Primary Bile Acid Diarrhea
Conditions
Keywords
Primary bile acid diarrhea,, FXR agonist,, bile acid malabsorption.
Brief summary
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.
Interventions
DRUGLJN452
Capsules containing LJN452
DRUGPlacebo to LJN452
Capsules containing placebo to LJN452
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients Reported With Adverse Events , Serious Adverse Events and Death. | up to Day 79 | Number of patients reported with adverse events , serious adverse events and death. |
| 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 frequency 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 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration-time Profile (AUCtau) of LJN452 | Day 1 (Period 1 & 2) and Day 12 (Period 1 & 2) | 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 \[mass x time / volume\] |
| (Cmax) of LJN452 | Day 1 (Period 1 & 2) and Day 12 (Period 1 & 2) | Cmax is the observed maximum plasma (or serum or blood) concentration following drug administration \[mass / volume\] |
| Time to Reach Maximum Concentration After Drug Administration (Tmax) | Day 1 (Period 1 & 2) and Day 12 (Period 1 & 2) | Tmax is the time to reach the maximum concentration after drug administration \[time\] |
| 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 | Baseline, Week 1 (Period 1 & 2), Week 2 (Period 1 & 2), 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 |
Countries
United Kingdom, United States
Participant flow
Recruitment details
In total, 20 patients were enrolled in this study and received at least one dose of LJN452 or matching placebo for 14 days in Period 1. There will be a washout period between 7 to 28 days followed by Period 2 drug if patient on LJN452 or Placebo in Period 1 they will take Placebo or LJN452 respectively in Period 2 for 14 days
Participants by arm
| Arm | Count |
|---|---|
| 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. | 10 |
| 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. | 10 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Abnormal laboratory value(s)# | 1 | 0 |
| Overall Study | Administrative problems | 0 | 1 |
| Overall Study | Protocol deviation | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo Followed by LJN452 | Total | LJN452 Followed by Placebo |
|---|---|---|---|
| Age, Continuous | 57.9 years STANDARD_DEVIATION 16.47 | 53.7 years STANDARD_DEVIATION 15.19 | 49.4 years STANDARD_DEVIATION 13.25 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 10 Participants | 20 Participants | 10 Participants |
| Sex: Female, Male Female | 8 Participants | 12 Participants | 4 Participants |
| Sex: Female, Male Male | 2 Participants | 8 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 17 | 0 / 19 |
| other Total, other adverse events | 9 / 17 | 14 / 19 |
| serious Total, serious adverse events | 0 / 17 | 0 / 19 |
Outcome results
Primary
Number of Patients Reported With Adverse Events , Serious Adverse Events and Death.
Number of patients reported with adverse events , serious adverse events and death.
Time frame: up to Day 79
Population: Safety analysis set consists of 20 patients(10 pts per treatment period),17 \&19 patients received at least 1 LJN \& 1 Placebo dose, respectively, therefore 17 pts in the LJN452 \&19 in the Placebo treatment periods were analyzed. Adverse events were summarized using descriptive statistics only with no formal statistical analysis performed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LJN452 ALL Patients | Number of Patients Reported With Adverse Events , Serious Adverse Events and Death. | AEs, Patients with AEs | 9 count of participants |
| LJN452 ALL Patients | Number of Patients Reported With Adverse Events , Serious Adverse Events and Death. | Study drug-related AEs | 0 count of participants |
| LJN452 ALL Patients | Number of Patients Reported With Adverse Events , Serious Adverse Events and Death. | Serious AEs | 0 count of participants |
| LJN452 ALL Patients | Number of Patients Reported With Adverse Events , Serious Adverse Events and Death. | Death | 0 count of participants |
| Placebo ALL Patients | Number of Patients Reported With Adverse Events , Serious Adverse Events and Death. | Death | 0 count of participants |
| Placebo ALL Patients | Number of Patients Reported With Adverse Events , Serious Adverse Events and Death. | AEs, Patients with AEs | 14 count of participants |
| Placebo ALL Patients | Number of Patients Reported With Adverse Events , Serious Adverse Events and Death. | Serious AEs | 0 count of participants |
| Placebo ALL Patients | Number of Patients Reported With Adverse Events , Serious Adverse Events and Death. | Study drug-related AEs | 4 count of participants |
Primary
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.
