FibroScan™ in Pediatric Cholestatic Liver Disease (FORCE)

Study Overview
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Brief Summary
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Noninvasive monitoring of liver fibrosis is an unmet need within the clinical management of pediatric chronic liver disease. While liver biopsy is often used in the initial diagnostic evaluation, subsequent biopsies are rarely performed because of inherent invasiveness and risks. This study will evaluate the role of non-invasive FibroScan™ technology to detect and quantify liver fibrosis.

Detailed Description
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Noninvasive monitoring of liver fibrosis is an unmet and critical need within the clinical management of children with chronic liver disease. While liver biopsy is often used in the initial diagnostic evaluation of children with liver disease, subsequent surveillance liver biopsy is rarely performed in children because of its inherent invasiveness and risks. Therefore, our understanding of the natural history of fibrosis progression in children is limited. The patchy nature of fibrosis in many important pediatric liver diseases [e.g. biliary atresia (BA) and cystic fibrosis liver disease (CFLD)] limits the utility of sequential liver biopsy even if it were to be employed in clinical practice in pediatrics. Thus, non-invasive means of assessing liver fibrosis throughout the liver would be highly desirable and clinically useful in pediatric hepatology. ChiLDReN is poised and uniquely qualified to conduct a comprehensive longitudinal assessment of the utility of FibroScan™-specific elastography, liver stiffness measurement (LSM) as a measure of hepatic fibrosis in children with serious chronic cholestatic liver disease.

Official Title
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Childhood Liver Disease Research Network (ChiLDReN): FibroScan™ in Pediatric Cholestatic Liver Disease (FORCE) Study Protocol

Conditions
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Biliary Atresia, Alagille Syndrome, Alpha1 Anti-Trypsin Deficiency, Portal Hypertension, Liver Fibrosis, Cholestasis

Intervention / Treatment
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* Other: Liver Stiffness Measurement (LSM)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age less than 21 years at the time of enrollment Participants enrolled in a ChiLDReN based prospective observational cohort study (PROBE, BASIC, or LOGIC) Willingness and ability to participate in the study for up to 24 months One of the following three diagnoses Biliary atresia per ChiLDReN criteria or, Alpha-1 antitrypsin deficiency (PiZZ or SZ) or, Alagille Syndrome per ChiLDReN criteria Exclusion Criteria: BA with known situs inversus or polysplenia/asplenia Presence of clinically significant ascites detected on physical examination Open wound near expected FibroScan probe application site Use of implantable active medical device such as a pacemaker or defibrillator Known pregnancy Prior liver transplant Unable or unwilling to give informed consent or assent

Ages Eligible for Study
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Maximum Age: 21 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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| All Subjects<br>All subjects will be recruited from the Children parent studies: LOGIC (NCT00571272), BASIC (NCT00345553) and PROBE (NCT00061828) and will undergo Liver Stiffness Measurement (LSM). Subjects in these studies have one or more of the following conditions: biliary atresia (BA), Alpha1 Anti-trypsin Deficiency (A1AT) or Alagille Syndrome (ALGS). | Other: Liver Stiffness Measurement (LSM)<br>* LSM will be measured via transient elastography utilizing the non-invasive FibroScan™ ultrasound device. LSM will be measured at Baseline, Year 1 and Year 2 visits.<br>* Other names: FibroScan™;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compare the distribution of LSM at enrollment between participants with and without portal hypertension | A linear model will be fit to FibroScan™ values at enrollment to assess the impact of portal hypertension on LSM, controlling for important covariates such as age, gender, and race | Enrollment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Liver Stiffness Measurement (LSM) obtained via transient elastography from baseline to LSM at the Year 1 and Year 2 visits in participants with biliary atresia (BA). | The key secondary aim (Aim 2) compares the one- and two-year FibroScan™ values to those at enrollment in participants with BA. | Baseline, Year 1 Visit, Year 2 Visit | 
| Number of participants in whom a valid FibroScan™ LSM can be obtained | The investigators will define two measures of the feasibility of FibroScans™ in the participant populations with a technically possible FibroScan™, defined as the number of subjects with at least 10 FibroScan™ measurements obtained divided by the number assessed. The proportion of subjects with FibroScans™ of acceptable quality is defined as the number of subjects with FibroScan™ LSM with the ratio of the interquartile range and median of the 10 measurements <30%, of which at least 6 are completed, divided by the number assessed. The proportions and their 95% confidence intervals will be provided using the Wald method; however, the Wilson-Score methods will be used if the sample sizes are small or the proportion is small for a disease group. We will perform separate analyses for subjects <2 years of age and for those >2 years of age. | Baseline, Year 1 Visit, Year 2 Visit | 
| FibroScan™ LSM values at enrollment and conventional laboratory determinants of liver disease ((Pediatric End Stage Liver Disease (PELD) and APRI (Aspartate Aminotransferase (AST) to Platelet Ratio Index)). | The analysis will be limited to subjects for whom a PELD can be calculated (i.e., those for whom the individual components of the PELD score are available). Note that PELD will be calculated for all pediatric participants including those greater than 12 years of age. PELD is calculated as PELD = 4.80 x [ln serum bilirubin (mg/dL)] + 18.57 x [ln INR] - 6.87 x [ln albumin (g/dL)] + 4.36(<1 year old) + 6.67(growth failure) [www.unos.org] APRI is calculated as APRI = AST/upper limit of normal AST x 100 [U/L] Platelet Count (109/L) [U/L]) | Baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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transient elastography, pediatric liver disease, biliary atresia, Alagille Syndrome, Alpha1 Anti-Trypsin Deficiency, liver fibrosis, cholestasis