Abstract
Objectives:
Triamcinolone acetonide extended-release (TA-ER) is approved in the US to treat pain associated with knee osteoarthritis (OA). Intra-articular corticosteroids (IACS) are often used to manage recurrence of pain and symptoms during the prolonged course of OA. Effectiveness of IACS in advanced knee OA is unknown, and lack of effective nonoperative treatments may accelerate consideration of total knee arthroplasty (TKA). This post hoc subgroup analysis of a Phase 3b, single-arm, open-label study (NCT03046446) evaluated the efficacy of initial and repeat administration TA ER in knee OA with a range of radiographic severity classified by Kellgren-Lawrence (KL) grade.
Methods:
Patients aged ≥40 years with symptomatic knee OA for ≥6 months, KL Grade 2-4, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) -A (pain) total sum score ≥6, and index knee pain for >15 days during the prior month received the 1st injection of TA-ER on Day 1. Patients received the 2nd injection at the first visit (Week 12, 16, 20, or 24) at which repeat dose criteria were met (ie, patient benefited from and tolerated the 1st injection without safety concerns and was clinically indicated to receive the 2nd injection). Patients who received 2 injections were evaluated every 4 weeks up to 52 weeks after the 1st injection. Patients who did not benefit from the 1st injection at Week 12 completed at Week 12. Patients who did not meet repeat dose criteria by Week 24 completed at Week 24. Safety was evaluated via treatment-emergent adverse events (TEAEs), and by index-knee radiography at end of study. Exploratory efficacy endpoints included WOMAC A (pain), -B (stiffness), C (function), and Knee Injury and Osteoarthritis Outcome Score-Quality of Life following each injection.
Results:
Of 208 enrolled patients, 179 received 2 injections. Of these, 56 (31.3%) had KL Grade 2, 68 (38.0%) had KL Grade 3, and 55 (30.7%) had KL Grade 4. The patient population reflected the ‘real-world’ knee OA population (Table). Demographics and baseline disease characteristics were generally similar across KL grade subgroups; however, as expected, age and time since OA diagnosis increased with KL grade. Prior index-knee OA treatments did not correlate with KL grade except for increased use of IA hyaluronic acid. The incidence of TEAEs and index-knee TEAEs were similar across KL grades (Table). Most TEAEs were Grade 1 or Grade 2 and there were no unexpected TEAEs. There were no indications of chondrolysis, osteonecrosis, subchondral insufficiency fractures, or clinically significant subchondral bone changes in any subgroup. Response rates for the 1st injection and median times to 2nd injection were 95% and 120 days for KL Grade 4, 96% and 118 days for KL Grade 3 and 94% and 113 days for KL Grade 2. Regardless of KL grade, mean WOMAC-A (pain) scores were comparable following injections (Figure). At 12 weeks after both the 1st and 2nd injections, mean scores were similar for patients with KL Grade 4 (1.34 and 1.36), KL Grade 3 (1.37 each), and KL Grade 2 (1.24 and 1.20) (Figure).
Conclusion:
Overall and across baseline KL grades, repeat administration of TA-ER using a dosing schedule tailored to patient response was well tolerated, with no radiographic evidence for an impact on cartilage. In this ‘real-world’ patient population, TA-ER reliably reduced OA symptoms with similar improvements observed after both injections across KL grade subgroups, including those with KL Grade 4 who may otherwise be considering TKA.
Demographics, baseline disease characteristics, and TEAEs by baseline Kellgren-Lawrence grade
| Demographics and Baseline Disease Characteristics | KL Grade 2 (N=56) | KL Grade 3 (N=68) | KL Grade 4 (N=55) | Total (N=179) |
|---|---|---|---|---|
| Women, n (%) | 31 (55.4) | 37 (54.4) | 28 (50.9) | 96 (53.6) |
| Age (years), mean (SD) | 57.7 (6.68) | 61.6 (9.25) | 63.3 (8.42) | 60.9 (8.53) |
| BMI (kg/m2), mean (SD) | 31.3 (4.81) | 32.2 (4.91) | 30.3 (4.85) | 31.3 (4.89) |
| Bilateral knee OA, n (%) | 35 (62.5) | 39 (57.4) | 30 (54.5) | 104 (58.1) |
| Years since primary diagnosis, mean (SD) | 7.2 (6.36) | 8.7 (7.89) | 9.0 (7.15) | 8.3 (7.22) |
| Prior index-knee surgery/procedure, n (%) | 22 (39.3) | 23 (33.8) | 29 (52.7) | 74 (41.3) |
| Prior index-knee IACS, n (%) | 24 (42.9) | 42 (61.8) | 29 (52.7) | 95 (53.1) |
| Prior index-knee IAHA, n (%) | 4 (7.1) | 12 (17.6) | 16 (29.1) | 32 (17.9) |
| WOMAC-A (pain), mean (SD) | 2.23 (0.674) | 2.11 (0.528) | 2.15 (0.571) | 2.15 (0.580) |
| TEAEs, n (%) | ||||
| ≥1 TEAE | 36 (64.3) | 45 (66.2) | 37 (67.3) | 118 (65.9) |
| ≥1 serious TEAE | 1 (1.8) | 1 (1.5) | 0 | 2 (1.1) |
| Discontinuations because of TEAE | 1 (1.8) | 1 (1.5) | 1 (1.8) | 3 (1.7) |
| Treatment-related TEAE | 3 (5.4) | 4 (5.9) | 3 (5.5) | 10 (5.6) |
| ≥1 index-knee TEAE | 19 (33.9) | 24 (35.3) | 19 (34.5) | 62 (34.6) |
| ≥1 serious index-knee TEAE | 0 | 0 | 0 | 0 |
| Discontinuations because of index-knee TEAE | 1 (1.8) | 1 (1.5) | 1 (1.8) | 3 (1.7) |
| Treatment-related index-knee TEAE | 1 (1.8) | 3 (4.4) | 3 (5.5) | 7 (3.9) |
BMI body mass index, CS corticosteroids, HA hyaluronic acid, IA intra-articular, OA osteoarthritis, TEAE treatment-emergent adverse event, WOMAC Western Ontario and McMaster Universities Osteoarthritis Index.
Comparison of mean WOMAC-A (pain) scores following the 1st and 2nd TA-ER injections for patients with baseline Kellgren-Lawrence Grade 2, Grade 3, or Grade 4.