Safety and Efficacy of Repeat Administration of Triamcinolone Acetonide Extended-release in Osteoarthritis of the Knee: A Phase 3b, Open-label Study

Andrew I Spitzer, John C Richmond, Virginia B Kraus, Andreas Gomoll, Deryk G Jones, Kim M Huffman, Charles Peterfy, Amy Cinar, Joelle Lufkin, Scott D Kelley, Andrew I Spitzer, John C Richmond, Virginia B Kraus, Andreas Gomoll, Deryk G Jones, Kim M Huffman, Charles Peterfy, Amy Cinar, Joelle Lufkin, Scott D Kelley

Abstract

Introduction: The aim of this work is to assess the safety and efficacy of repeat administration of triamcinolone acetonide extended-release (TA-ER) in patients with symptomatic knee osteoarthritis (OA), including those with advanced radiographic severity.

Methods: In this phase 3b, single-arm, open-label study, patients aged ≥ 40 years received the first intra-articular TA-ER injection on day 1. Patients received the second injection timed to the response to the first injection (at either week 12, 16, 20, or 24). Patients who received two injections were evaluated every 4 weeks for 52 weeks. Safety was evaluated via treatment-emergent adverse events and any change at 52 weeks in index-knee radiographs (chondrolysis, osteonecrosis, insufficiency fractures, subchondral bone changes). Exploratory efficacy endpoints included Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)-A (pain), -B (stiffness), -C (function), and Knee Injury and Osteoarthritis Outcome Score-Quality of Life (KOOS-QoL) after each injection. Initiative in Methods, Measurements and Pain Assessment in Clinical Trials (IMMPACT) criteria were used to determine moderate and substantial treatment response.

Results: A total of 208 patients were enrolled and received the first injection of TA-ER; 179 (86.1%) received the second injection (median time to second injection: 16.6 weeks). Both injections were well tolerated, with no unexpected adverse events or significant radiographic changes at week 52. The magnitude and duration of clinical benefit after the first and second injections were similar, and most patients reported a substantial (≥ 50%) analgesic response after both doses.

Conclusions: Repeat administration of TA-ER using a flexible dosing schedule timed to patient response was well tolerated, with no radiographic evidence of cartilage impact. Both injections resulted in similar improvements in OA symptoms across a broad spectrum of disease severity reflective of that seen in clinical practice.

Trial registration information: ClinicalTrials.gov identifier: NCT03046446.

Funding: Flexion Therapeutics, Inc. Plain language summary available for this article.

Keywords: Clinical study; Corticosteroid injection; Knee osteoarthritis; Safety.

Figures

Fig. 1
Fig. 1
Study design. ACR American College of Rheumatology, KOOS-QoL Knee injury and Osteoarthritis Outcome Score-Quality of Life, OA osteoarthritis, TA-ER triamcinolone acetonide extended-release, WOMAC Western Ontario and McMaster Universities Osteoarthritis Index
Fig. 2
Fig. 2
Patient disposition. *Discontinued before Week 12. †Includes 1 patient who received the second injection after Week 24. ‡Experienced clinical benefit from the first injection but discontinued before receiving the second injection. §Received the second injection but discontinued before Week 52 (i.e., 52 weeks after the first injection). | Disease progression defined as response to first and second injections but loss of effect sometime after the response to the second injection. Lack of efficacy defined as response to the first injection but no response to the second injection. Note: all discontinuations because of disease progression occurred ≥ 12 weeks after the second injection. AE adverse event
Fig. 3
Fig. 3
Timing of the second TA-ER injection for patients who received two injections (efficacy population). Does not include 1 patient who received the second injection after Week 24. TA-ER triamcinolone acetonide extended-release
Fig. 4
Fig. 4
Comparison of mean WOMAC-A (pain) scores following the first and second TA-ER injections for patients who received the second injection at a week 12 (N = 45), b week 16 (N = 60), c week 20 (N = 37), or d week 24 (N = 36) (efficacy population). TA-ER triamcinolone acetonide extended-release, WOMAC Western Ontario and McMaster Universities Osteoarthritis Index
Fig. 5
Fig. 5
Proportions of patients achieving moderate (≥ 30% improvement) and substantial (≥ 50% improvement) WOMAC-A (pain) response at 4 weeks after each injection for patients who received the second injection week 12 (N = 45), week 16 (N = 60), week 20 (N = 37), or week 24 (N = 36) (efficacy population). WOMAC Western Ontario and McMaster Universities Osteoarthritis Index

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