrolled participants who received at least 1 dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cenicriviroc 150 mg | Percentage of Participants With a Treatment-emergent Adverse Event (TEAE) | 83.3 percentage of participants |