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

Primary Biliary Cholangitis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02516605
• Other study ID #: CLJN452X2201
• Secondary ID: 2015-001590-41
• Status: Completed
• Phase: Phase 2
• Start date: September 9, 2015
• Est. completion date: August 2, 2018

Study information

• Verified date: October 2019
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 61
• Est. completion date: August 2, 2018
• Est. primary completion date: August 2, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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).

Related Conditions & MeSH terms

• Cholangitis
• Liver Cirrhosis, Biliary
• Primary Biliary Cholangitis

Intervention

Drug:
• Part 1: LJN452
LJN452 capsules administered once daily for 28 days
• Part 1: Placebo
Matching placebo capsules administered once daily for 28 days
• Part 2: LJN452 Dose level 1
LJN452 capsules administered once a day for 12 weeks
• Part 2: Placebo
Matching placebo to LJN452 administered once a day for 12 weeks
• Part 2: LJN452 Dose level 2
LJN452

Locations

Country	Name	City	State
Canada	Novartis Investigative Site	Calgary	Alberta
Canada	Novartis Investigative Site	Edmonton	Alberta
Germany	Novartis Investigative Site	Hamburg
Germany	Novartis Investigative Site	Hannover
Germany	Novartis Investigative Site	Heidelberg
Germany	Novartis Investigative Site	Muenchen
Germany	Novartis Investigative Site	Wuerzburg
Poland	Novartis Investigative Site	Lodz
Poland	Novartis Investigative Site	Myslowice
Poland	Novartis Investigative Site	Warsaw
Poland	Novartis Investigative Site	Wroclaw
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Saint-Petersburg
Russian Federation	Novartis Investigative Site	Samara
United Kingdom	Novartis Investigative Site	Birmingham	West Midlands
United Kingdom	Novartis Investigative Site	Cambridge
United Kingdom	Novartis Investigative Site	Hull
United Kingdom	Novartis Investigative Site	London
United Kingdom	Novartis Investigative Site	Newcastle upon Tyne
United States	Novartis Investigative Site	Atlanta	Georgia
United States	Novartis Investigative Site	Chicago	Illinois
United States	Novartis Investigative Site	Dallas	Texas
United States	Novartis Investigative Site	Manhasset	New York
United States	Novartis Investigative Site	Marietta	Georgia
United States	Novartis Investigative Site	Miami	Florida
United States	Novartis Investigative Site	Rialto	California
United States	Novartis Investigative Site	San Antonio	Texas
United States	Novartis Investigative Site	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Canada,  Germany,  Poland,  Russian Federation,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	Blood Pressure	Vital signs - Systolic Blood pressure	Screening, Baseline, day 1, day 7, day 14, day 21, day 28, day 56, day 84
Primary	Pulse Rate	Vital signs	Screening, Baseline, day 1, day 7, day 14, day 21, day 28, day 56, day 84
Primary	Body Temperature	Vital signs	Screening, Baseline, day 1, day 7, day 14, day 21, day 28, day 56, day 84
Primary	ECG - Heart Rate	Electrocardiogram (ECG)	Screening, Baseline, day 1, day 28
Primary	ECG Intervals - PR Interval	Electrocardiogram (ECG)	Screening, Baseline, day 1, day 28
Primary	Haemoglobin	Hematology panel for safety laboratory assessments.	Screening, Baseline, day 1, day 7, day 14, day 21, day 28, day 56, day 84
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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

External Links

•   A Plain Language Trial Summary is available on novartisclinicatrials.com