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

Phase 2

Completed

Conditions: Primary Biliary Cholangitis

Registration Number: NCT02516605

Lead Sponsor: Novartis Pharmaceuticals

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

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 61

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).

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
Plasma PK Parameter - Cmax	Day 1, Day 28	Tropifexor levels were determined in plasma using a validated LC-MS/MS method. Cmax=The observed maximum plasma concentration following drug administration \[mass /volume\]
Change From Baseline in Global Itch Visual Analogue Scale (VAS)	Day 7, Day 14, Day 21, Day 28, Day 56, and Day 84	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.
Plasma PK Parameter - AUC 0-8h	Day 1, Day 28	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 \[mass x time / volume\]
Change From Baseline in Itch Subdomain of PBC-40 Score	Baseline, Day 28, Day 56, Day 84	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.
Plasma PK Parameter - Tmax	Day 1, Day 28	Tropifexor levels were determined in plasma using a validated LC-MS/MS method. Tmax = The time to reach the maximum concentration after drug administration \[time\]
Changes From Baseline in Total PBC-40 Score	Baseline, Day 28, Day 56, Day 84	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.