TERMINATED

Evaluation of the Efficacy of Fomepizole in the Treatment of Acetaminophen Overdose

Conditions

Acetaminophen Drug Overdose Acetaminophen Overdose Acetaminophen Poisoning Drug-induced Liver Injury Liver Failure Liver Toxicity

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Study Overview

This clinical trial focuses on testing the efficacy of different digital interventions to promote re-engagement in cancer-related long-term follow-up care for adolescent and young adult (AYA) survivors of childhood cancer.

Description

This study is a randomized, placebo-controlled double-blinded clinical trial of patients presenting with acetaminophen poisoning who are at increased risk of developing liver injury. With this trial the investigators are hoping to show the superiority of acetylcysteine (NAC) + fomepizole (4-MP) compared to treatment with acetylcysteine alone. The primary objective of this trial is to determine the effect of fomepizole on the severity of acute liver injury in patients with acetaminophen poisoning.

Official Title

A Randomized Controlled Study to Evaluate the Efficacy of Fomepizole in the Treatment of Acetaminophen Overdose

Quick Facts

Study Start:2022-09-12

Study Completion:2025-11-08

Study Type:Not specified

Phase:Not Applicable

Enrollment:Not specified

Status:TERMINATED

Study ID

NCT05517668

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.

Ages Eligible for Study:10 Years to 99 Years

Sexes Eligible for Study:ALL

Accepts Healthy Volunteers:No

Standard Ages:CHILD, ADULT, OLDER_ADULT

Inclusion Criteria	Exclusion Criteria
1. Evidence of acute or repeated supratherapeutic ingestion (RSTI)\* of acetaminophen (serum acetaminophen greater or equal to 10 mg/L) after correction for bilirubin, when applicable\\ 2. Baseline AT Multiplication Product at screening (\[APAP\] multiplied by the serum AST or ALT in IU/L, whichever is higher) of 3000 or higher 3. Adults and children ages 10 years or older 4. Infusion of NAC started 8 hours or more post-ingestion 5. Infusion of the study medication begins as early as possible but not later than 24 hours after the initiation of the NAC infusion. 6. Patient presenting to or transferred to the participating site hospital and planned to be admitted to hospital for treatment and/or observation or treatment in Emergency Department 7. Provision of signed and dated informed consent form 8. Stated willingness to comply with mandatory study procedures and availability for the duration of the study	1. Serum ALT greater than 10,000 IU/L or serum AST greater than 20,000 IU/L at time of screening 2. Another overdose episode with acetaminophen within the preceding 14 days 3. Baseline ALT (defined as average of ALTs reported in preceding 12 months) above the ALT reference range for the hospital laboratory unless screening ALT is at least twice the patient's baseline value. 4. Evidence of chronic decompensated liver cirrhosis regardless of serum ALT activity\\\* 5. Known allergic reaction to acetylcysteine or a documented serious hypersensitivity reaction to fomepizole or other pyrazoles. 6. Pregnancy or lactation 7. Co-ingestion of other known activators or inhibitors of CYP2E1 (acetone, cimetidine, nicotine, isoniazid, pyridine, pyrazole, disulfiram). History of cigarette smoking, use of nicotine patches are allowed. 8. Concomitant ingestion of high dosage iron preparations (e.g., prenatal iron sulfate capsules) 9. In the site investigator's judgment, the patient has a condition that would interfere with evaluation of the efficacy of fomepizole. These conditions include, but are not limited to the following conditions: * Seizure in the previous 24 hours. History of seizure disorder under chronic treatment is allowed * Cardiac arrest in the preceding 14 days * Cardiac dysrhythmia that compromises cardiovascular function at screening * History of liver transplant * Shock liver 10. Treatment with another investigational drug within the preceding 30 days. 11. Previous participation in this study * Acute ingestion is defined as more than 4 grams ingested over 24-hour period. RSTI defined as more than 4 grams ingested/24 hour period for more than 24 hours. Note: the type of ingestion (acute vs. RSTI) or its timing relative to time of hospital admission do not affect neither study eligibility nor research subject management. * Bilirubinemia (high bilirubin in blood) may cause falsely elevated APAP levels when tested with spectrophotometric assay (SPA). In order to rule out this false elevation we recommend validating APAP level via liquid chromatography (LC) or mass spectrometry (MS) testing methods after we enroll a patient with APAP test results between 10 and 30 mg/L and total bilirubin ≥ 10 mg/dL. * Decompensated cirrhosis refers to a stage of liver cirrhosis where the liver is no longer able to function properly due to extensive damage, scarring, and fibrosis. Patients with decompensated cirrhosis may have symptoms such as jaundice (yellowing of the skin and eyes), ascites (abdominal swelling), gastrointestinal bleeding, spider angiomas (red, spider-like lesions on the skin), hepatic encephalopathy (confusion and cognitive impairment), or hepatorenal syndrome (kidney dysfunction). Decompensated cirrhosis is a more advanced and serious stage of liver disease, and patients may require hospitalization and more aggressive medical interventions, including liver transplantation.

