To Assess Safety, Tolerability and Efficacy of LJN452 in Patients With Primary Bile Acid Diarrhea.

A Double Blind, Randomized Placebo Controlled Crossover Multiple Dose Study of LJN452 to Assess Safety, Tolerability and Efficacy in Patients With Primary Bile Acid Diarrhea (pBAD).

The purpose of this study is to determine whether LJN452 improves the symptoms of bile acid diarrhea and to assess its safety and tolerability profile in patients with primary bile acid diarrhea (pBAD) to guide decision-making regarding further clinical development in this indication.

Study Overview

• Status: Completed
• Conditions: Primary Bile Acid Diarrhea
• Intervention / Treatment: Drug: LJN452; Drug: Placebo to LJN452

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, W2 1PG
    • Novartis Investigative Site
  • Sheffield, United Kingdom, S10 2JF
    • Novartis Investigative Site
  • Middlesex
    • Harrow, Middlesex, United Kingdom, HA1 3UJ
      • Novartis Investigative Site
• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • 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

Key Inclusion Criteria:

• A history of diarrheal symptoms for at least 3 months prior to dosing - Average stool frequency of at least 2 per day when off therapy AND Average stool form of >5 on Bristol Stool Chart.
• Previous laboratory or radiological confirmation of bile acid malabsorption with either fecal bile acid loss OR 7 day 75Selenium homocholic acid taurine (75SeHCAT) retention.
• Age ≥ 18 years.

Key Exclusion Criteria:

• Patients with other diagnoses leading to diarrhea, including colorectal neoplasia, ulcerative colitis, Crohn's disease, celiac disease, chronic pancreatitis, drug-induced diarrhea or active infection AND Patients who have not been investigated by standard clinical assessments to exclude these disorders.
• Treatment with bile acid sequestrants (colestyramine, colestipol, colesevelam) for 2 weeks before the first dose of LJN452. A washout of 14 days for these agents will be allowed before first dosing.
• Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant.
• A positive Hepatitis B surface antigen or Hepatitis C test result.
• History of immunodeficiency diseases, including a positive HIV (ELISA and Western blot) test result.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: LJN452 followed by placebo; Randomized patients in this arm will receive single oral dose of LJN452 daily for 14 days. There will be a washout period between 7 to 28 days followed by single oral dose of placebo daily for 14 days.	Drug: LJN452; Capsules containing LJN452; Drug: Placebo to LJN452; Capsules containing placebo to LJN452
EXPERIMENTAL: Placebo followed by LJN452; Randomized patients in this arm will receive single oral dose of placebo daily for 14 days. There will be a washout period between 7 to 28 days followed by single oral dose of LJN452 daily for 14 days.	Drug: LJN452; Capsules containing LJN452; Drug: Placebo to LJN452; Capsules containing placebo to LJN452

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients Reported With Adverse Events , Serious Adverse Events and Death.	Number of patients reported with adverse events , serious adverse events and death.	up to Day 79
Stool Frequency at Baseline, Week 1 (Period 1 & Period 2), Week 2 (Period 1 & Period 2), and Week 1 & 2 Combined	Stool frequency at Baseline, Week 1 (Period 1 & Period 2), Week 2 (Period 1 & Period 2), and Week 1 & 2 combined	Baseline, Week 1 (Period 1 & Period 2), Week 2 (Period 1 & Period 2), and Week 1 & 2 combined
Stool Form at Baseline, Week 1 (Period 1 & Period 2), Week 2 (Period 1 & Period 2), and Week 1 & 2 Combined	Stool Form at Baseline, Week 1 (Period 1 & Period 2), Week 2 (Period 1 & Period 2), and Week 1 & 2 combined Clinical Symptoms will be measured as change from baseline in stool types per Bristol Stool Scale. The Bristol Stool Scale is a medical aid designed to classify feces on a scale from 1 to 7 according to increasing wateriness.	Baseline, Week 1 (Period 1 & Period 2), Week 2 (Period 1 & Period 2), and Week 1 & 2 combined

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Plasma Concentration-time Profile (AUCtau) of LJN452	AUCtau- is the area under the plasma (or serum or blood) concentration-time curve from time zero to the end of the dosing interval tau [mass x time / volume]	Day 1 (Period 1 & 2) and Day 12 (Period 1 & 2)
(Cmax) of LJN452	Cmax is the observed maximum plasma (or serum or blood) concentration following drug administration [mass / volume]	Day 1 (Period 1 & 2) and Day 12 (Period 1 & 2)
Time to Reach Maximum Concentration After Drug Administration (Tmax)	Tmax is the time to reach the maximum concentration after drug administration [time]	Day 1 (Period 1 & 2) and Day 12 (Period 1 & 2)
Total Dose of Rescue Medication Used at Baseline, Week 1 (Period 1 & Period 2), Week 2 (Period 1 & Period 2), and Week 1 & 2 Combined	Total Dose of Rescue Medication used at Baseline, Week 1 (Period 1 & Period 2), Week 2 (Period 1 & Period 2), and Week 1 & 2 combined; Rescue Medication used was loperamide	Baseline, Week 1 (Period 1 & 2), Week 2 (Period 1 & 2), Week 1 & 2 combined

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Camilleri M, Nord SL, Burton D, Oduyebo I, Zhang Y, Chen J, Im K, Bhad P, Badman MK, Sanders DS, Walters JRF. Randomised clinical trial: significant biochemical and colonic transit effects of the farnesoid X receptor agonist tropifexor in patients with primary bile acid diarrhoea. Aliment Pharmacol Ther. 2020 Sep;52(5):808-820. doi: 10.1111/apt.15967. Epub 2020 Jul 23.

Helpful Links

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

Study record dates

Study Major Dates

• Study Start (ACTUAL): January 16, 2016
• Primary Completion (ACTUAL): January 25, 2018
• Study Completion (ACTUAL): January 25, 2018

Study Registration Dates

• First Submitted: March 15, 2016
• First Submitted That Met QC Criteria: March 15, 2016
• First Posted (ESTIMATE): March 18, 2016

Study Record Updates

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

More Information

Terms related to this study

• Keywords: Primary bile acid diarrhea,; FXR agonist,; bile acid malabsorption.
• Additional Relevant MeSH Terms: Signs and Symptoms, Digestive; Diarrhea
• Other Study ID Numbers: CLJN452X2202; 2015-003192-30 (EUDRACT_NUMBER)