A total of 152 patients with symptomatic knee osteoarthritis were randomized to receive either a combination of Apocynin and Paeonol 800 mg (APPA; n=75) or placebo (n=77) twice daily for 28 days. The primary outcome of interest was the change in pain measured using the WOMAC pain subscale. Secondary outcomes included WOMAC function and stiffness, as well as other patient-reported outcomes such as daily pain intensity and global assessment scores. Outcomes were assessed at baseline and on day 28. Overall, the study found no significant improvement in the primary or secondary outcomes for APPA compared to placebo. However, a predefined subgroup analysis revealed significant pain reduction in participants with nociplastic/neuropathic features. APPA was well-tolerated, with mild to moderate gastrointestinal side effects being the most common. These findings suggest that APPA may have a role in specific subgroups but not broadly in symptomatic knee osteoarthritis.