Safety and Efficacy Study of a New Formulation of Acetylcysteine Injection

A Multi-center, Double-blind, Randomized, Controlled Study to Determine the Efficacy and Safety of a New Formulation of Acetylcysteine Injection

The primary purpose of this study is determine if a new formulation of Acetadote is at least as effective as the current formulation in the prevention and treatment of acetaminophen overdose related liver injury.

Study Overview

• Status: Terminated
• Conditions: Acetaminophen Overdose
• Intervention / Treatment: Drug: Acetadote EF (Ethylenediaminetetraacetic Acid (EDTA) - Free); Drug: Acetadote

Detailed Description

The primary objective of this study is to demonstrate non-inferiority of efficacy determined by the proportion of subjects who develop hepatotoxicity when treated with a new formulation of Acetadote and the proposed new dosing regimen compared to the rate of hepatotoxicity with the current formulation of Acetadote and the current dosing regimen.

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85008
      • Maricopa Medical Center
  • California
    • Loma Linda, California, United States, 92350
      • Loma Linda University Medical Center
    • Orange, California, United States, 92868
      • University of California Irvine Medical Center
    • San Diego, California, United States, 92103
      • UCSD Medical Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Hospital
    • Denver, Colorado, United States, 80204
      • Denver Health and Hospital Authority
  • Connecticut
    • Hartford, Connecticut, United States, 06102
      • Hartford Hospital
  • Louisiana
    • Shreveport, Louisiana, United States, 71130
      • LSU Health Sciences Center - Shreveport
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
    • Worcester, Massachusetts, United States, 01655
      • UMass Memorial Medical Center
  • Michigan
    • Grand Rapids, Michigan, United States, 44506
      • Spectrum Health Butterworth Hospital
  • North Carolina
    • Greenville, North Carolina, United States, 27834
      • East Carolina University Medical Center
  • Ohio
    • Toledo, Ohio, United States, 43606
      • Toledo Hospital
  • Texas
    • Temple, Texas, United States, 76508
      • Scott & White Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1) Any subject requiring treatment with acetylcysteine for acute acetaminophen toxicity

Exclusion Criteria:

1. History of allergy or hypersensitivity to acetylcysteine or any component of Acetadote.
2. Exposed to investigational drugs within 30 days before Clinical Trial Material (CTM) administration.
3. Pregnant or nursing.
4. Less than 12 years of age.
5. Have a baseline alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >1000 U/L.
6. Have a baseline International Normalized. Ratio (INR) > 2.0
7. Be on dialysis or having existing renal injury such that the volume of the study drug administration would render the patient unsuitable for the study, in the opinion of the investigator.
8. Have congestive heart failure such that the volume of the study drug administration would render the patient unsuitable for the study, in the opinion of the investigator.
9. Inability to understand the requirements of the study. Subjects must be willing to provide written informed consent or consent of parent/legal guardian (as evidenced by signature on an informed consent document approved by an Institutional Review Board [IRB]), and agree to abide by the study restrictions. (If the subject is incapacitated, informed consent will be sought from a legally acceptable representative).
10. Refusal to provide written authorization for use and disclosure of protected health information.
11. Be otherwise unsuitable for the study, in the opinion of the Investigator.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Acetadote without EDTA; Acetadote EF [Ethylenediaminetetraacetic Acid (EDTA) - Free]	Drug: Acetadote EF (Ethylenediaminetetraacetic Acid (EDTA) - Free); Acetadote EF (Ethylenediaminetetraacetic Acid (EDTA) - Free) {new formulation} 200 mg/kg in 1000 ml diluent over 4 hours; then 100 mg/kg in 1000 ml diluent over 16 hours; Other Names: acetylcysteine
Active Comparator: Acetadote; Acetadote [Old formulation containing EDTA]	Drug: Acetadote; Acetadote [old formulation] 150 mg/kg in 200 mL diluent over 60 minutes; then Acetadote 50 mg/kg in 500 mL diluent over 4 hours; then Acetadote 100 mg/kg in 1000 mL diluent over 16 hours.; Other Names: acetylcysteine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Incidence of Hepatoxicity as Measured by the Percentage of Subjects With an Alanine Transaminase (ALT) or Aspartate Transaminase (AST) Value > 1000 U/L Versus Those With an ALT and AST < 1000 U/L	Because the study was terminated prematurely due to lack of enrollment, there was an insufficient sample size to conduct an efficacy analysis.	21 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To Evaluate the Percentage of Subjects Requiring Continued Therapy	Because the study was terminated prematurely due to lack of enrollment, there was an insufficient sample size to conduct an efficacy analysis.	21 hours
To Evaluate the Incidence of Clinical Need for Therapy Beyond the Current 21 Hour FDA Approved Dosing Regimen.	Because the study was terminated prematurely due to lack of enrollment, there was an insufficient sample size to conduct an efficacy analysis.	42 hours
To Evaluate the Incidence of Treatment Emergent Adverse Events		21-42 hours
To Evaluate the Incidence of Anaphylactoid Reaction.	Data analysis was conducted on the subjects enrolled in the study prior to study termination. Because the study was terminated prematurely due to lack of enrollment, there was an insufficient sample size to conduct an efficacy analysis.	1 hour

Collaborators and Investigators

• Sponsor: Cumberland Pharmaceuticals
• Investigators: Study Director: Art Wheeler, MD, Cumberland Pharmaceuticals, Inc.

Publications and helpful links

General Publications

• Bhushan M, Beck MH. Allergic contact dermatitis from disodium ethylenediamine tetra-acetic acid (EDTA) in a local anaesthetic. Contact Dermatitis. 1998 Mar;38(3):183. doi: 10.1111/j.1600-0536.1998.tb05702.x. No abstract available.
• van Laar T, van Hilten B, Neef C, Rutgers AW, Pavel S, Bruijn JA. The role of EDTA in provoking allergic reactions to subcutaneous infusion of apomorphine in patients with Parkinson's disease: a histologic study. Mov Disord. 1998 Jan;13(1):52-5. doi: 10.1002/mds.870130113.
• Kimura M, Kawada A. Contact dermatitis due to trisodium ethylenediaminetetra-acetic acid (EDTA) in a cosmetic lotion. Contact Dermatitis. 1999 Dec;41(6):341. doi: 10.1111/j.1600-0536.1999.tb06184.x. No abstract available.
• Marik PE. Propofol: therapeutic indications and side-effects. Curr Pharm Des. 2004;10(29):3639-49. doi: 10.2174/1381612043382846.

Study record dates

Study Major Dates

• Study Start: September 1, 2010
• Primary Completion (Actual): November 1, 2012
• Study Completion (Actual): May 1, 2013

Study Registration Dates

• First Submitted: May 4, 2010
• First Submitted That Met QC Criteria: May 5, 2010
• First Posted (Estimate): May 7, 2010

Study Record Updates

• Last Update Posted (Estimate): August 4, 2014
• Last Update Submitted That Met QC Criteria: August 1, 2014
• Last Verified: August 1, 2014

More Information

Terms related to this study

• Keywords: Acetaminophen overdose; induced hepatotoxicity, liver injury
• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Substance-Related Disorders; Drug Overdose; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Protective Agents; Respiratory System Agents; Anticoagulants; Antioxidants; Antidotes; Chelating Agents; Sequestering Agents; Free Radical Scavengers; Expectorants; Iron Chelating Agents; Calcium Chelating Agents; Acetylcysteine; N-monoacetylcystine; Edetic Acid; Pentetic Acid
• Other Study ID Numbers: CPI-NAC-001