Time frame: Baseline, Week 1 (Period 1 & Period 2), Week 2 (Period 1 & Period 2), and Week 1 & 2 combined
Population: PD analysis set included all patients with available PD data and no protocol deviations with relevant impact on PD data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LJN452 ALL Patients | Stool Form at Baseline, Week 1 (Period 1 & Period 2), Week 2 (Period 1 & Period 2), and Week 1 & 2 Combined | Baseline | 5.5 score on a scale | Standard Deviation 0.87 |
| LJN452 ALL Patients | Stool Form at Baseline, Week 1 (Period 1 & Period 2), Week 2 (Period 1 & Period 2), and Week 1 & 2 Combined | Week 1 (Period 1 & 2) | 5.3 score on a scale | Standard Deviation 0.78 |
| LJN452 ALL Patients | Stool Form at Baseline, Week 1 (Period 1 & Period 2), Week 2 (Period 1 & Period 2), and Week 1 & 2 Combined | Week 2 (Period 1 & 2) | 4.9 score on a scale | Standard Deviation 0.82 |
| LJN452 ALL Patients | Stool Form at Baseline, Week 1 (Period 1 & Period 2), Week 2 (Period 1 & Period 2), and Week 1 & 2 Combined | Week 1 & 2(Period 1 & 2) | 5.1 score on a scale | Standard Deviation 0.81 |
| Placebo ALL Patients | Stool Form at Baseline, Week 1 (Period 1 & Period 2), Week 2 (Period 1 & Period 2), and Week 1 & 2 Combined | Week 1 & 2(Period 1 & 2) | 5.2 score on a scale | Standard Deviation 0.9 |
| Placebo ALL Patients | Stool Form at Baseline, Week 1 (Period 1 & Period 2), Week 2 (Period 1 & Period 2), and Week 1 & 2 Combined | Baseline | 5.1 score on a scale | Standard Deviation 0.94 |
| Placebo ALL Patients | Stool Form at Baseline, Week 1 (Period 1 & Period 2), Week 2 (Period 1 & Period 2), and Week 1 & 2 Combined | Week 2 (Period 1 & 2) | 5.1 score on a scale | Standard Deviation 1.01 |
| Placebo ALL Patients | Stool Form at Baseline, Week 1 (Period 1 & Period 2), Week 2 (Period 1 & Period 2), and Week 1 & 2 Combined | Week 1 (Period 1 & 2) | 5.3 score on a scale | Standard Deviation 0.79 |
Comparison: Week 1 (Period 1 \& 2)p-value: 0.53395% CI: [-0.27, 0.52]Mixed Models Analysis
Comparison: Week 2 (Period 1 \& 2)p-value: 0.6495% CI: [-0.49, 0.3]Mixed Models Analysis
Comparison: Week 1\&2 (Period 1 \& 2)p-value: 0.91695% CI: [-0.27, 0.3]Mixed Models Analysis
Primary
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
Time frame: Baseline, Week 1 (Period 1 & Period 2), Week 2 (Period 1 & Period 2), and Week 1 & 2 combined
Population: PD analysis set included all patients with available PD data and no protocol deviations with relevant impact on PD data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LJN452 ALL Patients | Stool Frequency at Baseline, Week 1 (Period 1 & Period 2), Week 2 (Period 1 & Period 2), and Week 1 & 2 Combined | Baseline | 18.0 Stools per week | Standard Deviation 9.39 |
| LJN452 ALL Patients | Stool Frequency at Baseline, Week 1 (Period 1 & Period 2), Week 2 (Period 1 & Period 2), and Week 1 & 2 Combined | Week 1 (Period 1 & 2) | 20.0 Stools per week | Standard Deviation 11.62 |
| LJN452 ALL Patients | Stool Frequency at Baseline, Week 1 (Period 1 & Period 2), Week 2 (Period 1 & Period 2), and Week 1 & 2 Combined | Week 2 (Period 1 & 2) | 18.8 Stools per week | Standard Deviation 9.68 |
| LJN452 ALL Patients | Stool Frequency at Baseline, Week 1 (Period 1 & Period 2), Week 2 (Period 1 & Period 2), and Week 1 & 2 Combined | Week 1 & 2(Period 1 & 2) | 19.4 Stools per week | Standard Deviation 10.56 |
| Placebo ALL Patients | Stool Frequency at Baseline, Week 1 (Period 1 & Period 2), Week 2 (Period 1 & Period 2), and Week 1 & 2 Combined | Week 1 & 2(Period 1 & 2) | 16.8 Stools per week | Standard Deviation 9.11 |
| Placebo ALL Patients | Stool Frequency at Baseline, Week 1 (Period 1 & Period 2), Week 2 (Period 1 & Period 2), and Week 1 & 2 Combined | Baseline | 15.9 Stools per week | Standard Deviation 6.92 |
| Placebo ALL Patients | Stool Frequency at Baseline, Week 1 (Period 1 & Period 2), Week 2 (Period 1 & Period 2), and Week 1 & 2 Combined | Week 2 (Period 1 & 2) | 17.5 Stools per week | Standard Deviation 10.88 |
