Acute Liver Failure, Hepatic Encephalopathy
Conditions
Keywords
acute liver failure, hepatic encephalopathy, acetaminophen toxicity, N-acetylcysteine
Brief summary
We have completed patient enrollment in the the double blind, randomized, placebo-controlled trial of intravenous (IV) N-acetylcysteine (NAC) vs. placebo for the treatment of non-acetaminophen ALF. The purpose of this study is to examine the safety and efficacy of intravenous NAC in children with ALF for whom no antidote or other specific treatment is available. Inclusion in the NAC Study required enrollment in the Pediatric Acute Liver Failure (PALF) Study Registry.
Detailed description
The Pediatric Acute Liver Failure (PALF) Study Group to identify, characterize, and develop management strategies for infants, children and adolescents who present with acute liver failure. The PALF study group includes 20 sites (17 in the United States, 2 in the United Kingdom, and 1 in Canada). The primary objective of the Pediatric Acute Liver Failure (PALF) study is to collect, maintain, analyze, and report clinical, epidemiological, and outcome data in children with ALF, including information derived from biospecimens. Patients enrolled in the PALF study registry were able to enroll in the NAC study providing they met the additional required inclusion/exclusion criteria.
Interventions
DRUGN-acetylcysteine
The study drug is administered as a continuous infusion at a dose of 150 mg/kg/day for up to 7 days following entry into the study. The infusion is discontinued at the time of death, liver transplant or discharge.
DRUGPlacebo
Eligible children were adaptively allocated within strata defined by age (less than 2 years of age or at least 2 years old) and hepatic encephalopathy (grade 0-1 or 2-4) to receive N-acetylcysteine (150 mg/kg/d) in 5% dextrose (D5W) and water or placebo consisting of an equal volume of D5W alone. Volumes were adjusted for small children. Study medications were infused over 24 hours for up to 7 consecutive days in a dedicated line without other medications. Treatment was stopped earlier than 7 days in the case of hospital discharge, liver transplantation, or death within 7 days of randomization.
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
University of Pittsburgh
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
No minimum to 18 Years
Healthy volunteers
No
Inclusion criteria
* Meet entry criteria for and be enrolled in the Pediatric Acute Liver Failure prospective database. * Able to be evaluated and initiate treatment within the first 24 hours of hospitalization * Patients transferred from referring hospitals to the study site may be considered for enrollment, provided that no other treatment protocol has begun, and that no liver support device (BAL, extracorporeal liver assist device, transgenic pig perfusion) has been used or is contemplated. * Use of fresh frozen plasma infusions will not disqualify patients from participation.
Exclusion criteria
* older than 18 years of age * pregnancy * ALF that is secondary to acute acetaminophen toxicity, mushroom poisoning, or a known malignancy. * Patients who exhibit signs of cerebral herniation, have intractable arterial hypotension, require inotropic drugs, or demonstrate signs of sepsis (temperature ≥ 39.5o C or bacteremia) at the time of enrollment * No exclusion will be made on the basis of race, ethnic group or gender. * Criteria for inclusion of females and minorities will be those established in the NIH guidelines
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Survival | One year following randomization | Spontaneous survival without transplant plus survival following transplantation |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cumulative Percent Incidence of Transplantation by 1 Year | Within 1 year of randomization | — |
| Length of Hospital Stay | Randomization to hospital discharge | — |
| Categorized Length of ICU Stay | Within 7 days of randomization | The length of ICU stay was categorized as number of days in ICU within 7 days of randomization, unless participant either died or received an LTx within this time period. Special categories were created for these cases. |
| Spontaneous Recovery | One year following randomization | Survival without liver transplantation |
| Highest Coma Grade of Hepatic Encephalopathy | Within 7 days of randomization | West Haven Criteria for hepatic encephalopathy (Grade 0 - IV ) is used for participants \> 3 year of age. Coma grade IV indicates a participant who is comatose , with no reflexes, is decerebrate and has abnormal EEG changes with very slow delta activity. For participants less than 3 years the Whittington Scale was used. The Whittington scale does not use EEG changes and has only 3 levels, early (grades I and II), Mid (III) with somnolence, stupor, combativeness and Late (IV) for participants who are comatose with absent reflexes and decerebrate or decorticate posturing. |
| Infectious Complication | Within 7 days of randomization | — |
| Number of Organ Systems Failing | Within 7 days of randomization | — |
Countries
Canada, United Kingdom, United States
Participant flow
Recruitment details
Participants were from an established registry of children with acute liver failure. Entry criteria: children \<18 years, absence of a known chronic liver disease, biochemical evidence of acute liver injury, and a liver-based coagulopathy. Evidence of hepatic encephalopathy was required if the prothrombin time (PT) was between 15-19.9 seconds
Participants by arm
| Arm | Count |
|---|---|
