Biliary AtresiaPhase 2NCT03499249
N-Acetylcysteine in Biliary Atresia After Kasai Portoenterostomy
A Phase 2 study testing N-Acetyl cysteine in people with Biliary Atresia, run by Baylor College of Medicine at 1 site in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 0 to 90 days
- Conditions the study is for
- Biliary Atresia
- What is being tested?
- N-Acetyl cysteine
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 13 participants
- Where
- 1 siteUnited States
- Study dates
- 18 May 2018to 23 Mar 2024
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 0 to 90 days
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- Age less than or equal to 90 days at time of KP (standard age range in which KPs are performed)
- BA diagnosis made by intraoperative cholangiography and KP performed at Texas Children's Hospital, Texas Medical Center Campus
- Legal guardian(s) sign consent after understanding risks and investigational nature of study
Who cannot join
- Decompensated liver disease (INR >1.3) despite parenteral Vitamin K administration)
- KP not performed for any reason (i.e., normal intraoperative cholangiography, or liver found to be too diseased intraoperatively to proceed with KP)
- Active respiratory infection
- 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)
- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
Texas Children's Hospital and Baylor College of Medicine
Houston, Texas, 77030
About this study
Official title: 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.
Read the 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.
- Conditions
- Biliary Atresia
- Being tested
- N-Acetyl cysteine
- Keywords
- Biliary Atresia, N-Acetylcysteine, Glutathione, Kasai portoenterostomy, Bile flow, Serum bile acids, Serum bilirubin
- Medical subject headings
- Biliary Atresia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
N-Acetyl cysteineDrug
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
| Study group | Role | What they receive |
|---|---|---|
| N-Acetylcysteine Treatment | Experimental | 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 Receives: Drug: N-Acetyl cysteine |
What is being measured
The primary outcome is the main question the study is designed to answer.
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)
Expected is ~5% of participants based on historical controls (see protocol for summary of historical controls); a higher number is a better outcome
Measured: Within 24 weeks after KP
Secondary outcomes (3)
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)
fold-change from baseline (ratio); a fold-change <1 is a better outcome.
Measured: 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
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.
Measured: 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
Units are number of patients, higher number is worse outcome
Measured: Within four weeks after KP
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted17 Apr 2018
- Study start18 May 2018
- Primary completion31 Oct 2022
- Study completion23 Mar 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (23)Papers the sponsor has linked to this study.
- Other trials for Biliary AtresiaStudies of the same condition, open and under way.
- More trials run by Baylor College of MedicineThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- This is a Phase 2 clinical trial using the two-stage "minimax" design described by Simon (Simon, 1989). As a Phase 2 trial, the trial's objective is to determine whether NAC has sufficient biological activity as adjunctive therapy for BA to warrant further study. By choosing the two-stage "minimax" design, we gain two advantages: (i) early termination if the drug is not efficacious, and (ii) using historical controls and therefore an overall smaller sample size to test the hypothesis, i.e., no randomization or control arm. This study design only identifies large effects (response \>20%). For BA this is appropriate, because the field is in need of a robust therapy that can substantially limit liver damage and delay/prevent need for liver transplantation.
- Masking
- None (open label)
- Enrolment
- 13 participants (actual)
Sponsor and investigators
- Lead sponsor
- Baylor College of Medicine
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Sanjiv Harpavat, Baylor College of Medicine
- Investigators
- Sanjiv Harpavat, MD. PhD, Principal investigator, Baylor College of Medicine
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03499249
- Sponsor's protocol ID
- H-40962
- Other IDs
- 135796
- Status last verified
- Mar 2024
- First submitted
- 4 Apr 2018
- Last updated
- 26 Mar 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Ahola T, Lapatto R, Raivio KO, Selander B, Stigson L, Jonsson B, Jonsbo F, Esberg G, Stovring S, Kjartansson S, Stiris T, Lossius K, Virkola K, Fellman V. N-acetylcysteine does not prevent bronchopulmonary dysplasia in immature infants: a randomized controlled trial. J Pediatr. 2003 Dec;143(6):713-9. doi: 10.1067/S0022-3476(03)00419-0.
