A Multi-part, Double Blind Study to Assess Safety, Tolerability and Efficacy of Tropifexor (LJN452) in PBC Patients

Study Overview
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Brief Summary
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A multi-part study to assess safety, tolerability and efficacy of tropifexor (LJN452) in patients with primary biliary cholangitis

Official Title
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A Multi-part, Randomized, Double-blind, Placebo-controlled Study to Assess the Safety, Tolerability and Efficacy of Tropifexor (LJN452) in Patients With Primary Biliary Cholangitis

Conditions
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Primary Biliary Cholangitis

Intervention / Treatment
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* Drug: Part 1: LJN452
* Drug: Part 1: Placebo
* Drug: Part 2: LJN452 Dose level 1
* Drug: Part 2: Placebo
* Drug: Part 2: LJN452 Dose level 2


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years Diagnosis of PBC as demonstrated by the presence of at least 2 of the following 3 diagnostic criteria: History of alkaline phosphatase (ALP) elevated above upper limit of normal (ULN) for at least 6 months Positive antimitochondrial antibodies (AMA) titer or if AMA negative or in low titer (<1:80) PBC specific antibodies (anti-GP210 and/or anti-SP100 and/or antibodies against the major M2 components (PDC-E2, 2-oxo-glutaric acid dehydrogenase complex)) Previous liver biopsy findings consistent with PBC At least 1 of the following markers of disease severity: ALP ≥ 1.67 × ULN Total bilirubin > ULN but < 1.5 × ULN In addition, patients must meet the following biochemical criteria at enrollment: Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 5 × ULN Total bilirubin ≤ 1.5 × ULN INR ≤ ULN Taking UDCA for at least 12 months, or for at least 6 months and has reached maximal response to UDCA with a plateau in alkaline phosphatase, with no changes in dose for ≥ 3 months prior to Day 1. Patients must weigh at least 40 kg to participate in the study, and must have a body mass index (BMI) within the range of 18 - 40 kg/m2. BMI = Body weight (kg) / [Height (m)]2 Exclusion Criteria: Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception for 30 days before randomization, during dosing and for 30 days following the end of treatment. Presence of other concomitant liver diseases. Cirrhosis with complications, including history or presence of: Variceal bleed Uncontrolled ascites Encephalopathy Spontaneous bacterial peritonitis Significant hepatic impairment as defined by Child-Pugh classification of B or C, history of liver transplantation, current placement on a liver transplant list or current Model for End Stage Liver Disease (MELD) score ≥15. History of conditions that may cause increases in ALP (e.g., Paget's disease). Use of investigational drugs, or immunosuppressive drugs at the time of enrollment, or within 5 half-lives, or 30 days of randomization, whichever is longer; or longer if required by local regulations. Use of high dose oral steroids to treat co-morbid conditions (e.g., airways disease) will be allowed but must be properly documented as such in concomitant medications. Currently taking obeticholic acid or have taken obeticholic acid within 30 days of randomization Previous participation in CLJN452X2201 and received study medication within three months of randomization (or longer if required by local regulations).

