N-Acetylcysteine in Biliary Atresia After Kasai Portoenterostomy

March 23, 2024 updated by: Sanjiv Harpavat, Baylor College of Medicine

A Phase 2 Trial of N-Acetylcysteine in Biliary Atresia After Kasai Portoenterostomy

Biliary atresia (BA) is a devastating liver disease of infancy, characterized by bile duct obstruction leading to liver fibrosis, cirrhosis, and eventual need for transplantation in most cases. BA is treated with Kasai portoenterostomy (KP). KPs can achieve bile drainage and improve outcomes. However, even with standard evidence of "good bile flow," bile flow rarely normalizes completely and liver disease continues to progress.

In this study, the investigators test whether intravenous N-acetylcysteine (NAC) can improve bile flow after KP. The rationale is that NAC leads to synthesis of glutathione, which is a powerful stimulator of bile flow. The primary objective is to determine whether NAC normalizes total serum bile acid (TSBA) concentrations within 24 weeks of KP. Achieving normal TSBAs is uncommon with current standard-of-care, and is predicted to be associated with better long-term outcomes. The secondary objectives are to describe how other parameters commonly followed in BA change with NAC therapy, as well as report adverse events occurring with therapy and in the first two years of life. This study follows the "minimax" Phase 2 clinical trial design.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Biliary atresia (BA) is a disease characterized by fibro-obliteration of extrahepatic bile ducts leading to impaired bile flow (Sokol et al., 2007). BA is treated with the Kasai portoenterostomy (KP), an operation which connects the liver directly to the intestine in attempt to relieve bile back-up and promote bile flow. KPs have variable success. KPs occasionally normalize bile flow and stop disease progression (Jimenez-Rivera et al., 2013). More commonly, however, bile flow never completely normalizes after KP. This can be detected by elevated total bilirubin (TB) or conjugated bilirubin (Bc) serum concentrations, or, when TB and Bc are normal, elevated total serum bile acids (TSBA) concentrations (Bezerra et al., 2014; Shneider et al., 2015; Venkat et al., 2014). Impaired flow leads to fibrosis, cirrhosis, and eventual need for liver transplantation. Given these uneven results, therapies are urgently needed to enhance the KP's success.

The investigators hypothesize that N-acetylcysteine (NAC) will improve outcomes after KP, because NAC is a precursor for the powerful choleretic molecule glutathione (Ballatori and Truong, 1989, 1992, Ballatori et al., 1986, 1989). The hypothesis assumes that better bile flow will lead to better outcomes. This is supported by previous reports demonstrating that good bile flow correlates with slower disease progression in BA. For example, a recent study showed infants with good bile flow after KP were significantly less likely to develop failure-to-thrive, ascites, hypoalbuminemia, or coagulopathy in the first two years of life (Shneider et al., 2015). Furthermore, these infants had significantly higher transplant-free survival in the same time period. In this study, TB <2.0 mg/dL within three months of KP was used as the marker for good bile flow.

NAC has a number of properties that make it an especially attractive potential therapeutic agent. First, glutathione creates an osmotic gradient in the bile duct lumen which drives one-third of total bile flow in humans (the other drivers are bile acids and secretin/bicarbonate) (Ballatori and Truong, 1989, 1992, Ballatori et al., 1986, 1989). Second, NAC is a Food and Drug Administration-approved therapy for another serious liver condition in neonates and children (acetaminophen overdose). It has also been used for other liver and non-liver indications in neonates, with few reported adverse events (Ahola et al., 2003; Flynn et al., 2003; Jenkins et al., 2016; Kortsalioudaki et al., 2008; Mager et al., 2008; Soghier and Brion, 2006; Squires et al., 2013; Wiest et al., 2014). Third, glutathione is an anti-oxidant, which could scavenge the free radicals contributing to cirrhosis. Preclinical studies are also promising, with glutathione's strong choleretic properties best established in rat flow studies and NAC's hepatoprotective effects documented in rescuing different mouse models of cholestasis (Ballatori et al., 1986; Galicia-Moreno et al., 2009, 2012; Tahan et al., 2007).

To test the hypotheses, the investigators will administer intravenous NAC continuously for seven days and determine the number of subjects with normal TSBAs (0-10 umol/L) within 24 weeks of KP. In addition, markers of BA progression, such as abnormal laboratory results, failure-to-thrive, and occurrence of complications related to chronic liver disease, will be described over the first two years of life. Finally, all adverse events occurring during NAC infusion and in the 21 days after its completion will be recorded. The study employs the two-stage "minimax" Phase 2 clinical trial design, a design commonly used in oncological trials to determine whether a particularly therapy has sufficient activity to warrant a larger Phase 3 trial (Simon, 1989). The two-stage "minimax" design offers two distinct advantages compared to other designs: (i) early termination if the drug is not efficacious; and (ii) small sample sizes, because historical controls rather than a separate control arm are used.

