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

• ClinicalTrials.gov Identifier: NCT02516605
• Recruitment Status: Completed
• First Posted: August 6, 2015
• Results First Posted: November 13, 2019
• Last Update Posted: January 5, 2021
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: August 4, 2015
• First Posted Date: August 6, 2015
• Results First Submitted Date: August 1, 2019
• Results First Posted Date: November 13, 2019
• Last Update Posted Date: January 5, 2021
• Actual Study Start Date: September 9, 2015
• Actual Primary Completion Date: August 2, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 25, 2019)

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

Original Primary Outcome Measures (submitted: August 4, 2015)

• Change in cholestatic markers from baseline [ Time Frame: Baseline, 28 Days ]
  Evaluate the change in cholestatic markers following administration of LJN452
• Number of patients with adverse events, serious adverse events and death [ Time Frame: 86 days ]
  Determine safety and tolerability of LJN452

Current Secondary Outcome Measures (submitted: October 25, 2019)

• Plasma PK Parameter - AUC 0-8h [ Time Frame: 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]
• Plasma PK Parameter - Cmax [ Time Frame: 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]
• Plasma PK Parameter - Tmax [ Time Frame: 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 [ Time Frame: 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.
• Change From Baseline in Itch Subdomain of PBC-40 Score [ Time Frame: 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.
• Change From Baseline in Global Itch Visual Analogue Scale (VAS) [ Time Frame: 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.

Original Secondary Outcome Measures (submitted: August 4, 2015)

• Change from baseline in disease specific quality of life [ Time Frame: Baseline, 28 days ]
  Evaluate change in quality of life using PBC-40 PRO
• Change from baseline in itch as determined by the itch domain in the PBC-40 [ Time Frame: Baseline, 28 days ]
  Evaluate the change in itch using the itch domain in the PBC-40
• Change from baseline in itch as determined by 10mm VAS [ Time Frame: Baseline, 28 Days ]
  Evaluate the change in itch from baseline with a 10 mm VAS
• Area under the plasma concentration-time profile (AUCtau) [ Time Frame: Day 1, Day 7, Day 14, Day 21, Day 28, Day 29, Day 56 ]
  Evalaute AUCtau
• Maximum plasma concentration of LJN452 (Cmax) [ Time Frame: Day 1, Day 7, Day 14, Day 21, Day 28, Day 29, Day 56 ]
  Evaluate Cmax
• Minimum plasma concentration of LJN452 (Cmin) [ Time Frame: Day 1, Day 7, Day 14, Day 21, Day 28, Day 29, Day 56 ]
  Evaluate Cmin
• Average steady state plasma concentration following multiple doses of LJN452 (Cav,ss) [ Time Frame: Day 1, Day 7, Day 14, Day 21, Day 28, Day 29, Day 56 ]
  Evaluate Cav,ss
• Time to reach maximum concentration after durg administration (Tmax) [ Time Frame: Day 1, Day 7, Day 14, Day 21, Day 28, Day 29, Day 56 ]
  Evalute Tmax
• Apparent systemic clearance from plasma (CL/F) [ Time Frame: Day 1, Day 7, Day 14, Day 21, Day 28, Day 29, Day 56 ]
  Evaluate CL/F
• Accumulation ratio of LJN452 (Racc) [ Time Frame: Day 1, Day 7, Day 14, Day 21, Day 28, Day 29, Day 56 ]
  Evaluate Racc

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Multi-part, Double Blind Study to Assess Safety, Tolerability and Efficacy of Tropifexor (LJN452) in PBC Patients
• 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
• Brief Summary: A multi-part study to assess safety, tolerability and efficacy of tropifexor (LJN452) in patients with primary biliary cholangitis
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
• Condition: Primary Biliary Cholangitis

Intervention

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

Study Arms

• Experimental: LJN452
  Interventions:

  • Drug: Part 1: LJN452
  • Drug: Part 2: LJN452 Dose level 1
  • Drug: Part 2: LJN452 Dose level 2
• Placebo Comparator: Placebo
  Interventions:

  • Drug: Part 1: Placebo
  • Drug: Part 2: Placebo

• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 6, 2018): 61
• Original Estimated Enrollment (submitted: August 4, 2015): 90
• Actual Study Completion Date: August 2, 2018
• Actual Primary Completion Date: August 2, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

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).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, Germany, Poland, Russian Federation, United Kingdom, United States

Administrative Information

• NCT Number: NCT02516605
• Other Study ID Numbers: CLJN452X2201; 2015-001590-41 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes

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

• Current Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Original Responsible Party: Same as current
• Current Study Sponsor: Novartis Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Novartis
• Verification Date: October 2019