PubMed 14657813Ballatori N, Truong AT. Relation between biliary glutathione excretion and bile acid-independent bile flow. Am J Physiol. 1989 Jan;256(1 Pt 1):G22-30. doi: 10.1152/ajpgi.1989.256.1.G22.
PubMed 2912148Ballatori N, Truong AT. Glutathione as a primary osmotic driving force in hepatic bile formation. Am J Physiol. 1992 Nov;263(5 Pt 1):G617-24. doi: 10.1152/ajpgi.1992.263.5.G617.
PubMed 1443136Ballatori N, Jacob R, Boyer JL. Intrabiliary glutathione hydrolysis. A source of glutamate in bile. J Biol Chem. 1986 Jun 15;261(17):7860-5.
PubMed 2872220Ballatori N, Truong AT, Ma AK, Boyer JL. Determinants of glutathione efflux and biliary GSH/GSSG ratio in perfused rat liver. Am J Physiol. 1989 Mar;256(3 Pt 1):G482-90. doi: 10.1152/ajpgi.1989.256.3.G482.
PubMed 2564253Bezerra JA, Spino C, Magee JC, Shneider BL, Rosenthal P, Wang KS, Erlichman J, Haber B, Hertel PM, Karpen SJ, Kerkar N, Loomes KM, Molleston JP, Murray KF, Romero R, Schwarz KB, Shepherd R, Suchy FJ, Turmelle YP, Whitington PF, Moore J, Sherker AH, Robuck PR, Sokol RJ; Childhood Liver Disease Research and Education Network (ChiLDREN). Use of corticosteroids after hepatoportoenterostomy for bile drainage in infants with biliary atresia: the START randomized clinical trial. JAMA. 2014 May 7;311(17):1750-9. doi: 10.1001/jama.2014.2623.
PubMed 24794368Flynn DM, Mohan N, McKiernan P, Beath S, Buckels J, Mayer D, Kelly DA. Progress in treatment and outcome for children with neonatal haemochromatosis. Arch Dis Child Fetal Neonatal Ed. 2003 Mar;88(2):F124-7. doi: 10.1136/fn.88.2.f124.
PubMed 12598501Galicia-Moreno M, Rodriguez-Rivera A, Reyes-Gordillo K, Segovia J, Shibayama M, Tsutsumi V, Vergara P, Moreno MG, Muriel P. N-acetylcysteine prevents carbon tetrachloride-induced liver cirrhosis: role of liver transforming growth factor-beta and oxidative stress. Eur J Gastroenterol Hepatol. 2009 Aug;21(8):908-14. doi: 10.1097/MEG.0b013e32831f1f3a.
PubMed 19398917Galicia-Moreno M, Favari L, Muriel P. Antifibrotic and antioxidant effects of N-acetylcysteine in an experimental cholestatic model. Eur J Gastroenterol Hepatol. 2012 Feb;24(2):179-85. doi: 10.1097/MEG.0b013e32834f3123.
PubMed 22241216Jenkins DD, Wiest DB, Mulvihill DM, Hlavacek AM, Majstoravich SJ, Brown TR, Taylor JJ, Buckley JR, Turner RP, Rollins LG, Bentzley JP, Hope KE, Barbour AB, Lowe DW, Martin RH, Chang EY. Fetal and Neonatal Effects of N-Acetylcysteine When Used for Neuroprotection in Maternal Chorioamnionitis. J Pediatr. 2016 Jan;168:67-76.e6. doi: 10.1016/j.jpeds.2015.09.076. Epub 2015 Nov 3.
PubMed 26545726Jimenez-Rivera C, Jolin-Dahel KS, Fortinsky KJ, Gozdyra P, Benchimol EI. International incidence and outcomes of biliary atresia. J Pediatr Gastroenterol Nutr. 2013 Apr;56(4):344-54. doi: 10.1097/MPG.0b013e318282a913.
PubMed 23263590Kortsalioudaki C, Taylor RM, Cheeseman P, Bansal S, Mieli-Vergani G, Dhawan A. Safety and efficacy of N-acetylcysteine in children with non-acetaminophen-induced acute liver failure. Liver Transpl. 2008 Jan;14(1):25-30. doi: 10.1002/lt.21246.
