The impact of screening period pain inconsistency on placebo response in intra-articular knee osteoarthritis trials

OBJECTIVE: Placebo response (PR) presents a significant challenge in osteoarthritis (OA) trials. Screening Period Pain Inconsistency (SPPI) has been associated with heightened PR in placebo-treated patients. However, existing studies have overlooked whether increasing versus decreasing pain during the screening period affects this relationship differently. This study examines the impact of SPPI magnitude and direction on PR. DESIGN: In a post-hoc analysis of a Phase 2b randomized, double-blind, placebo-controlled knee OA trial, 143 participants receiving intra-articular placebo were categorized into absolute and directional quartiles based on SPPI. The primary endpoint was the change in WOMAC pain from baseline at week 52 in the placebo group, assessed to determine the long-term impact of SPPI on pain changes, using a mixed model for repeated measures. RESULTS: Participants with the highest SPPI had a greater reduction in WOMAC pain scores across the trial period compared to those with more stable pain (group aQ4-aQ1: LSM -11.72, 95%CI: -17.43 to -6.02). The greatest PR was observed in participants whose pain increased during the screening period (group dQ4-dQ1: LSM -6.67, 95%CI: -12.47 to -0.86) and was significant from week 2 (LSM -7.92, 95%CI: -13.65 to -2.19). CONCLUSIONS: These findings extend earlier observations by revealing that not only the magnitude, but also the direction of screening pain fluctuation (worsening pain before randomization) predicts PR. These results highlight SPPI as a potential adjustment variable to enhance assay sensitivity and mitigate PR in intra-articular knee OA trials, supporting the development of more effective therapies for chronic pain conditions like OA.