Observed efficacy and clinically important improvements in participants with osteoarthritis treated with subcutaneous tanezumab: results from a 56-week randomized NSAID-controlled study

Abstract

Background: A recent phase 3 study demonstrated that treatment with tanezumab, a nerve growth factor inhibitor, or nonsteroidal anti-inflammatory drugs (NSAIDs) improves pain and physical function in participants with moderate-to-severe osteoarthritis (OA) of the hip or knee. Here, we evaluated the time course and clinical importance of these initial efficacy findings using a mixture of primary, secondary, and post hoc endpoints.

Methods: Participants on stable NSAID therapy and with a history of inadequate response to other standard OA analgesics were enrolled in an 80-week (56-week treatment/24-week safety follow-up), randomized, NSAID-controlled, phase 3 study primarily designed to assess the safety of tanezumab for moderate-to-severe OA of the knee or hip. Participants received oral NSAID (twice daily naproxen, celecoxib, or diclofenac) or subcutaneous tanezumab (2.5mg or 5mg every 8 weeks). Non-responders were discontinued at week 16. Changes from baseline in WOMAC Pain and Physical Function, Patient's Global Assessment of Osteoarthritis (PGA-OA), and average pain in the index joint were compared between tanezumab and NSAID groups over the 56-week treatment period. Clinically meaningful response (e.g., ≥30% and ≥50% improvement in WOMAC Pain and Physical Function), rescue medication use, and safety were also assessed.

Results: All groups improved WOMAC Pain, WOMAC Physical Function, PGA-OA, and average pain in the index joint over the 56-week treatment period relative to baseline. Across all groups, improvements generally occurred from the time of first assessment (week 1 or 2) to week 16 and then slightly decreased from week 16 to 24 before stabilizing from weeks 24 to 56. The magnitude of improvement and the proportion of participants achieving ≥30% and ≥50% improvement in these measures was greater (unadjusted p≤0.05) with tanezumab than with NSAID at some timepoints on or before week 16. Adverse events of abnormal peripheral sensation, prespecified joint safety events, and total joint replacement surgery occurred more frequently with tanezumab than with NSAID.

Conclusions: Tanezumab and NSAID both provided early and sustained (up to 56 weeks) efficacy relative to baseline. Improvements in pain and function were clinically meaningful in a substantial proportion of participants. Adverse events of abnormal peripheral sensation and joint safety events occurred more frequently with tanezumab than with NSAID.

Trial registration: ClinicalTrials.gov NCT02528188 . Registered on 19 July 2015.

Keywords: Clinical-trial; Efficacy; Nerve growth factor; Nonsteroidal anti-inflammatory drugs; Osteoarthritis; Tanezumab.

Fig. 1

Change in WOMAC Pain, WOMAC Physical Function, and PGA-OA. LS mean (SE) changes, from baseline, in WOMAC Pain (A), WOMAC Physical Function (B), and PGA-OA (C) scores are shown over the 56-week treatment period. *Unadjusted p ≤ 0.05 for tanezumab 2.5mg versus NSAID. +Unadjusted p ≤ 0.05 for tanezumab 5mg versus NSAID. LS, least squares; NSAID, nonsteroidal anti-inflammatory drug; PGA-OA, Patient’s Global Assessment of Osteoarthritis; SE, standard error; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index

Fig. 2

Change in average pain in the index joint. LS mean (SE) changes, from baseline, in average pain in the index joint scores are shown over the first 7 days (A) and full 56 weeks (B) of treatment. *Unadjusted p ≤ 0.05 for tanezumab 2.5mg versus NSAID. +Unadjusted p ≤ 0.05 for tanezumab 5mg versus NSAID. LS, least squares; NSAID, nonsteroidal anti-inflammatory drug; SE, standard error

Fig. 3

WOMAC Pain responders. The proportion of patients achieving ≥30% (A), ≥50% (B), ≥70% (C), or ≥90% (D) reductions from baseline in WOMAC Pain at weeks 2, 4, 8, 16, and 56 is shown. Proportions shown above each bar are rounded to the nearest percent. *Unadjusted p ≤ 0.05 versus NSAID. NSAID, nonsteroidal anti-inflammatory drug; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index

Fig. 4

WOMAC Physical Function responders. The proportion of patients achieving ≥30% (A), ≥50% (B), ≥70% (C), or ≥90% (D) reductions from baseline in WOMAC Physical Function at weeks 2, 4, 8, 16, and 56 is shown. Proportions shown above each bar are rounded to the nearest percent. *Unadjusted p ≤ 0.05 versus NSAID. NSAID, nonsteroidal anti-inflammatory drug; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index

Fig. 5

Average pain in the index joint responders. The proportion of patients achieving ≥30% (A), ≥50% (B), ≥70% (C), or ≥90% (D) reductions from baseline in average pain in the index joint at weeks 2, 4, 8, 16, and 56 is shown. Proportions shown above each bar are rounded to the nearest percent. *Unadjusted p ≤ 0.05 versus NSAID. NSAID, nonsteroidal anti-inflammatory drug

Fig. 6

OMERACT-OARSI responders. The proportion of patients meeting OMERACT-OARSI responder criteria at weeks 2, 4, 8, 16, and 56 is shown. Response criteria were defined as a within-patient improvement from baseline of (i) ≥ 50% and ≥ 2 points in either WOMAC Pain or Physical Function or (ii) ≥ 20% and ≥ 1 point in two of the following: WOMAC Pain, WOMAC Physical Function, or PGA-OA. Proportions shown above each bar are rounded to the nearest percent. *Unadjusted p ≤ 0.05 versus NSAID. NSAID, nonsteroidal anti-inflammatory drug; OMERACT-OARSI, Outcome Measures in Arthritis Clinical Trials-Osteoarthritis Research Society International; PGA-OA, Patient’s Global Assessment of Osteoarthritis; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index