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

NCT05517668 | Terminated Phase 2 DMC FDA Drug

• 2 other identifiers: 21-4745160034
• Study Type: interventional
• Target: 29
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

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

Outcome Measures

Primary Outcomes (1)

• Difference in serum alanine transaminase (ALT) from presentation to peak recorded ALT

  Determine the effect of fomepizole on the severity of acute liver injury in patients with acetaminophen ingestion. Serum ALT is a recognized measure of liver injury. A smaller increase in ALT indicates the efficacy of the study drug.

  ALT will be measured at baseline, then at 12, 20, 32, 44, etc. hours after starting NAC (and every 12 hours afterwards) as long as patient is receiving medication (either NAC or NAC and 4-MP), two to three days on average.

Secondary Outcomes (7)

• Time to meet endpoints for termination of acetylcysteine infusion

  Study participants will be evaluated for study medication discontinuation at 12, 20, 32, 44, etc. hours after starting NAC (every 12 hours afterwards) as long as patient is receiving medication (either NAC or NAC and 4-MP), two to three days on average.

• Peak INR

  INR will be measured at baseline, then at 12, 20, 32, 44, etc. hours after starting NAC (and every 12 hours afterwards) as long as patient is receiving medication (either NAC or NAC and 4-MP), two to three days on average.

• Peak aspartate aminotransferase (AST)

  AST will be measured at baseline then at 12, 20, 32, 44, etc. hours after starting NAC (and every 12 hours afterwards) as long as patient is receiving medication (either NAC or NAC and 4-MP), two to three days on average.

• Peak creatinine

  Creatinine will be measured at baseline then at 12, 20, 32, 44, etc. hours after starting NAC (and every 12 hours afterwards) as long as patient is receiving medication (either NAC or NAC and 4-MP), two to three days on average.

• Measurement of protein adducts

  Protein adducts will be measured at 2, 5, 12, 20, 32, 44, etc. hours after starting NAC (and every 12 hours afterwards) as long as patient is receiving medication (either NAC or NAC and 4-MP), two to three days on average.

Other Outcomes (1)

• Measurement to perform a candidate gene analysis of CYP2E1, glutathione synthetase, UDP-glucuronosyltransferases, JNK related to APAP toxicity.

  Pharmacogenomics will be measured at 5 hours after study subject starts receiving NAC.

Study Arms (2)

N-acetylcysteine (NAC) only (Control)

ACTIVE COMPARATOR

Patients randomized to Control group will receive placebo (D5W) in addition to N-acetylcysteine. Study participants will receive study drug (fomepizole or placebo) throughout the study.

Drug: Intravenous infusion of N-acetylcysteine

N-acetylcysteine (NAC) and Fomepizole (4-MP) (Study)

EXPERIMENTAL

Patients randomized to Study group will receive fomepizole (diluted in D5W) in addition to N-acetylcysteine. Study participants will receive study drug (fomepizole or placebo) throughout the study. If randomized to Study group, the infusion of the study medication should be initiated as soon as feasible but no later than 24 hours after the commencement of acetylcysteine therapy.

Drug: Intravenous infusion of N-acetylcysteine; Drug: Intravenous infusion of Fomepizole (4-MP)

Interventions

Intravenous infusion of N-acetylcysteine DRUG

If randomized to Control, the participant will receive only N-acetylcysteine. The dose will be determined by the site investigator. Typical continued infusion rate is 6.25 mg/kg/hr. The control drug (D5W) will be administered using the same schedule as fomepizole.

N-acetylcysteine (NAC) and Fomepizole (4-MP) (Study); N-acetylcysteine (NAC) only (Control)

Intravenous infusion of Fomepizole (4-MP) DRUG

If randomized to fomepizole, the proposed infusion schedule for fomepizole closely mirrors the dosing outlined in the medication's package insert. Specifically, the Antizol (fomepizole) doses (bags) #1-5 allocated for the study will precisely adhere to the manufacturer's recommendations from the package insert. This entails an initial loading dose of 15 mg/kg followed by four subsequent doses of 10 mg/kg. The dose of fomepizole will not be adjusted based on age, presence of liver injury or renal insufficiency.

N-acetylcysteine (NAC) and Fomepizole (4-MP) (Study)

Eligibility Criteria

• Age: 10 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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\*\*
• Baseline AT Multiplication Product at screening (\[APAP\] multiplied by the serum AST or ALT in IU/L, whichever is higher) of 3000 or higher
• Adults and children ages 10 years or older
• Infusion of NAC started 8 hours or more post-ingestion
• Infusion of the study medication begins as early as possible but not later than 24 hours after the initiation of the NAC infusion.
• 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
• Provision of signed and dated informed consent form
• Stated willingness to comply with mandatory study procedures and availability for the duration of the study

You may not qualify if:

• Serum ALT greater than 10,000 IU/L or serum AST greater than 20,000 IU/L at time of screening
• Another overdose episode with acetaminophen within the preceding 14 days
• 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.
• Evidence of chronic decompensated liver cirrhosis regardless of serum ALT activity\*\*\*
• Known allergic reaction to acetylcysteine or a documented serious hypersensitivity reaction to fomepizole or other pyrazoles.
• Pregnancy or lactation
• 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.
• Concomitant ingestion of high dosage iron preparations (e.g., prenatal iron sulfate capsules)
• 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
• Treatment with another investigational drug within the preceding 30 days.

Sponsors & Collaborators

• Richard Dart, MD, PhD: lead
• Johnson & Johnson Consumer Inc., McNeil Consumer Healthcare Division: collaborator

Study Sites (1)

Denver Health and Hospital Authority

Denver, Colorado, 80204, United States

Location

MeSH Terms

Conditions

Drug Overdose; Chemical and Drug Induced Liver Injury; Liver Failure

Interventions

4-methylpiperazine-2,6-dione

Condition Hierarchy (Ancestors)

Prescription Drug Misuse; Drug Misuse; Substance-Related Disorders; Chemically-Induced Disorders; Mental Disorders; Liver Diseases; Digestive System Diseases; Drug-Related Side Effects and Adverse Reactions; Poisoning; Hepatic Insufficiency

Study Officials

• Richard Dart, MD, PhD

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

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, CARE PROVIDER
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Director RMPDS

Study Record Dates

• First Submitted: August 10, 2022
• First Posted: August 26, 2022
• Study Start: September 12, 2022
• Primary Completion: October 31, 2025
• Study Completion: November 8, 2025
• Last Updated: November 25, 2025

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)