| N-acetylcysteine (NAC) Eligible children were adaptively allocated by age (less than 2 years of age or at least 2 years old) and HE (grade 0-1 or 2-4) to receive NAC (150 mg/kg/d) in 5% dextrose (D5W) infused over 24 hours for up to 7 consecutive days N-acetylcysteine: The study drug is administered as a continuous infusion at a dose of 150 mg/kg/day for up to 7 days following entry into the study. | 92 |
| Placebo Eligible children were adaptively allocated within strata defined by age (less than 2 years of age or at least 2 years old) and HE (grade 0-1 or 2-4) to receive 5% dextrose (D5W) infused over 24 hours for up to 7 consecutive
Dextrose in water: placebo consisting of an equal volume of D5W alone for up to 7 days following entry into the study | 92 |
| Total | 184 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | N-acetylcysteine (NAC) | Total | Placebo |
|---|---|---|---|
| Age, Categorical <=18 years | 92 Participants | 184 Participants | 92 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 3.7 years | 4.1 years | 4.5 years |
| Coma Grade of Hepatic Encephalopathy 0-1 | 65 participants | 133 participants | 68 participants |
| Coma Grade of Hepatic Encephalopathy 2-4 | 27 participants | 51 participants | 24 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 8 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 15 Participants | 30 Participants | 15 Participants |
| Race (NIH/OMB) More than one race | 3 Participants | 7 Participants | 4 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 5 Participants | 2 Participants |
| Race (NIH/OMB) White | 68 Participants | 133 Participants | 65 Participants |
| Region of Enrollment Canada | 2 participants | 5 participants | 3 participants |
| Region of Enrollment United Kingdom | 29 participants | 50 participants | 21 participants |
| Region of Enrollment United States | 61 participants | 129 participants | 68 participants |
| Sex: Female, Male Female | 45 Participants | 83 Participants | 38 Participants |
| Sex: Female, Male Male | 47 Participants | 101 Participants | 54 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 19 / 92 | 16 / 92 |
| serious Total, serious adverse events | 5 / 92 | 4 / 92 |
Outcome results
Primary
Survival
Spontaneous survival without transplant plus survival following transplantation
Time frame: One year following randomization
Population: All participants who were enrolled in the study were included in the survival analysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| N-acetylcysteine (NAC) | Survival | 68 Participants |
| Placebo | Survival | 76 Participants |
p-value: 0.19Log Rank
Secondary
Categorized Length of ICU Stay
The length of ICU stay was categorized as number of days in ICU within 7 days of randomization, unless participant either died or received an LTx within this time period. Special categories were created for these cases.
Time frame: Within 7 days of randomization
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| N-acetylcysteine (NAC) | Categorized Length of ICU Stay | 3 days | 2 participants |
| N-acetylcysteine (NAC) | Categorized Length of ICU Stay | 2 days | 3 participants |
| N-acetylcysteine (NAC) | Categorized Length of ICU Stay | 0 days | 29 participants |
| N-acetylcysteine (NAC) | Categorized Length of ICU Stay | 1 day | 3 participants |
| N-acetylcysteine (NAC) | Categorized Length of ICU Stay | 4 days | 1 participants |
| N-acetylcysteine (NAC) | Categorized Length of ICU Stay | 5 days | 4 participants |
| N-acetylcysteine (NAC) | Categorized Length of ICU Stay | 6 days | 5 participants |
| N-acetylcysteine (NAC) | Categorized Length of ICU Stay | 7 days | 9 participants |
| N-acetylcysteine (NAC) | Categorized Length of ICU Stay | underwent LTx w/i 7 days of randomization | 28 participants |
| N-acetylcysteine (NAC) | Categorized Length of ICU Stay | died w/o LTx w/i 7 days of randomization | 8 participants |
| Placebo | Categorized Length of ICU Stay | 7 days | 14 participants |
| Placebo | Categorized Length of ICU Stay | 1 day | 4 participants |
| Placebo | Categorized Length of ICU Stay | 5 days | 3 participants |
| Placebo | Categorized Length of ICU Stay | 2 days | 4 participants |
| Placebo | Categorized Length of ICU Stay | died w/o LTx w/i 7 days of randomization | 5 participants |
| Placebo | Categorized Length of ICU Stay | 0 days | 34 participants |
| Placebo | Categorized Length of ICU Stay | 6 days | 3 participants |
| Placebo | Categorized Length of ICU Stay | 3 days | 0 participants |
| Placebo | Categorized Length of ICU Stay | underwent LTx w/i 7 days of randomization | 22 participants |
| Placebo | Categorized Length of ICU Stay | 4 days | 3 participants |
p-value: 0.29Cochran-Armitage trend
Secondary
Cumulative Percent Incidence of Transplantation by 1 Year
Time frame: Within 1 year of randomization
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| N-acetylcysteine (NAC) | Cumulative Percent Incidence of Transplantation by 1 Year | 45 percentage of participants |
| Placebo | Cumulative Percent Incidence of Transplantation by 1 Year | 35 percentage of participants |
p-value: 0.21Pepe and Mori test of CIF difference
Secondary
Highest Coma Grade of Hepatic Encephalopathy
West Haven Criteria for hepatic encephalopathy (Grade 0 - IV ) is used for participants \> 3 year of age. Coma grade IV indicates a participant who is comatose , with no reflexes, is decerebrate and has abnormal EEG changes with very slow delta activity. For participants less than 3 years the Whittington Scale was used. The Whittington scale does not use EEG changes and has only 3 levels, early (grades I and II), Mid (III) with somnolence, stupor, combativeness and Late (IV) for participants who are comatose with absent reflexes and decerebrate or decorticate posturing.