| Placebo ALL Patients | Stool Frequency at Baseline, Week 1 (Period 1 & Period 2), Week 2 (Period 1 & Period 2), and Week 1 & 2 Combined | Week 1 (Period 1 & 2) | 16.2 Stools per week | Standard Deviation 7.19 |
Comparison: Week 1 (Period 1 \& 2)p-value: 0.0195% CI: [0.98, 7.11]Mixed Models Analysis
Comparison: Week 2 (Period 1 \& 2)p-value: 0.40195% CI: [-1.77, 4.38]Mixed Models Analysis
Comparison: Week 1\&2 (Period 1 \& 2)p-value: 0.01995% CI: [0.46, 4.89]Mixed Models Analysis
Secondary
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 \[mass x time / volume\]
Time frame: Day 1 (Period 1 & 2) and Day 12 (Period 1 & 2)
Population: PK analysis set: Patients with at least one valid PK concentration measurement and no major protocol deviations affecting PK No statistical Analysis
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LJN452 ALL Patients | Area Under the Plasma Concentration-time Profile (AUCtau) of LJN452 | Day 1 | 23.6 hr*ng/mL | Standard Deviation 7.24 |
| LJN452 ALL Patients | Area Under the Plasma Concentration-time Profile (AUCtau) of LJN452 | Day 12 | 22.1 hr*ng/mL | Standard Deviation 4.83 |
Secondary
(Cmax) of LJN452
Cmax is the observed maximum plasma (or serum or blood) concentration following drug administration \[mass / volume\]
Time frame: Day 1 (Period 1 & 2) and Day 12 (Period 1 & 2)
Population: PK analysis set: Patients with at least one valid PK concentration measurement and no major protocol deviations affecting PK - No statistical Analysis
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LJN452 ALL Patients | (Cmax) of LJN452 | Day 1 | 1.63 ng/mL | Standard Deviation 0.414 |
| LJN452 ALL Patients | (Cmax) of LJN452 | Day 12 | 1.82 ng/mL | Standard Deviation 0.704 |
Secondary
Time to Reach Maximum Concentration After Drug Administration (Tmax)
Tmax is the time to reach the maximum concentration after drug administration \[time\]
Time frame: Day 1 (Period 1 & 2) and Day 12 (Period 1 & 2)
Population: PK analysis set: Patients with at least one valid PK concentration measurement and no major protocol deviations affecting PK; No statistical Analysis
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| LJN452 ALL Patients | Time to Reach Maximum Concentration After Drug Administration (Tmax) | Day 1 | 5.00 hr |
| LJN452 ALL Patients | Time to Reach Maximum Concentration After Drug Administration (Tmax) | Day 12 | 5.00 hr |
Secondary
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
Time frame: Baseline, Week 1 (Period 1 & 2), Week 2 (Period 1 & 2), Week 1 & 2 combined
Population: Safety analysis set consists of 20 patients(10 pts per treatment period),17 \&19 patients received at least 1 LJN \& 1 Placebo dose, respectively, therefore 17 pts in the LJN452 \&19 in the Placebo treatment periods were analyzed. Adverse events were summarized using descriptive statistics only with no formal statistical analysis performed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LJN452 ALL Patients | 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 | Baseline | 0.9 mg | Standard Deviation 3.5 |
| LJN452 ALL Patients | 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 | Week 2 (Period 1 & 2) | 0.5 mg | Standard Deviation 1.37 |
| LJN452 ALL Patients | 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 | Week 1 (Period 1 & 2) | 0.6 mg | Standard Deviation 1.75 |
| LJN452 ALL Patients | 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 | Week 1 & 2(Period 1 & 2) | 0.6 mg | Standard Deviation 1.54 |
| Placebo ALL Patients | 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 | Week 1 (Period 1 & 2) | 0.7 mg | Standard Deviation 2.06 |
| Placebo ALL Patients | 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 | Baseline | 1.3 mg | Standard Deviation 5.66 |
| Placebo ALL Patients | 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 | Week 1 & 2(Period 1 & 2) | 0.7 mg | Standard Deviation 1.85 |
| Placebo ALL Patients | 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 | Week 2 (Period 1 & 2) | 0.7 mg | Standard Deviation 1.68 |