Primary Sclerosing Cholangitis (PSC) and suspected liver fibrosis
Conditions
Interventions
Part 1: Participants will receive 40 mg PLN-74809 or matching placebo once a
day for 12 weeks
Part 2: Participants will receive 80 or 160 mg or matching placebo once a day
for 12 weeks
Part 3: Par
Sponsors
Pliant Therapeutics Inc.,
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: Inclusion Criteria: General and Administrative 1. Aged 18 to 75 years, inclusive. 2. Female participants of childbearing potential must use a contraceptive method with a failure rate of 1 × the upper limit of normal (ULN). 8. Serum aspartate aminotransferase (AST) and serum alanine aminotransferase (ALT) concentration 1.5 × ULN may be enrolled if they have Gilbert*s Syndrome and a direct bilirubin = 7.7 at Screening OR - Liver stiffness measurement (LSM) >= 8 kPa but = 2.4 kPa but = 140,000/mm3. 12. Albumin >= 3.3 g/dL. 13. International normalized ratio (INR) <= 1.3 in the absence of anticoagulant therapy. 14. Serum carbohydrate antigen 19-9 (CA19-9) value <= 130 U/mL. Prior and Concomitant Medications 15. If receiving treatment with UDCA, therapy is at a dose of < 25 mg/kg/day, has been stable for at least 3 months before screening, will remain stable from screening through Day 1 (baseline), and is expected to remain stable for the duration of the study. 16. If receiving allowed concomitant medications for the treatment of IBD, therapy must be stable from screening and expected to remain stable for the duration of the study. Medical History and Comorbid Conditions 17. Participants with IBD must have had a colonoscopy showing no evidence of dysplasia within no more than 18 months before screening. 18. Participants with IBD must have no evidence of active disease and a partial Mayo score of < 2, with a score of < 1 on the Rectal Bleeding domain, between screening through Day 1. 19. Participants with IBD who are receiving treatment with bio
Exclusion criteria
Exclusion criteria: Exclusion Criteria: Primary Sclerosing Cholangitis Diagnosis 1. Other causes of liver disease, including secondary sclerosing cholangitis or viral, metabolic, or alcoholic liver disease, as assessed clinically. 2. Known or suspected overlapping clinical and histologic diagnosis of autoimmune hepatitis. 3. Small duct PSC with no evidence of large duct involvement (evidence of PSC on historical liver histology, with normal bile ducts on cholangiography). Liver Disease Status 4. Presence of a clinically significant dominant stricture based on the combination of radiological, biochemical, and clinical features. 5. Presence of a percutaneous drain or bile duct stent. 6. Serum alkaline phosphatase (ALP) concentration > 10 times ULN. 7. Worsening of liver disease, defined as 2 consecutive ALP, ALT, or AST measurements obtained >= 2 weeks apart during the screening period that increase by > 30% and represent either a Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 that is associated with new or worsening symptoms or a CTCAE Grade 2 with or without new or worsening symptoms, as defined by CTCAE Version 5.0. 8. Ascending cholangitis within 60 days of screening, as assessed clinically or use of antibiotics for acute cholangitis within 60 days of screening. 9. IgG4-associated cholangitis. 10. Positive anti-mitochondrial antibody. 11. Presence of liver cirrhosis as assessed by historical liver histology, ultrasound based liver stiffness measurement (FibroScan® value > 14.4 kPa), MRE > 4.9 kPa, and/or signs and symptoms of hepatic decompensation (including, but not limited to, jaundice, ascites, variceal hemorrhage, and/or hepatic encephalopathy). 12. Presence of hepatic impairment, end-stage liver disease, and/or a model for end stage liver disease (MELD) score >= 15. 13. Prior or planned liver transplantation during the study. Medical History and Comorbid Conditions 14. Presence of end-stage renal disease that requires dialysis. 15. History, current clinical or radiological suspicion, or diagnosis of cholangiocarcinoma, other hepatobiliary malignancy, colorectal cancer, or other abdominal malignancy at any time. 16. Human immunodeficiency virus (HIV), hepatitis A virus, hepatitis B virus, and/or hepatitis C virus infection, with the exception of those who have been successfully treated for hepatitis C infection and have achieved sustained virologic response for >= 1 year 17. History of malignancy within the past 5 years or ongoing malignancy other than basal cell carcinoma, resected noninvasive cutaneous squamous cell carcinoma, or treated cervical carcinoma in situ. 18. Clinical evidence of active bacterial, viral, or fungal infection that required antibiotic or antifungal therapy within 30 days before screening. 