A Phase 2 interventional study of N-Acetyl cysteine in Biliary Atresia, sponsored by Baylor College of Medicine. Completed at 1 site in United States. Open to participants aged 0 Days to 90 Days. Per ClinicalTrials.gov, last updated 2024-03-26.
Sponsored by Baylor College of Medicine · Phase 2, Interventional, and Treatment
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.
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.
77 studies on the registry are indexed under Biliary Atresia; 25 are open to participants now.
This study's enrollment of 13 is below the median of 45 across 43 interventional studies indexed under Biliary Atresia.
Browse Biliary Atresia studies →Baylor College of Medicine is the lead sponsor of 747 studies on the registry; 110 are open to participants now.
Of its 84 completed or terminated interventional studies of FDA-regulated products, 45 (54%) have results posted.
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Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
A drug or device being studied in a clinical trial.
It may be new, or already approved and being studied for another use, dose or form. Criteria often leave out people who took part in another study of one within a recent period, commonly 30 days or five half-lives.
Blood tests of how long blood takes to clot. The INR is the prothrombin time (PT) put on a common scale; about 1 is usual for someone not taking a blood thinner.
Criteria often make an exception for people on a blood thinner such as warfarin, whose INR is raised on purpose.
GFR (glomerular filtration rate) is how much blood the kidneys filter each minute. It is usually estimated from a blood test — eGFR, by formulas such as CKD-EPI or MDRD — and some studies ask for it to be measured directly instead. Usually given in mL/min/1.73 m².
Check the method, the units and the minimum the study states. A value of 90 or above is in the normal-or-high range, but kidney damage can show in other tests too.
How quickly the kidneys clear creatinine, a waste product, from the blood. A study may estimate it from a blood test with age, weight and sex (often by the Cockcroft–Gault formula), or measure it using blood and urine collected over a set time. Given in mL/min; higher is better.
Investigational drug or device
A drug or device being studied in a clinical trial.
It may be new, or already approved and being studied for another use, dose or form. Criteria often leave out people who took part in another study of one within a recent period, commonly 30 days or five half-lives.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
INR, PT and aPTT (clotting tests)
Blood tests of how long blood takes to clot. The INR is the prothrombin time (PT) put on a common scale; about 1 is usual for someone not taking a blood thinner.
Criteria often make an exception for people on a blood thinner such as warfarin, whose INR is raised on purpose.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
GFR and eGFR (kidney filtering)
GFR (glomerular filtration rate) is how much blood the kidneys filter each minute. It is usually estimated from a blood test — eGFR, by formulas such as CKD-EPI or MDRD — and some studies ask for it to be measured directly instead. Usually given in mL/min/1.73 m².
Check the method, the units and the minimum the study states. A value of 90 or above is in the normal-or-high range, but kidney damage can show in other tests too.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Creatinine clearance (CrCl)
How quickly the kidneys clear creatinine, a waste product, from the blood. A study may estimate it from a blood test with age, weight and sex (often by the Cockcroft–Gault formula), or measure it using blood and urine collected over a set time. Given in mL/min; higher is better.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
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
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
Time frame: Within 24 weeks after KP
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.
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
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.
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
Units are number of patients, higher number is worse outcome
Time frame: Within four weeks after KP
| Milestone | N-Acetylcysteine Treatment |
|---|---|
| Started | 13 |
| Completed | 12 |
| Not completed | 1 |
| Withdrew: Physician decision | 1 |
Expected is \~5% of participants based on historical controls (see protocol for summary of historical controls); a higher number is a better outcome
| Participants | N-Acetylcysteine Treatment |
|---|---|
| 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) | 0 |
fold-change from baseline (ratio); a fold-change \<1 is a better outcome.
| fold change over baseline | N-Acetylcysteine Treatment |
|---|---|
| AST 3 days after KP | 1.5 ± 0.5 |
| AST 7 days after KP | 1.4 ± 0.4 |
| ALT 3 days after KP | 3.3 ± 2.3 |
| ALT 7 days after KP | 2.1 ± 0.5 |
| GGT 3 days after KP | 0.9 ± 0.3 |
| GGT 7 days after KP | 1.7 ± 0.9 |
| Bc 3 days after KP | 1.3 ± 0.4 |
| Bc 7 days after KP | 1.3 ± 0.4 |
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.
| Participants | N-Acetylcysteine Treatment |
|---|---|
| NG feeds or TPN initiation | 4 |
| Splenomegaly | 7 |
| Thrombocytopenia | 5 |
| Ascites | 4 |
| GI bleed | 0 |
| Portal hypertension | 5 |
| Liver transplant or death | 4 |
Units are number of patients, higher number is worse outcome
| Participants | N-Acetylcysteine Treatment |
|---|---|
| Tachycardia | 1 |
| Other | 0 |
Collected over Within 28 days of KP (7 days of treatment and 21 days afterwards) for Serious adverse events, and Non-serious adverse events. Outcome measure. In first 2 years of life for All-Cause Mortality (this was also outcome measure #3).. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| N-Acetylcysteine Treatment | 0/13 (0%) | 5/13 (38.5%) | 11/13 (84.6%) |
| Event | N-Acetylcysteine Treatment |
|---|---|
| Febrile illnessInfections and infestations | 2/13 |
| ALT 700 IU/L >pre-KP valueHepatobiliary disorders | 1/13 |
| INR >2.0Blood and lymphatic system disorders | 1/13 |
| TachycardiaCardiac disorders | 1/13 |
| Event | N-Acetylcysteine Treatment |
|---|---|
| GGT 400 IU/L >pre-KP valueHepatobiliary disorders | 8/13 |
| AST 400 IU/L >pre-KP valueHepatobiliary disorders | 6/13 |
| Loss of an IVInvestigations | 4/13 |
| Emesis with feedsGastrointestinal disorders | 3/13 |
| Conjugated bilirubin 3 mg/dL >pre-KP valueHepatobiliary disorders | 2/13 |
| Febrile illnessInfections and infestations | 1/13 |
| Total bilirubin 5 mg/dL >pre-KP valueHepatobiliary disorders | 1/13 |
| Age, Categorical(Participants) | N-Acetylcysteine Treatment |
|---|---|
| <=18 years | 13 |
| Between 18 and 65 years | 0 |
| >=65 years | 0 |
| Age, Continuous(days) | N-Acetylcysteine Treatment |
|---|---|
| Mean | 36 ± 22 |
| Sex: Female, Male(Participants) | N-Acetylcysteine Treatment |
|---|---|
| Female | 5 |
| Male | 8 |
| Race/Ethnicity, Customized(participants) | N-Acetylcysteine Treatment |
|---|---|
| Hispanic, all races | 7 |
| Non-Hispanic Asian | 1 |
| Non-Hispanic Black | 3 |
| non-Hispanic White | 2 |
| Region of Enrollment(participants) | N-Acetylcysteine Treatment |
|---|---|
| United States | 13 |
| Aspartate aminotransferase (AST), Alanine Aminotransferase (ALT), Gamma-glutamyltransferase (GGT)(IU/L) | N-Acetylcysteine Treatment |
|---|---|
| AST | 123 ± 83 |
| ALT | 80 ± 56 |
| GGT | 360 ± 322 |
PDFs hosted by the registry, ClinicalTrials.gov.
Plan to share: No
Ran from May 2018 to primary completion in Oct 2022, 53 months.
Results were first posted in Jan 2024, 1 year 2 months after primary completion.
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Studies of the drug tested here: Acetylcysteine