Randomized Study of the Efficacy and Safety of IV Acetaminophen Compared with Placebo for Treatment of Fever

Background:

Acetaminophen has been well known as an effective analgesic and antipyretic for more than a century. IV acetaminophen (IV APAP) is approved for the short‐term treatment of acute pain and fever in nearly 70 countries outside of the United States, and more than 300 million 1‐g doses have been distributed since its first approval in Europe in 2002. IV APAP is under clinical investigation in the United States (Acetavance™, Cadence Pharmaceuticals).

Methods:

This randomized, double‐blind, placebo‐controlled study (CPI‐APF‐302) was conducted in 60 healthy adult males with an endotoxin‐induced fever to assess the antipyretic efficacy of IV APAP (1 g/100 mL) versus placebo over 6 hours. After an overnight admission, each subject was assessed to rule out fever or occult infection. Eligible subjects then received IV endotoxin (E. coli 0:113, lot 6, obtained from NIH) 1 ng/kg as a test dose and were observed for 1 hour. Subsequently, a 4 ng/kg pyrogenic IV endotoxin dose was administered, and subjects were monitored until a core temperature > 38.6X was reached. Subjects achieving a sufficient fever response were randomly assigned to receive either IV APAP (n = 31) or matching placebo (n = 29) when near their peak temperature response. Core temperature was continuously monitored using the VitalSense Integrated Physiological Monitoring System (Respiron‐ics). The primary efficacy outcome was WSTD6 (defined as the weighted sum of temperature differences from baseline to the temperature at each assessment point through 6 hours compared with the temperature at TO). Secondary end points included WSTD3, maximum temperature reduction, subjects' global evaluation, and the percentage of subjects with a temperature < 38°C. Safety evaluations included spontaneous adverse event (AE) reporting, physical examinations, and clinical laboratory assessments.

Results:

Statistically significant results favoring IV APAP were observed for the primary end point of WSTD6 (P = 0.0001). Differences in the following secondary end points were also statistically significant in favor of IV APAP: WSTD3 (P < 0.0001), maximum temperature reduction from TO to T360 (P = 0.0376), and percentage of subjects with temperature < 38°C from TO to T360 minutes (P = 0.006). IV APAP demonstrated a rapid onset of action, showing statistically superior temperature differences from baseline compared to placebo 15 minutes after completing the infusion (P = 0.0085). The frequency of AEs, including hepatic AEs, was comparable between the placebo and IV APAP treatment groups. All treatments were well tolerated. No subject was discontinued prematurely from the study due to an adverse event. Two subjects in each group received rescue medication.

Conclusions:

This study shows that IV acetaminophen in a single 1‐g dose is safe and effective in reducing endotoxin‐induced fever over a 6‐hour period and demonstrates results consistent with what has been observed clinically with oral acetaminophen over the last 50 years.

Author Disclosure:

M. Royal, Cadence Pharmaceuticals, employee/shareholder; L. Fong, Cadence Pharmaceuticals, employee/ shareholder; H. Smith, Cadence Pharmaceuticals, employee/shareholder; C. Pan, Cadence Pharmaceuticals, employee/shareholder; Stephen Daniels, Premier Research, Contract Research Organization; J. Breitmeyer, Cadence Pharmaceuticals, employee/shareholder.