Study Type

Interventional

Enrollment (Actual)

13

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Texas
      • Houston, Texas, United States, 77030
        • Texas Children's Hospital and Baylor College of Medicine

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

1 second to 2 months (Child)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Age less than or equal to 90 days at time of KP (standard age range in which KPs are performed)
  2. BA diagnosis made by intraoperative cholangiography and KP performed at Texas Children's Hospital, Texas Medical Center Campus
  3. Legal guardian(s) sign consent after understanding risks and investigational nature of study

Exclusion Criteria:

  1. Decompensated liver disease (INR >1.3) despite parenteral Vitamin K administration)
  2. KP not performed for any reason (i.e., normal intraoperative cholangiography, or liver found to be too diseased intraoperatively to proceed with KP)
  3. Active respiratory infection
  4. Renal impairment, as defined by having an eGFR < 60 mL/min/1.73m2 or creatinine clearance < 60 mL/min (https://www.niddk.nih.gov/health-information/communication-programs/nkdep/laboratory-evaluation/glomerular-filtration-rate-calculators/children-conventional-units)
  5. Presence of severe concurrent illnesses, such as pulmonary (i.e., bronchopulmonary dysplasia), neurological, cardiovascular, metabolic, endocrine, and renal disorders, which may be congenital or acquired, that would interfere with the conduct and results of the study

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: N-Acetylcysteine Treatment
Will receive continuous intravenous NAC therapy (6.25 mg/kg/hour of 10 mg/ml solution, or 0.625 ml/kg/hour, to give 150 mg/kg/day), starting within 24 hours of completion of KP and lasting for a total of 7 days
Drug: N-Acetyl cysteine
Intravenous NAC therapy (6.25 mg/kg/hour of 10 mg/ml solution, or 0.625 ml/kg/hour, to give 150 mg/kg/day), starting within 24 hours of completion of KP and lasting for a total of 7 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Patients With Biliary Atresia (BA) Achieving Total Serum Bile Acids Less Than or Equal to 10 *U*Mol/L Within 24 Weeks of Kasai Portoenterostomy (KP)
Time Frame: Within 24 weeks after KP
Expected is ~5% of participants based on historical controls (see protocol for summary of historical controls); a higher number is a better outcome
Within 24 weeks after KP

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), Gamma-glutamyltransferase (GGT) Fold, and Conjugated Bilirubin (Bc) Change Above Baseline at 3 Days and 7 Days After KP (During Treatment)
Time Frame: 3 days after KP compared to baseline (before KP); 7 days after KP compared to baseline (before KP)
fold-change from baseline (ratio); a fold-change <1 is a better outcome.
3 days after KP compared to baseline (before KP); 7 days after KP compared to baseline (before KP)
Number of Patients Experiencing Sentinel Events in the First 2 Years of Life
Time Frame: First two years of life
Events include Nasogastric (NG) feeds or Total Parental Nutrition (TPN) initiation, Splenomegaly (based on ultrasound findings), Thrombocytopenia (platelets <150,000/mm3), Ascites (recorded when diuretics were needed for fluid accumulation), GI bleed (varices documented by endoscopy), Portal hypertension (one of the following: ascites, or combination of splenomegaly and thrombocytopenia), and Liver transplant or death; units are number of patients, higher numbers are worse outcomes.
First two years of life
Number of Patients With Adverse Events Possibly Related to NAC, Including Rash, Urticaria, Pruritus, Tachycardia, Hypotension, Vomiting, Edema, Anaphylaxis, and Intravenous Line Issues
Time Frame: Within four weeks after KP
Units are number of patients, higher number is worse outcome
Within four weeks after KP

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Baylor College of Medicine

Investigators

  • Principal Investigator: Sanjiv Harpavat, MD. PhD, Baylor College of Medicine

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

May 18, 2018

Primary Completion (Actual)

October 31, 2022

Study Completion (Actual)

March 23, 2024

Study Registration Dates

First Submitted

April 4, 2018

First Submitted That Met QC Criteria

April 9, 2018

First Posted (Actual)

April 17, 2018

Study Record Updates

Last Update Posted (Actual)

March 26, 2024

Last Update Submitted That Met QC Criteria

March 23, 2024

Last Verified

March 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • H-40962
  • 135796 (Other Identifier: FDA IND Identifier)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Biliary Atresia

Clinical Trials on N-Acetyl cysteine

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Indonesia

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

3
Subscribe