Time frame: Within 7 days of randomization
Population: All enrolled participants where coma grade could be assessed. Four participants (two in each randomization arm) could not have coma grade assessed during the 7 days after randomization.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| N-acetylcysteine (NAC) | Highest Coma Grade of Hepatic Encephalopathy | I | 16 participants |
| N-acetylcysteine (NAC) | Highest Coma Grade of Hepatic Encephalopathy | III | 15 participants |
| N-acetylcysteine (NAC) | Highest Coma Grade of Hepatic Encephalopathy | II | 20 participants |
| N-acetylcysteine (NAC) | Highest Coma Grade of Hepatic Encephalopathy | IV | 11 participants |
| N-acetylcysteine (NAC) | Highest Coma Grade of Hepatic Encephalopathy | 0 | 28 participants |
| Placebo | Highest Coma Grade of Hepatic Encephalopathy | IV | 6 participants |
| Placebo | Highest Coma Grade of Hepatic Encephalopathy | 0 | 27 participants |
| Placebo | Highest Coma Grade of Hepatic Encephalopathy | I | 21 participants |
| Placebo | Highest Coma Grade of Hepatic Encephalopathy | II | 19 participants |
| Placebo | Highest Coma Grade of Hepatic Encephalopathy | III | 17 participants |
p-value: 0.54Cochran-Armitage tren
Secondary
Infectious Complication
Time frame: Within 7 days of randomization
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| N-acetylcysteine (NAC) | Infectious Complication | 20 Participants |
| Placebo | Infectious Complication | 21 Participants |
p-value: 0.86Chi-squared
Secondary
Length of Hospital Stay
Time frame: Randomization to hospital discharge
Population: All participants enrolled in study with hospital stay information, 2 participants (1 in each arm) did not have hospital discharge information.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| N-acetylcysteine (NAC) | Length of Hospital Stay | 103 days |
| Placebo | Length of Hospital Stay | 21 days |
p-value: 0.053Kruskal-Wallis
Secondary
Number of Organ Systems Failing
Time frame: Within 7 days of randomization
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| N-acetylcysteine (NAC) | Number of Organ Systems Failing | 1 | 21 participants |
| N-acetylcysteine (NAC) | Number of Organ Systems Failing | 3 | 11 participants |
| N-acetylcysteine (NAC) | Number of Organ Systems Failing | 2 | 15 participants |
| N-acetylcysteine (NAC) | Number of Organ Systems Failing | 4 | 1 participants |
| N-acetylcysteine (NAC) | Number of Organ Systems Failing | 0 | 44 participants |
| Placebo | Number of Organ Systems Failing | 4 | 3 participants |
| Placebo | Number of Organ Systems Failing | 0 | 46 participants |
| Placebo | Number of Organ Systems Failing | 1 | 23 participants |
| Placebo | Number of Organ Systems Failing | 2 | 12 participants |
| Placebo | Number of Organ Systems Failing | 3 | 8 participants |
p-value: 0.74Cochran-Armitage trend
Secondary
Spontaneous Recovery
Survival without liver transplantation
Time frame: One year following randomization
Population: All participants enrolled in study
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| N-acetylcysteine (NAC) | Spontaneous Recovery | 33 participants |
| Placebo | Spontaneous Recovery | 49 participants |
p-value: 0.03Log Rank