Acetaminophen for the Reduction of Oxidative Injury in Severe Sepsis (ACROSS)

Phase IIa Randomized Controlled Trial of Acetaminophen for the Reduction of Oxidative Stress in Severe Sepsis

Cell-free hemoglobin can be measured in the plasma of patients with sickle cell anemia, hemodialysis, after red blood cell transfusion, and in patients with sepsis. Cell-free hemoglobin in these patient population has been associated with poor outcomes, including an association with an increased risk of death. Acetaminophen may have a protective effect in these patient populations by inhibiting hemoprotein-mediated lipid peroxidation. The purpose of the present trial is to study the effect of acetaminophen on lipid peroxidation in adults with severe sepsis and detectable cell-free hemoglobin.

The primary hypothesis is that systemic markers of oxidative stress and lipid peroxidation, as measured by F2-isoprostanes, will be significantly lower in patients with severe sepsis and detectable cell-free hemoglobin who receive acetaminophen compared to placebo. The secondary hypothesis is that patients with severe sepsis and detectable cell-free hemoglobin treated with acetaminophen will have better clinical outcomes, including decreased incidence of acute kidney injury and lower rates of hospital mortality, compared to those who receive placebo.

Study Overview

• Status: Completed
• Conditions: Severe Sepsis
• Intervention / Treatment: Drug: placebo; Drug: Acetaminophen

• Study Type: Interventional
• Enrollment (Actual): 44
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Males and Female >=18 years old
• Admitted to an Intensive Care Unit
• Severe Sepsis
• Detectable plasma cell-free hemoglobin

Exclusion Criteria:

• patients who received acetaminophen in the past 48 hours prior to enrollment
• intolerance or allergy to acetaminophen
• measured AST/ALT >400 U/L in the 24 hours prior to enrollment
• chronic liver disease defined by a Child-Pugh score >4
• cannot swallow or have no enteral feeding access
• patients with no detectable cell-free hemoglobin
• patients transitioned to palliative care
• pregnant patients or women of childbearing potential without a documented pregnancy test

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: Acetaminophen; Patients will receive acetaminophen at the dose of 1 gram by mouth or by enteral feeding tube every six hours for a total of 72 hours.	Drug: Acetaminophen
Placebo Comparator: Placebo; Patients will receive placebo by mouth or by enteral feeding tube every six hours for 72 hours.	Drug: placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
F2-isoprostanes After 72 Hours of Acetaminophen or Placebo	F2-isoprostanes are a marker of oxidative stress, specifically lipid peroxidation.	72 hours after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
In-hospital Mortality	percent of patients who died in the hospital	Patients will be followed through the end of their hospital stay, an average of 5 weeks
Serum Creatinine After 72 Hours of Treatment With Acetaminophen or Placebo	serum creatinine measurements at 72 hours	72 hours

Collaborators and Investigators

• Sponsor: Vanderbilt University

Study record dates

Study Major Dates

• Study Start: April 1, 2013
• Primary Completion (Actual): December 1, 2013
• Study Completion (Actual): December 1, 2013

Study Registration Dates

• First Submitted: November 26, 2012
• First Submitted That Met QC Criteria: November 30, 2012
• First Posted (Estimate): December 3, 2012

Study Record Updates

• Last Update Posted (Actual): December 26, 2017
• Last Update Submitted That Met QC Criteria: November 28, 2017
• Last Verified: November 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Toxemia; Physiological Effects of Drugs; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Antipyretics; Acetaminophen
• Other Study ID Numbers: APAP-121486