Biliary Atresia
Conditions
Keywords
Biliary Atresia, Placebo-controlled, Pharmacokinetics, Pharmacodynamics, Obeticholic Acid, Efficacy, Post-hepatoportoenterostomy
Brief summary
This study will evaluate the efficacy, safety and tolerability, as well as PK/PD of OCA in eligible pediatric participants with biliary atresia with successful hepatoportoenterostomy (HPE, also known as a Kasai portoenterostomy). The double-blind period comprises of 2 phases: dose titration phase and age expansion treatment phase.
Interventions
DRUGOCA
OCA will be administered.
DRUGMatching Placebo
Matching Placebo will be administered.
Sponsors
Intercept Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Caregiver)
Eligibility
Sex/Gender
ALL
Age
1 Days to 18 Years
Healthy volunteers
No
Inclusion criteria
* Male or female pediatric participants from birth to \<18 years old. Note: Participants aged \<2 years old will not be enrolled until after review of safety data during the planned interim analysis and agreement from the Data Safety Monitoring Board (DSMB) that there is sufficient safety data to enroll this age group. * Diagnosis of non-syndromic biliary atresia. * Demonstrated successful HPE as defined by total bilirubin \<2 milligrams per deciliter (mg/dL) (34.2 micromoles per liter \[μmol/L\]) at least 3 months post-HPE procedure.
Exclusion criteria
* Prior liver transplant or active status on transplant list. * Participants diagnosed with biliary atresia splenic malformation (BASM). * Conjugated (direct) bilirubin ≥ upper limit of normal (ULN) of site-specific reference range. If conjugated bilirubin is not available: total bilirubin ≥2 mg/dL (34.2 mol/L). * Platelets \<120,000/μL * International normalized ratio (INR) ≥1.5. * Current or history of complications of decompensated chronic liver disease including: 1. Gastroesophageal varices and/or variceal bleeding 2. Clinically evident ascites related to portal hypertension 3. Hepatic encephalopathy 4. Prior placement of portosystemic shunt 5. Hepatopulmonary syndrome or portopulmonary hypertension 6. Hepatorenal syndrome 7. Any evidence of portal hypertension based on imaging (e.g., cavernous transformation of portal vein, abdominal varices, etc.) 8. Hepatocellular carcinoma 9. Childs-Pugh B or C * Height and weight Z-score \<-2 per site-specific reference ranges. * Acholic (pale) stools. * Aspartate aminotransferase (AST) \>4x ULN. * Alanine aminotransferase \>4x ULN * GGT \>500 Units per Liter (U/L) * On anticoagulation therapy * Albumin \<3.5 grams per deciliter (g/dL). * Inability to swallow tablets (i.e., tablet or mini-tablet formulations).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Composite Liver-Related Clinical Events | Up to Week 48 | Number of participants experiencing any of the following: All-cause death; Liver transplantation; Hospitalization (≥24 hours) for variceal bleeding, hepatic encephalopathy, or spontaneous bacterial peritonitis; Clinically relevant ascites requiring therapeutic paracentesis have been presented. No clinical outcome events were reported at the time of the study termination; hence It was not possible to conduct the planned primary efficacy analysis. |
| Change From Baseline in Pediatric End-stage Liver Disease (PELD) Score | Baseline and up to Week 48 | The Pediatric End-stage Liver Disease (PELD) score is a scale used to assess the severity of chronic liver disease in pediatric participants younger than 12 years of age. The total PELD score ranges from negative values to positive values, with no absolute minimum or maximum, with higher scores indicating more severe liver disease and greater urgency for liver transplantation. The score is calculated using total bilirubin, international normalized ratio (INR), albumin, age at listing, and growth failure. Baseline was defined as the last assessment prior to first study drug administration. Change from baseline was calculated as the last post-baseline value minus the baseline value. A negative change from baseline indicates improvement, while a positive change indicates worsening. |
