Randomized Controlled Noninferiority Trial to Compare Extended Release Acetaminophen and Ibuprofen for the Treatment of Ankle Sprains

Study objective To compare acetaminophen extended release 1,300 mg 3 times daily and ibuprofen 400 mg 3 times daily for treatment of signs and symptoms of grade I or II lateral ankle sprains. Methods Patients (N=260) 18 years or older and with grade I or II lateral ankle sprains were randomized to receive acetaminophen extended release 1,300 mg 3 times daily or ibuprofen 400 mg 3 times daily for 9 days. Primary endpoint was change from baseline at day 4 in pain on walking. Other endpoints included change from baseline at day 9 in pain on walking; change from baseline at days 4 and 9 in ability to walk and ankle swelling, bruising, and range of motion; satisfaction with treatment on days 4 and 9; percentage of patients with positive anterior drawer test on day 4; and time to resume normal activity. Safety assessments consisted of reported adverse events. This study had a noninferiority design in which the hypothesis was that acetaminophen extended release was not inferior to ibuprofen for treatment of signs and symptoms of grade I or II lateral ankle sprains. Results The difference in least squares means (acetaminophen extended release, ibuprofen) with respect to the primary endpoint within the per-protocol population was −0.88; acetaminophen extended release was comparable to ibuprofen for the primary endpoint because the upper limit (3.26) of the 1-sided 95% confidence interval (CI) for the difference in least squares means did not exceed the noninferiority limit of 6.90. The intention-to-treat population was used to test the second step of the 2-step testing process because the null hypothesis was rejected in the noninferiority test. For this analysis, the difference between acetaminophen extended release and ibuprofen in the least squares mean change from baseline for the primary endpoint was −1.63 (not significant). Results showed that acetaminophen extended release was noninferior to ibuprofen with respect to the secondary endpoints. No serious drug-related adverse events were reported. The most common adverse events, reported by 6.5% of patients, were in the gastrointestinal system (mainly nausea and upper abdominal pain). Conclusion Acetaminophen extended release 3,900 mg daily was comparable to ibuprofen 1,200 mg daily for treatment of grade I or II lateral ankle sprains. Both treatments were well tolerated.