PubMed 18161828Lynch RM, Robertson R. Anaphylactoid reactions to intravenous N-acetylcysteine: a prospective case controlled study. Accid Emerg Nurs. 2004 Jan;12(1):10-5. doi: 10.1016/j.aaen.2003.07.001.
PubMed 14700565Mager DR, Marcon M, Wales P, Pencharz PB. Use of N-acetyl cysteine for the treatment of parenteral nutrition-induced liver disease in children receiving home parenteral nutrition. J Pediatr Gastroenterol Nutr. 2008 Feb;46(2):220-3. doi: 10.1097/MPG.0b013e3180653ce6. No abstract available.
PubMed 18223385Shneider BL, Magee JC, Karpen SJ, Rand EB, Narkewicz MR, Bass LM, Schwarz K, Whitington PF, Bezerra JA, Kerkar N, Haber B, Rosenthal P, Turmelle YP, Molleston JP, Murray KF, Ng VL, Wang KS, Romero R, Squires RH, Arnon R, Sherker AH, Moore J, Ye W, Sokol RJ; Childhood Liver Disease Research Network (ChiLDReN). Total Serum Bilirubin within 3 Months of Hepatoportoenterostomy Predicts Short-Term Outcomes in Biliary Atresia. J Pediatr. 2016 Mar;170:211-7.e1-2. doi: 10.1016/j.jpeds.2015.11.058. Epub 2015 Dec 24.
PubMed 26725209
Study at a glance
From the registry record, last updated by the sponsor on 26 Mar 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase 2 Trial of N-Acetylcysteine in Biliary Atresia After Kasai Portoenterostomy
- ClinicalTrials.gov ID
- NCT03499249
- Acronym / sponsor ID
- H-40962
- Conditions
- Biliary Atresia
- Keywords
- Biliary Atresia, N-Acetylcysteine, Glutathione, Kasai portoenterostomy, Bile flow, Serum bile acids, Serum bilirubin
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 13 participants (actual)
- Lead sponsor
- Baylor College of MedicineUniversity, hospital or other
- Study start
- 18 May 2018 (actual)
- Primary completion
- 31 Oct 2022 (actual)
- Study completion
- 23 Mar 2024 (actual)
- First posted
- 17 Apr 2018 (actual)
- Results
- Posted 10 Jan 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- This is a Phase 2 clinical trial using the two-stage "minimax" design described by Simon (Simon, 1989). As a Phase 2 trial, the trial's objective is to determine whether NAC has sufficient biological activity as adjunctive therapy for BA to warrant further study. By choosing the two-stage "minimax" design, we gain two advantages: (i) early termination if the drug is not efficacious, and (ii) using historical controls and therefore an overall smaller sample size to test the hypothesis, i.e., no randomization or control arm. This study design only identifies large effects (response >20%). For BA this is appropriate, because the field is in need of a robust therapy that can substantially limit liver damage and delay/prevent need for liver transplantation.
| Arm | Type | Receives |
|---|---|---|
| N-Acetylcysteine Treatment | Experimental | Drug: N-Acetyl cysteineWill 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 |
Who may qualify
- Ages
- 0 to 90 days
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (3 listed)
- Age less than or equal to 90 days at time of KP (standard age range in which KPs are performed)
- BA diagnosis made by intraoperative cholangiography and KP performed at Texas Children's Hospital, Texas Medical Center Campus
- Legal guardian(s) sign consent after understanding risks and investigational nature of study
Key exclusion criteria (5 listed)
- Decompensated liver disease (INR >1.3) despite parenteral Vitamin K administration)
- KP not performed for any reason (i.e., normal intraoperative cholangiography, or liver found to be too diseased intraoperatively to proceed with KP)
- Active respiratory infection
- 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)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| N-Acetyl cysteineIntravenous 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-Acetylcysteine Treatment |
Primary outcome
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
3 secondary outcomes
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)
Number of Patients Experiencing Sentinel Events in the First 2 Years of Life
Time frame: 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
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 26 Mar 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 14657813Ahola T, Lapatto R, Raivio KO, Selander B, Stigson L, Jonsson B, Jonsbo F, Esberg G, Stovring S, Kjartansson S, Stiris T, Lossius K, Virkola K, Fellman V. N-acetylcysteine does not prevent bronchopulmonary dysplasia in immature infants: a randomized controlled trial. J Pediatr. 2003 Dec;143(6):713-9. doi: 10.1067/S0022-3476(03)00419-0.