19. History of unstable or deteriorating cardiac disease within the previous 6 months, including, but not limited to: a. Unstable angina pectoris or myocardial infarction b. Congestive heart failure requiring hospitalization c. Uncontrolled clinically significant arrhythmias d. Clinically significant electrocardiogram (ECG) abnormalities, including but not limited to, QT interval corrected for heart rate using Fridericia's formula (QTcF) > 450 msec for males or > 460 msec for females at Screening Visit 1 or prior to administration o
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| The primary endpoint is the nature and proportion of AEs between PLN-74809 and placebo groups (descriptive). Safety data from all participants who received at least one dose of study drug will be incorporated into the final safety analysis. Further details of the safety analyses will be provided in the SAP. AEs will be collected from the time the participant signs the ICF until the last study visit. Treatment-emergent adverse events (TEAEs) are defined as AEs that emerged or worsened in severity after the first administration of study drug. AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA®). All AEs will be graded for severity per the CTCAE grading scale and listed by participant and summarized by last treatment taken at onset of AE. All AEs will be listed by participant and summarized by last treatment taken at onset of AE. The incidence of AEs, the incidence of TEAEs, the incidence of treatment-related AEs, and the severity of AEs will be summarized by system organ class, preferred term, and maximum severity. In cases where a participant reports multiple occurrences of the same event (preferred term), the greatest severity will be included in the summary. The number and percentage of participants with SAEs and treatment-related SAEs and participants who withdraw prematurely due to an AE will be tabulated by study treatment and dose. Clinical laboratory test parameters will be graded using the CTCAE grading scale for individual participants and values outside the reference ranges will be flagged. The incidence of treatment-emergent laboratory abnormalities will be summarized by severity and treatment group. For each parameter, summary statistics will be calculated for each measure and summarized by treatment and dose. Individual ECG results will be listed for each participant. Summaries of ECGs by treatment and dose will include changes from baseline for each parameter. Vital sign measurements, other labor | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary Pharmacokinetic Endpoints Plasma PLN-74809 concentrations (total and unbound concentrations) at each sampling timepoint will be presented in listings and descriptive summary statistics by dose and visit. The data will also be presented graphically. Further details of the analyses will be provided in the SAP to be prepared and agreed prior to final *database lock* at the end of the study. The PK analysis plan and report may be prepared separately from the SAP as appropriate. Exploratory Endpoints Absolute and relative changes from Baseline to Week 12 in liver fibrosis biomarkers (including PRO-C3 and ELF) and in ALP will be presented in numerical and graphical forms by treatment and dose utilizing data from the timepoints specified in the Schedule of Events (Appendix 1 of the protocol version 1.0 dated 14 December 2020). Changes from Baseline to Week 12 in magnetic resonance (MR)-based liver imaging will also be evaluated, as well as changes in PROs. More details will be provided in the statistical analysis plan. Urine, plasma and serum samples will be analyzed for biomarkers (presence or actual concentration). These samples will be used to determine the levels of these markers in participants and the relationship between these markers. Results will be presented by listings, descriptive summary statistics and in graphical form by treatment and dose and expressed as the relative change (and or absolute) for each participant. In addition, relationships between PK and PD may be evaluated in an exploratory fashion and presented in graphical manner. | — |
Countries
Netherlands
Outcome results
None listed