Ages Eligible for Study
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Minimum Age: 18 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LJN452<br> | Drug: Part 1: LJN452<br>* LJN452 capsules administered once daily for 28 days<br>* Other names: tropifexor;Drug: Part 2: LJN452 Dose level 1<br>* LJN452 capsules administered once a day for 12 weeks<br>* Other names: tropifexor;Drug: Part 2: LJN452 Dose level 2<br>* LJN452<br>* Other names: tropifexor;|
| Placebo Comparator: Placebo<br> | Drug: Part 1: Placebo<br>* Matching placebo capsules administered once daily for 28 days<br>Drug: Part 2: Placebo<br>* Matching placebo to LJN452 administered once a day for 12 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fold Change in Serum Gamma-glutamyl Transferase (GGT) | Fold change in serum gamma-glutamyl transferase (GGT) from baseline to Day 28 | Baseline to Day 28 | 
| Blood Pressure | Vital signs - Systolic Blood pressure | Screening, Baseline, day 1, day 7, day 14, day 21, day 28, day 56, day 84 | 
| Pulse Rate | Vital signs | Screening, Baseline, day 1, day 7, day 14, day 21, day 28, day 56, day 84 | 
| Body Temperature | Vital signs | Screening, Baseline, day 1, day 7, day 14, day 21, day 28, day 56, day 84 | 
| ECG - Heart Rate | Electrocardiogram (ECG) | Screening, Baseline, day 1, day 28 | 
| ECG Intervals - PR Interval | Electrocardiogram (ECG) | Screening, Baseline, day 1, day 28 | 
| Haemoglobin | Hematology panel for safety laboratory assessments. | Screening, Baseline, day 1, day 7, day 14, day 21, day 28, day 56, day 84 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma PK Parameter - AUC 0-8h | Tropifexor levels were determined in plasma using a validated LC-MS/MS method. AUC0-t=The area under the plasma concentration-time curve from time zero to time 't' where t is a defined time point after administration [mass x time / volume] | Day 1, Day 28 | 
| Plasma PK Parameter - Cmax | Tropifexor levels were determined in plasma using a validated LC-MS/MS method. Cmax=The observed maximum plasma concentration following drug administration [mass /volume] | Day 1, Day 28 | 
| Plasma PK Parameter - Tmax | Tropifexor levels were determined in plasma using a validated LC-MS/MS method. Tmax = The time to reach the maximum concentration after drug administration [time] | Day 1, Day 28 | 
| Changes From Baseline in Total PBC-40 Score | Baseline is defined as the latest available predose value. The PBC-40 is a paper-based, patient-derived, disease-specific health-related quality of life (HRQOL) patient reported outcome (PRO) measure which was developed and validated for use in PBC patients (Jacoby et al 2005). It consists of 40 questions arranged in 6 domains with between 3 and 11 questions in each domain. Each question is scored from 1 to 5 in increasing order of severity. All questions within a domain are summed and all domain totals are summed to obtain a total score. The total score range is between a minimum of 40 and a maximum of 200. Higher scores represent a poorer quality of life. The median difference from baseline in total sum score for each treatment group is presented. | Baseline, Day 28, Day 56, Day 84 | 
| Change From Baseline in Itch Subdomain of PBC-40 Score | Baseline is defined as the latest available predose value. The PBC-40 is a paper-based, patient-derived, disease-specific health-related quality of life (HRQOL) patient reported outcome (PRO) measure which was developed and validated for use in PBC patients (Jacoby et al 2005). It consists of 40 questions arranged in 6 domains with between 3 and 11 questions in each domain. Each question is scored from 1 to 5 in increasing order of severity. This dataset focuses on the itch subdomain which consists of 3 questions. These 3 questions within the itch subdomain are summed to obtain a total score for the itch subdomain. The total score range is between a minimum of 3 and a maximum of 15. Higher scores represent a poorer quality of life. The median change from baseline in total itch subdomain score in each treatment group is presented. | Baseline, Day 28, Day 56, Day 84 | 
| Change From Baseline in Global Itch Visual Analogue Scale (VAS) | Baseline is defined as the latest available predose value. The Global Itch Visual Analogue Scale, a 100 mm visual analogue scale (VAS), was used to assess the severity of patients itch (ranging from 0 = none at all to 100 = the worst imaginable itch). The score range is between a minimum of 0 and a maximum of 100. The score (distance in mm from left) on the VAS was recorded by the patient marking with a line and used to test for an effect of tropifexor over placebo. The mean change from baseline in itch VAS score in each treatment group is presented. | Day 7, Day 14, Day 21, Day 28, Day 56, and Day 84 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Primary Biliary Cirrhosis, PBC, Primary Biliary Cholangitis