Inclusion Criteria

Exclusion Criteria

1. Evidence of acute or repeated supratherapeutic ingestion (RSTI)\* of acetaminophen (serum acetaminophen greater or equal to 10 mg/L) after correction for bilirubin, when applicable\*\*
2. Baseline AT Multiplication Product at screening (\[APAP\] multiplied by the serum AST or ALT in IU/L, whichever is higher) of 3000 or higher
3. Adults and children ages 10 years or older
4. Infusion of NAC started 8 hours or more post-ingestion
5. Infusion of the study medication begins as early as possible but not later than 24 hours after the initiation of the NAC infusion.
6. Patient presenting to or transferred to the participating site hospital and planned to be admitted to hospital for treatment and/or observation or treatment in Emergency Department
7. Provision of signed and dated informed consent form
8. Stated willingness to comply with mandatory study procedures and availability for the duration of the study

1. Serum ALT greater than 10,000 IU/L or serum AST greater than 20,000 IU/L at time of screening
2. Another overdose episode with acetaminophen within the preceding 14 days
3. Baseline ALT (defined as average of ALTs reported in preceding 12 months) above the ALT reference range for the hospital laboratory unless screening ALT is at least twice the patient's baseline value.
4. Evidence of chronic decompensated liver cirrhosis regardless of serum ALT activity\*\*\*
5. Known allergic reaction to acetylcysteine or a documented serious hypersensitivity reaction to fomepizole or other pyrazoles.
6. Pregnancy or lactation
7. Co-ingestion of other known activators or inhibitors of CYP2E1 (acetone, cimetidine, nicotine, isoniazid, pyridine, pyrazole, disulfiram). History of cigarette smoking, use of nicotine patches are allowed.
8. Concomitant ingestion of high dosage iron preparations (e.g., prenatal iron sulfate capsules)
9. In the site investigator's judgment, the patient has a condition that would interfere with evaluation of the efficacy of fomepizole. These conditions include, but are not limited to the following conditions:
* Seizure in the previous 24 hours. History of seizure disorder under chronic treatment is allowed
* Cardiac arrest in the preceding 14 days
* Cardiac dysrhythmia that compromises cardiovascular function at screening
* History of liver transplant
* Shock liver
10. Treatment with another investigational drug within the preceding 30 days.
11. Previous participation in this study
* Acute ingestion is defined as more than 4 grams ingested over 24-hour period. RSTI defined as more than 4 grams ingested/24 hour period for more than 24 hours. Note: the type of ingestion (acute vs. RSTI) or its timing relative to time of hospital admission do not affect neither study eligibility nor research subject management.
* Bilirubinemia (high bilirubin in blood) may cause falsely elevated APAP levels when tested with spectrophotometric assay (SPA). In order to rule out this false elevation we recommend validating APAP level via liquid chromatography (LC) or mass spectrometry (MS) testing methods after we enroll a patient with APAP test results between 10 and 30 mg/L and total bilirubin ≥ 10 mg/dL.
* Decompensated cirrhosis refers to a stage of liver cirrhosis where the liver is no longer able to function properly due to extensive damage, scarring, and fibrosis. Patients with decompensated cirrhosis may have symptoms such as jaundice (yellowing of the skin and eyes), ascites (abdominal swelling), gastrointestinal bleeding, spider angiomas (red, spider-like lesions on the skin), hepatic encephalopathy (confusion and cognitive impairment), or hepatorenal syndrome (kidney dysfunction). Decompensated cirrhosis is a more advanced and serious stage of liver disease, and patients may require hospitalization and more aggressive medical interventions, including liver transplantation.

Contacts and Locations

Principal Investigator

Richard Dart, MD, PhD

PRINCIPAL_INVESTIGATOR

Rocky Mountain Poison and Drug Safety, division of Denver Health and Hospital Authority

Study Locations (Sites)

Denver Health and Hospital Authority

Denver, Colorado, 80204

United States

Collaborators and Investigators

Sponsor: Richard Dart, MD, PhD

Richard Dart, MD, PhD, PRINCIPAL_INVESTIGATOR, Rocky Mountain Poison and Drug Safety, division of Denver Health and Hospital Authority

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 Registration Dates

Study Start Date2022-09-12

Study Completion Date2025-11-08

Study Record Updates

Study Start Date2022-09-12

Study Completion Date2025-11-08

Terms related to this study

Additional Relevant MeSH Terms

Acetaminophen
Drug Overdose
Acetaminophen Overdose
Acetaminophen Poisoning
Drug-induced Liver Injury
Liver Failure
Liver Toxicity