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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02516605
Recruitment Status : Completed
First Posted : August 6, 2015
Results First Posted : November 13, 2019
Last Update Posted : November 13, 2019
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

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

Condition or disease Intervention/treatment Phase
Primary Biliary Cholangitis 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 Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 61 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
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
Actual Study Start Date : September 9, 2015
Actual Primary Completion Date : August 2, 2018
Actual Study Completion Date : August 2, 2018


Arm Intervention/treatment
Experimental: LJN452 Drug: Part 1: LJN452
LJN452 capsules administered once daily for 28 days
Other Name: tropifexor

Drug: Part 2: LJN452 Dose level 1
LJN452 capsules administered once a day for 12 weeks
Other Name: tropifexor

Drug: Part 2: LJN452 Dose level 2
LJN452
Other Name: tropifexor

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




Primary Outcome Measures :
  1. 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

  2. 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

  3. Pulse Rate [ Time Frame: Screening, Baseline, day 1, day 7, day 14, day 21, day 28, day 56, day 84 ]
    Vital signs

  4. Body Temperature [ Time Frame: Screening, Baseline, day 1, day 7, day 14, day 21, day 28, day 56, day 84 ]
    Vital signs

  5. ECG - Heart Rate [ Time Frame: Screening, Baseline, day 1, day 28 ]
    Electrocardiogram (ECG)

  6. ECG Intervals - PR Interval [ Time Frame: Screening, Baseline, day 1, day 28 ]
    Electrocardiogram (ECG)

  7. 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.


Secondary Outcome Measures :
  1. 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]

  2. 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]

  3. 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]

  4. 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.

  5. 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.

  6. 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02516605


Locations
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United States, California
Novartis Investigative Site
Rialto, California, United States, 92377
United States, Florida
Novartis Investigative Site
Miami, Florida, United States, 33136
United States, Georgia
Novartis Investigative Site
Atlanta, Georgia, United States, 30308
Novartis Investigative Site
Marietta, Georgia, United States, 30060
United States, Illinois
Novartis Investigative Site
Chicago, Illinois, United States, 60612
United States, New York
Novartis Investigative Site
Manhasset, New York, United States, 11030
United States, Texas
Novartis Investigative Site
Dallas, Texas, United States, 75390
Novartis Investigative Site
San Antonio, Texas, United States, 78215
United States, Washington
Novartis Investigative Site
Seattle, Washington, United States, 98104
Canada, Alberta
Novartis Investigative Site
Calgary, Alberta, Canada, T2N 4N1
Novartis Investigative Site
Edmonton, Alberta, Canada, T6G 2B7
Germany
Novartis Investigative Site
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
Poland
Novartis Investigative Site
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
Russian Federation
Novartis Investigative Site
Moscow, Russian Federation, 117198
Novartis Investigative Site
Saint-Petersburg, Russian Federation, 194044
Novartis Investigative Site
Samara, Russian Federation, 443011
United Kingdom
Novartis Investigative Site
Birmingham, West Midlands, United Kingdom, B15 2TH
Novartis Investigative Site
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
Sponsors and Collaborators
Novartis Pharmaceuticals
  Study Documents (Full-Text)

Documents provided by Novartis ( Novartis Pharmaceuticals ):
Study Protocol  [PDF] November 27, 2017
Statistical Analysis Plan  [PDF] October 4, 2018

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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT02516605    
Other Study ID Numbers: CLJN452X2201
2015-001590-41 ( EudraCT Number )
First Posted: August 6, 2015    Key Record Dates
Results First Posted: November 13, 2019
Last Update Posted: November 13, 2019
Last Verified: October 2019
Individual Participant Data (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


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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
Primary Biliary Cirrhosis, PBC
Primary Biliary Cholangitis
Additional relevant MeSH terms:
Layout table for MeSH terms
Cholangitis
Liver Cirrhosis, Biliary
Bile Duct Diseases
Biliary Tract Diseases
Digestive System Diseases
Cholestasis, Intrahepatic
Cholestasis
Liver Diseases
Liver Cirrhosis