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

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

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

Study Overview

• Status: Completed
• Conditions: Primary Biliary Cholangitis
• Intervention / Treatment: Drug: Part 1: LJN452; Drug: Part 2: LJN452 Dose level 1; Drug: Part 2: LJN452 Dose level 2; Drug: Part 1: Placebo; Drug: Part 2: Placebo

• Study Type: Interventional
• Enrollment (Actual): 61
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4N1
      • Novartis Investigative Site
    • Edmonton, Alberta, Canada, T6G 2B7
      • Novartis Investigative Site
• Germany
  • Hamburg, Germany, 20246
    • Novartis Investigative Site
  • Hannover, Germany, 30625
    • Novartis Investigative Site
  • Heidelberg, Germany, 69120
    • Novartis Investigative Site
  • Muenchen, Germany, 81377
    • Novartis Investigative Site
  • Wuerzburg, Germany, 97080
    • Novartis Investigative Site
• Poland
  • Lodz, Poland, 91-347
    • Novartis Investigative Site
  • Myslowice, Poland, 41-400
    • Novartis Investigative Site
  • Warsaw, Poland, 02-097
    • Novartis Investigative Site
  • Wroclaw, Poland, 50-449
    • Novartis Investigative Site
• Russian Federation
  • Moscow, Russian Federation, 117198
    • Novartis Investigative Site
  • Saint-Petersburg, Russian Federation, 194044
    • Novartis Investigative Site
  • Samara, Russian Federation, 443011
    • Novartis Investigative Site
• United Kingdom
  • Cambridge, United Kingdom, CB2 2QQ
    • Novartis Investigative Site
  • Hull, United Kingdom, HU3 2JZ
    • Novartis Investigative Site
  • London, United Kingdom, NW3 2PF
    • Novartis Investigative Site
  • Newcastle upon Tyne, United Kingdom, NE1 4LP
    • Novartis Investigative Site
  • West Midlands
    • Birmingham, West Midlands, United Kingdom, B15 2TH
      • Novartis Investigative Site
• United States
  • California
    • Rialto, California, United States, 92377
      • Novartis Investigative Site
  • Florida
    • Miami, Florida, United States, 33136
      • Novartis Investigative Site
  • Georgia
    • Atlanta, Georgia, United States, 30308
      • Novartis Investigative Site
    • Marietta, Georgia, United States, 30060
      • Novartis Investigative Site
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Novartis Investigative Site
  • New York
    • Manhasset, New York, United States, 11030
      • Novartis Investigative Site
  • Texas
    • Dallas, Texas, United States, 75390
      • Novartis Investigative Site
    • San Antonio, Texas, United States, 78215
      • Novartis Investigative Site
  • Washington
    • Seattle, Washington, United States, 98104
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Schramm C, Wedemeyer H, Mason A, Hirschfield GM, Levy C, Kowdley KV, Milkiewicz P, Janczewska E, Malova ES, Sanni J, Koo P, Chen J, Choudhury S, Klickstein LB, Badman MK, Jones D. Farnesoid X receptor agonist tropifexor attenuates cholestasis in a randomised trial in patients with primary biliary cholangitis. JHEP Rep. 2022 Jul 21;4(11):100544. doi: 10.1016/j.jhepr.2022.100544. eCollection 2022 Nov.

Helpful Links

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

Study record dates

Study Major Dates

• Study Start (Actual): September 9, 2015
• Primary Completion (Actual): August 2, 2018
• Study Completion (Actual): August 2, 2018

Study Registration Dates

• First Submitted: August 4, 2015
• First Submitted That Met QC Criteria: August 4, 2015
• First Posted (Estimate): August 6, 2015

Study Record Updates

• Last Update Posted (Actual): January 5, 2021
• Last Update Submitted That Met QC Criteria: December 9, 2020
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Keywords: Primary Biliary Cholangitis; Primary Biliary Cirrhosis, PBC
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Liver Diseases; Fibrosis; Biliary Tract Diseases; Bile Duct Diseases; Cholestasis, Intrahepatic; Cholestasis; Liver Cirrhosis; Cholangitis; Liver Cirrhosis, Biliary
• Other Study ID Numbers: CLJN452X2201; 2015-001590-41 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No