Background/Purpose: Osteoarthritis (OA) is the most common cause of disability in the US and is frequently managed with non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDs, including diclofenac, are associated with dose-related gastrointestinal, cardiovascular, and renal adverse events (AEs). As a result, the US Food and Drug Administration issued a Public Health Advisory encouraging physicians to prescribe NSAIDs at “the lowest effective dose for the shortest duration consistent with individual patient treatment goals.” The efficacy of new, submicron particle NSAIDs is under investigation. These drugs have enhanced absorption and may be efficacious at lower doses than commercially available NSAIDs. We report phase 3 safety data in patients with OA pain dosed up to 12 weeks with diclofenac submicron particle capsules.

Methods: This randomized, multicenter, double-blind, parallel-group study enrolled 305 patients 41 to 90 years of age with OA of the hip or knee, which was documented radiologically (Kellgren-Lawrence grade II–III). Enrolled patients were chronic NSAID and/or acetaminophen users with a WOMAC pain subscore ≥40 mm/100-mm at baseline and a documented OA pain “flare” (increase in WOMAC pain subscale ≥15 mm) following NSAID discontinuation. Patients received either diclofenac submicron particle capsules 35 mg TID or BID, or placebo. The primary endpoint was mean change from baseline in WOMAC pain subscore at week 12. Safety and tolerability were also assessed.

Results: Most patients were female (203/305, 66.6%) with an age (mean ± SD) of 61.6 ± 8.9 years. Diclofenac submicron particle capsules 35 mg TID provided significantly better pain relief than placebo (P = 0.0024) with numerical evidence of pain relief in the diclofenac submicron particle capsules 35 mg BID treatment group, although this did not achieve statistical significance (P = 0.0795). The most frequent AEs (>3% in any treatment group) were generally similar across treatment groups (Table). Serious AEs occurred in 3.0% (9/305) of patients and were generally comparable across treatment groups. No serious gastrointestinal bleeds or cardiovascular or renal AEs occurred in any treatment group. The most frequent AEs in patients who withdrew from the study (≥1% in any treatment group) included diarrhea (3/305, 1.0%), upper abdominal pain (3/305, 1.0%), and alanine aminotransferase elevation (3/305, 1.0%). There was no difference across treatment groups for withdrawals due to AEs.

Conclusion: Investigational, lower-dose diclofenac submicron particle capsules were generally well-tolerated in a phase 3 study of patients with OA. No serious gastrointestinal bleeds or cardiovascular or renal AEs occurred over 12 weeks of treatment.