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

Study Overview
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Brief Summary
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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.

Official Title
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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).

Conditions
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Primary Bile Acid Diarrhea

Intervention / Treatment
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* Drug: LJN452
* Drug: Placebo to LJN452


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LJN452 followed by placebo<br>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<br>* Capsules containing LJN452<br>Drug: Placebo to LJN452<br>* Capsules containing placebo to LJN452<br>|
| Experimental: Placebo followed by LJN452<br>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<br>* Capsules containing LJN452<br>Drug: Placebo to LJN452<br>* Capsules containing placebo to LJN452<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Primary bile acid diarrhea,, FXR agonist,, bile acid malabsorption.