Objective: Describe the radiograph-based screening program and frequencies of ineligibility in 3 large, international, randomized, double-blind, phase 3 studies of subcutaneous tanezumab in patients with osteoarthritis (OA).
Design: Standardized bilateral shoulder, hip, and knee screening radiographs were obtained by trained imaging technologists and centrally read by 1 of 5 musculoskeletal radiology experts trained using a program-specific imaging atlas. Inter-reader consistency was tracked with test cases blindly inserted into the reader queue. Readers attended quarterly calibration meetings. Protocol-specified radiographic exclusion criteria included rapidly progressive OA (RPOA) or risk factors for RPOA (including severe malalignment of the knee, subchondral insufficiency fracture, atrophic OA, and osteonecrosis). Patients reporting disproportionate pain to radiographic evidence of OA in the hip or knee (without other pathology) were ineligible under a nonradiographic exclusion criterion.
Results: At >480 international sites, 23,079 patients entered screening and 13,797 were radiographically assessed. Across 6 sets of quarterly testing, pairwise central reader agreement on radiographic eligibility was 72-87% (kappa: 0.41-0.71) and on radiographic OA grading 77-84% (kappa: 0.68-0.75). Among the 5,773/13,797 (41.8%) patients who met exclusionary criteria, 27% had disproportionate pain to radiographic findings (~10% of knee/hip radiographs). RPOA or risk factors for RPOA were each identified in <5% of patients (usually 1 joint) and <3% of knee/hip/shoulders.
Conclusions: The phase 3 tanezumab screening program demonstrated the utility of radiographs to screen patients entering NGF inhibitor trials. A high degree of reader concordance was achieved. RPOA and risk factors for RPOA were not commonly observed. NCT02697773, NCT02709486, NCT02528188.
Keywords: X-rays; antibodies; clinical trial phase 3; nerve growth factor; radiography.