Evaluation methods

The primary outcome measure was the diary-based 11-point NRS for pain in the target joint, and the primary endpoint was the mean change from baseline in NRS for pain over 12 weeks after the first injection. Secondary endpoints comprised joint-specific endpoints for the hip, ankle, shoulder, and elbow joints over 12 weeks after the first injection using the Western Ontario and McMaster Universities Osteoarthritis 3.1 index (WOMAC) [17], Self-Administered Foot Evaluation Questionnaire (SAFE-Q) [18], Shoulder36 [19], and Patient-Rated Elbow Evaluation (Japanese Version) (PREE-J) [20], respectively. In addition, the proportion of responders, patient and physician global assessment scores (100-mm visual analog scale [VAS]), Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) [21–23], EuroQol 5 Dimensions (EQ-5D) [24], joint range of motion, and acetaminophen consumption were assessed.

Safety was evaluated according to treatment-emergent adverse events (TEAE) discovered after the initial injection, which were reported in accordance with the definitions in Supplementary Table 2, Additional file 2. The relationship of TEAE to the study drug was assessed by a blinded investigator. TEAEs of special interest were TEAEs relating to the injection site, gastrointestinal disorders, cardiovascular disorders, renal dysfunction, hypersensitivity, and anaphylactic reaction. To confirm safety, the target joint was radiographed before the first injection of the study drug and at Week 12 or discontinuation. Joints were assessed by the investigator for morphological changes (osteophyte, joint space narrowing, osteosclerosis, and epiphyseal deformity) according to the study protocol (Supplementary Table 3, Additional file 3). In addition, manual joint examination, laboratory testing (hematology, blood biochemistry, and urinalysis), and vital signs measurement were performed, and the investigator determined whether any abnormal change in these four tests corresponded to a TEAE.