| Change From Baseline in Model of End-stage Liver Disease With Sodium (MELD-NA) Score | Baseline and up to Week 48 | The Model of End-stage Liver Disease with Sodium (MELD-Na) score is a scale used to assess the severity of chronic liver disease in participants 12 years of age and older, ranging from 6 (less ill) to 40 (gravely ill). Higher scores indicate more severe liver disease and greater urgency for liver transplantation. The score is derived from total bilirubin, serum creatinine, INR, and serum sodium. Baseline was defined as the last assessment prior to first study drug administration. Change from baseline was calculated as the last post-baseline value minus the baseline value. A negative change from baseline indicates improvement, while a positive change indicates worsening. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Improvement in GGT and Direct Bilirubin (Composite Responder Endpoint) | Up to Week 48 | Participants were considered responders if both of the following criteria were met at EOS: ≥40% reduction from baseline in Gamma Glutamyl Transferase (GGT), and ≥25% reduction from baseline in direct (conjugated) bilirubin. Participants with missing values were considered non-responders. |
| Change From Baseline in GGT | Baseline and up to Week 48 | Blood samples were collected to assess GGT levels. Baseline was defined as the last assessment prior to first study drug administration. Change from baseline was computed by subtracting the baseline value from the post-baseline value, with a positive change indicating improvement. |
| Change From Baseline in Total and Direct (Conjugated) Bilirubin | Baseline and up to Week 48 | Blood samples were collected to assess direct bilirubin levels. Baseline was defined as the last assessment prior to first study drug administration. Change from baseline was computed by subtracting the baseline value from the post-baseline value, with a positive change indicating improvement. |
| Change From Baseline in Endogenous Bile Acids | Baseline and up to Week 48 | Plasma samples were collected to assess endogenous bile acids. Baseline was defined as the last assessment prior to first study drug administration. Change from baseline was computed by subtracting the baseline value from the post-baseline value, with a positive change indicating improvement. |
| Change From Baseline in Liver Stiffness as Assessed by Transient Elastography | Baseline and up to Week 48 | Liver stiffness was measured using ultrasound elastography. Baseline was defined as the last assessment prior to first study drug administration. Change from baseline was computed by subtracting the baseline value from the post-baseline value, with a positive change indicating improvement. |
| Number of Participants Reporting Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | Up to Week 48 | TEAEs were defined as adverse events that were reported or worsened on or after the first dose of study treatment. Serious adverse events are adverse events resulting in death, are immediately life threatening, requires in-patient hospitalization or prolongation of existing hospitalization, or results in persistent or significant disability/incapacity. |
| Change From Baseline in Plasma Levels of Fat-Soluble Vitamin D | Baseline and Week 48 | Plasma samples were collected to assess levels of fat-soluble vitamins D. Baseline was defined as the last assessment prior to first study drug administration. Change from baseline was computed by subtracting the baseline value from the post-baseline value, with a positive change indicating improvement. |
| Change From Baseline in Plasma Levels of Fat-Soluble Vitamin K | Baseline and Week 48 | Plasma samples were collected to assess levels of fat-soluble vitamin K. Baseline was defined as the last assessment prior to first study drug administration. Change from baseline was computed by subtracting the baseline value from the post-baseline value, with a positive change indicating improvement. |
Countries
Australia, Canada, China, Hong Kong, Israel, Malaysia, New Zealand, Singapore, Taiwan, Turkey (Türkiye)
Contacts
STUDY_DIRECTORLynda Szczech, MD
Intercept Pharmaceuticals
Participant flow
Recruitment details
This was a global, multicenter, double-blind, placebo-controlled study that evaluated efficacy, safety, and tolerability as well as pharmacokinetic/pharmacodynamic of Obeticholic Acid (OCA) in pediatric participants with biliary atresia with successful Hepatoportoenterostomy (HPE).
Pre-assignment details
A total of 28 participants were enrolled.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 7.4 years STANDARD_DEVIATION 4.31 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 20 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 3 Participants |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 14 |
| other Total, other adverse events | 13 / 14 | 11 / 14 |
| serious Total, serious adverse events | 3 / 14 | 0 / 14 |
Outcome results
None listed