- Background: PubMed 2912148Ballatori N, Truong AT. Relation between biliary glutathione excretion and bile acid-independent bile flow. Am J Physiol. 1989 Jan;256(1 Pt 1):G22-30. doi: 10.1152/ajpgi.1989.256.1.G22.
- Background: PubMed 1443136Ballatori N, Truong AT. Glutathione as a primary osmotic driving force in hepatic bile formation. Am J Physiol. 1992 Nov;263(5 Pt 1):G617-24. doi: 10.1152/ajpgi.1992.263.5.G617.
- Background: PubMed 2872220Ballatori N, Jacob R, Boyer JL. Intrabiliary glutathione hydrolysis. A source of glutamate in bile. J Biol Chem. 1986 Jun 15;261(17):7860-5.
- Background: PubMed 2564253Ballatori N, Truong AT, Ma AK, Boyer JL. Determinants of glutathione efflux and biliary GSH/GSSG ratio in perfused rat liver. Am J Physiol. 1989 Mar;256(3 Pt 1):G482-90. doi: 10.1152/ajpgi.1989.256.3.G482.
- Background: PubMed 24794368Bezerra JA, Spino C, Magee JC, Shneider BL, Rosenthal P, Wang KS, Erlichman J, Haber B, Hertel PM, Karpen SJ, Kerkar N, Loomes KM, Molleston JP, Murray KF, Romero R, Schwarz KB, Shepherd R, Suchy FJ, Turmelle YP, Whitington PF, Moore J, Sherker AH, Robuck PR, Sokol RJ; Childhood Liver Disease Research and Education Network (ChiLDREN). Use of corticosteroids after hepatoportoenterostomy for bile drainage in infants with biliary atresia: the START randomized clinical trial. JAMA. 2014 May 7;311(17):1750-9. doi: 10.1001/jama.2014.2623.
- Background: PubMed 12598501Flynn DM, Mohan N, McKiernan P, Beath S, Buckels J, Mayer D, Kelly DA. Progress in treatment and outcome for children with neonatal haemochromatosis. Arch Dis Child Fetal Neonatal Ed. 2003 Mar;88(2):F124-7. doi: 10.1136/fn.88.2.f124.
- Background: PubMed 19398917Galicia-Moreno M, Rodriguez-Rivera A, Reyes-Gordillo K, Segovia J, Shibayama M, Tsutsumi V, Vergara P, Moreno MG, Muriel P. N-acetylcysteine prevents carbon tetrachloride-induced liver cirrhosis: role of liver transforming growth factor-beta and oxidative stress. Eur J Gastroenterol Hepatol. 2009 Aug;21(8):908-14. doi: 10.1097/MEG.0b013e32831f1f3a.
- Background: PubMed 22241216Galicia-Moreno M, Favari L, Muriel P. Antifibrotic and antioxidant effects of N-acetylcysteine in an experimental cholestatic model. Eur J Gastroenterol Hepatol. 2012 Feb;24(2):179-85. doi: 10.1097/MEG.0b013e32834f3123.
- Background: PubMed 26545726Jenkins DD, Wiest DB, Mulvihill DM, Hlavacek AM, Majstoravich SJ, Brown TR, Taylor JJ, Buckley JR, Turner RP, Rollins LG, Bentzley JP, Hope KE, Barbour AB, Lowe DW, Martin RH, Chang EY. Fetal and Neonatal Effects of N-Acetylcysteine When Used for Neuroprotection in Maternal Chorioamnionitis. J Pediatr. 2016 Jan;168:67-76.e6. doi: 10.1016/j.jpeds.2015.09.076. Epub 2015 Nov 3.
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- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Sanjiv Harpavat, MD. PhD principal investigator
Baylor College of Medicine
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing N-Acetyl cysteine in people with Biliary Atresia, run by Baylor College of Medicine at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 26 Mar 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 10 Jan 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03499249, which also lists 23 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Mar 2024.