Primary Prophylaxis for Variceal Bleed in Biliary Atresia

Study Overview
=================
Brief Summary
-----------------
Biliary atresia is the commonest etiology of neonatal cholestasis and is the most common indication for pediatric liver transplantation world-wide. Kasai-portoenterostomy (KPE) is the operative procedure of choice which helps in restoration of biliary flow and preventing rapid progression of fibrosis. Only 50-60% of infants have a successful surgery in terms of normalization of bilirubin (<2 mg/dL) after 3 months. Remaining 40-50% have rapid progression of PHT and eventual decompensation. Additionally, around 50-70% of infants with successful KPE have 1 or more episodes of cholangitis, and the severe ones if left untreated lead to progressive portal hypertension. Moreover in Indian setting a significant number of infants with biliary atresia reach late when the KPE is not feasible, and this group develops very rapid PHT and decompensation. Hence, overall around 70-80% of infants and children develop PHT within 5 years of age. Variceal bleed has been shown to be an important determinant of survival in infants with high bilirubin. Usage of beta-blockers in adult cirrhotics has been shown to reduce the progression of varices and incidence of variceal bleed. Although many pediatric hepatology centers worldwide use beta-blockers, there has been no controlled trial specifically to address this issue in children with biliary atresia. So, we planned this study to evaluate the efficacy of beta-blockers as primary prophylaxis for prevention of variceal bleed in biliary atresia children.

Detailed Description
-----------------
(a) Aim and Objectives: Aim: To study the effect of beta-blockers for primary prophylaxis of variceal bleed in infants and children with biliary atresia. Primary objective: Bleeding free survival over 18 months FU Secondary objectives: (i) Progression, persistence or regression of esophageal and gastric varices, and portal hypertensive gastropathy over 3, 6, 12 and 18 months FU (ii) Overall survival at 18 months FU (b) Methodology: This will be an open label randomized controlled study where infants and children with biliary atresia from 6 months to 5 years fulfilling inclusion and exclusion criteria will be enrolled to receive propanolol or placebo for a duration of 18 months or till the occurrence of variceal bleed. i. Study design: Open label randomized controlled study with stratified randomization. ii. Intervention: Beta-blocker (Propanolol) versus placebo. iii. Study period: 1.5 years iv. Study population: Infants and children from 6 months to 5 years of age with Biliary atresia fulfilling the inclusion and exclusion criteria. (c) Expected outcome of the project: Beta-blockers reduce the incidence of variceal bleed in infants and children with biliary atresia.

Official Title
-----------------
Propanolol for Primary Prophylaxis for Variceal Bleed in Biliary Atresia - An Open Label Randomized Controlled Study

Conditions
-----------------
Portal Hypertension, Biliary Atresia

Intervention / Treatment
-----------------
* Drug: Propanolol
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Infants and children with biliary atresia from 6 months to 5 years of age fulfilling either of the following conditions: i. With unsuccessful Kasai portoenterostomy procedure with a bilirubin >2 mg/dL, or ii. Who did not underwent Kasai portoenterostomy, or iii. With successful Kasai portoenterostomy procedure with a bilirubin <2 mg/dL, but with features of portal hypertension i.e. clinical splenomegaly and/or thrombocytopenia (platelets < 1,00,000/mm3). Exclusion Criteria: i. History suggestive of hyper-reactive airway disease. ii. Congestive heart failure iii. Any degree of heart block (I,, II, III) iv. Infants and children already on beta-blockers in last 4 weeks. v. Portal vein atresia or thrombosis. vi. History of variceal bleed. vii. Infants and children on prophylactic or therapeutic endotherapy (band ligation or sclerotherapy). viii. Potential liver transplant within 1 month.

Ages Eligible for Study
-----------------
Minimum Age: 6 Months
Maximum Age: 5 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Open label Randomized controlled trial - Block randomization
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Propanolol<br>Dose: 1 to 8 mg/kg/day in 1 to 2 divided doses adjusted to achieve target reduction in resting heart rate by 25% from baseline Frequency: once to Twice daily Route of Administration: Oral Duration: 18 months | Drug: Propanolol<br>* Non-selective Beta-blocker<br>|
| Placebo Comparator: Placebo<br>Placebo in a similar manner | Other: Placebo<br>* Inactive drug<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bleeding free survival over 18 months follow-up |  | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression, persistence or regression of esophageal varices |  | 3 months | 
| Progression, persistence or regression of gastric varices |  | 3 months | 
| Progression, persistence or regression of portal hypertensive gastropathy |  | 3 months | 
| Progression, persistence or regression of esophageal varices |  | 6 months | 
| Progression, persistence or regression of gastric varices |  | 6 months | 
| Progression, persistence or regression of portal hypertensive gastropathy |  | 6 months | 
| Progression, persistence or regression of esophageal varices |  | 12 months | 
| Progression, persistence or regression of gastric varices |  | 12 months | 
| Progression, persistence or regression of portal hypertensive gastropathy |  | 12 months | 
| Progression, persistence or regression of esophageal varices |  | 18 months | 
| Progression, persistence or regression of gastric varices |  | 18 months | 
| Progression, persistence or regression of portal hypertensive gastropathy |  | 18 months | 
| Overall survival |  | 6 months | 
| Overall survival |  | 12 months | 
| Overall survival |  | 18 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Variceal bleed, primary prophylaxis, Biliary atresia