Background/Purpose: Tanezumab is a nerve growth factor monoclonal antibody in development for osteoarthritis (OA). Following a clinical hold due to concerns around adverse joint events, the tanezumab clinical trial program implemented comprehensive radiographic eligibility criteria. We describe the frequencies of exclusionary radiographic findings during screening in three Phase III randomized studies of subcutaneous tanezumab.

Methods: NCT02697773¹ was a 40-week placebo-controlled study (16-week treatment). NCT02709486² was a 48-week placebo-controlled study (24-week treatment). NCT02528188^3,4 was an 80-week active-controlled (oral NSAID) study (56-week treatment). Bilateral shoulder, hip and knee screening radiographs were taken by trained imaging technologists and read by one of five central musculoskeletal radiology experts (central readers). Central readers were trained using a program-specific imaging atlas and underwent periodic re-calibration sessions.⁵ Eligibility criteria for all studies included an OA diagnosis in the index hip or knee based on ACR criteria and a Kellgren Lawrence (KL) grade of ≥2 on radiograph as diagnosed by the central reader. Radiographic exclusion criteria included a KL grade of 0 or 1 in a non-index knee or hip with patient reported pain of ≥7 on a 0-10 numerical rating scale, without other exclusionary radiographic findings (discordant pain to X-ray), confounding joint or systemic conditions (severe malalignment of the knee, inflammatory joint disease etc.), presence of rapidly progressive OA type 2 (RPOA2), or potential risk factors for RPOA (such as osteonecrosis, subchondral insufficiency fracture, or atrophic OA; Figure 1) in any joint. 

Results: In the three studies, conducted at >480 international sites, 23,079 patients were screened and 13,797 proceeded to radiography (producing 81,055 knee, hip or shoulder screening radiographs read by the central reader). Overall, 8024 patients (58.2%) were declared radiographically eligible. Among the 5773 (41.8%) patients declared ineligible, exclusionary radiographic findings were noted in 1 (4116 [29.8%]), 2 (1268 [9.2%]), 3 (279 [2.0%]), 4 (108 [0.8%]), or 6 joints (2 [0.01%]). The most common exclusionary radiographic finding in both knees and hips was discordant pain to X-ray (Table 1; ~1 in 10 screening X-rays), with other findings being much rarer (≤~1 in 35), particularly in the hip (≤~1 in 100). Exclusionary radiographic findings were rare in the shoulder ─ the most common was osteonecrosis (~1 in 325, vs ~1 in 250 and 100 in the knee and hip, respectively).

Conclusion: Conclusion: The Phase III tanezumab trial program included comprehensive radiographic screening. The most common exclusionary finding in knees and hips was pain discordant to X-ray (~1 in 10 screening X-rays).

Disclosures: Studies sponsored by Pfizer and Eli Lilly and Company.

References:

1. Schnitzer T., JAMA. 2019. 322(1):37-48.
2. Berenbaum F., et al. Ann Rheum Dis. 2020. 79:800-10.
3. Hochberg M., et al. ACR/ARHP Annual Scientific Meeting. 2019. 71(s10):2243.
4. Hochberg M., et al. ACR/ARHP Annual Scientific Meeting. 2019. 71(S10):4888.
5. Roemer F., et al. Semin Arthritis Rheum. 2017. 47(3):323-30.

Table 1: Most common exclusionary radiographic findings from three Phase III trials of subcutaneous tanezumab

Figure 1: Examples of exclusionary radiographic findings

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/radiographic-exclusionary-findings-during-screening-for-three-phase-iii-trials-of-subcutaneous-tanezumab-in-patients-with-moderate-to-severe-hip-or-knee-osteoarthritis/