Clinical trial NCT02516605: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Primary Biliary Cholangitis
Keywords: Primary Biliary Cirrhosis, PBC
Primary Biliary Cholangitis
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2015-08-06
Enrollment: 61
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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


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).

Primary outcomes:
measure: Fold Change in Serum Gamma-glutamyl Transferase (GGT)
timeFrame: Baseline to Day 28
measure: Blood Pressure
timeFrame: Screening, Baseline, day 1, day 7, day 14, day 21, day 28, day 56, day 84
measure: Pulse Rate
timeFrame: Screening, Baseline, day 1, day 7, day 14, day 21, day 28, day 56, day 84
measure: Body Temperature
timeFrame: Screening, Baseline, day 1, day 7, day 14, day 21, day 28, day 56, day 84
measure: ECG - Heart Rate
timeFrame: Screening, Baseline, day 1, day 28
measure: ECG Intervals - PR Interval
timeFrame: Screening, Baseline, day 1, day 28
measure: Haemoglobin
timeFrame: Screening, Baseline, day 1, day 7, day 14, day 21, day 28, day 56, day 84
Secondary outcomes:
measure: Plasma PK Parameter - AUC 0-8h
timeFrame: Day 1, Day 28
measure: Plasma PK Parameter - Cmax
timeFrame: Day 1, Day 28
measure: Plasma PK Parameter - Tmax
timeFrame: Day 1, Day 28
measure: Changes From Baseline in Total PBC-40 Score
timeFrame: Baseline, Day 28, Day 56, Day 84
measure: Change From Baseline in Itch Subdomain of PBC-40 Score
timeFrame: Baseline, Day 28, Day 56, Day 84
measure: Change From Baseline in Global Itch Visual Analogue Scale (VAS)
timeFrame: Day 7, Day 14, Day 21, Day 28, Day 56, and Day 84
Other outcomes:
Locations:
city: Rialto
country: United States
facility: Novartis Investigative Site
state: California
city: Miami
country: United States
facility: Novartis Investigative Site
state: Florida
city: Atlanta
country: United States
facility: Novartis Investigative Site
state: Georgia
city: Marietta
country: United States
facility: Novartis Investigative Site
state: Georgia
city: Chicago
country: United States
facility: Novartis Investigative Site
state: Illinois
city: Manhasset
country: United States
facility: Novartis Investigative Site
state: New York
city: Dallas
country: United States
facility: Novartis Investigative Site
state: Texas
city: San Antonio
country: United States
facility: Novartis Investigative Site
state: Texas
city: Seattle
country: United States
facility: Novartis Investigative Site
state: Washington
city: Calgary
country: Canada
facility: Novartis Investigative Site
state: Alberta
city: Edmonton
country: Canada
facility: Novartis Investigative Site
state: Alberta
city: Hamburg
country: Germany
facility: Novartis Investigative Site
city: Hannover
country: Germany
facility: Novartis Investigative Site
city: Heidelberg
country: Germany
facility: Novartis Investigative Site
city: Muenchen
country: Germany
facility: Novartis Investigative Site
city: Wuerzburg
country: Germany
facility: Novartis Investigative Site
city: Lodz
country: Poland
facility: Novartis Investigative Site
city: Myslowice
country: Poland
facility: Novartis Investigative Site
city: Warsaw
country: Poland
facility: Novartis Investigative Site
city: Wroclaw
country: Poland
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Saint-Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Samara
country: Russian Federation
facility: Novartis Investigative Site
city: Birmingham
country: United Kingdom
facility: Novartis Investigative Site
state: West Midlands
city: Cambridge
country: United Kingdom
facility: Novartis Investigative Site
city: Hull
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: Newcastle upon Tyne
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
References:
citation: 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.