Triamcinolone Acetonide Extended-release Research Articles

The effect of intra-articular extended-release triamcinolone acetonide on OARSI-recommended physical performance measures in adults with bilateral symptomatic knee osteoarthritis

ObjectiveWhile the effect of triamcinolone acetonide extended-release (TA-ER) on reducing knee osteoarthritis (OA) pain has been reported, the effects on physical performance are incompletely understood. This open label clinical trial systematically evaluated the effects of intra-articular TA-ER on physical performance, self-reported function, and quality of life in participants with bilateral symptomatic knee OA 6, 12 (primary) and 24 weeks following bilateral injection of TA-ER (32 ​mg). MethodsSeventy participants were enrolled (61.4% women; age 64.0 ​± ​11.7; BMI 31.8 ​± ​5.7 ​kg/m2). Physical performance was measured by 30-s chair stand test, 40 ​m fast paced walk test (FPWT), and stair negotiation test at baseline and each follow-up visit. Physical function and quality of life (QOL) were measured with the Knee Injury and Osteoarthritis Outcome Score (KOOS-PS) and pain was measured with numeric rating scale (NRS). ResultsIn comparison with baseline, self-reported pain, function, and quality of life were improved at each follow-up through 24 weeks and the number of chair-stands significantly improved following treatment by (mean ​± ​SE) 1.9 ​± ​0.6 ​at 6-week (p ​= ​0.0048) and by 1.8 ​± ​0.5 ​at 12-week follow-up (p ​= ​0.0011) but was not statistically significant at 24-week follow-up (0.6 ​± ​0.6; p ​= ​0.4711). Stair negotiation times were 7.2 ​± ​3.7, 7.1 ​± ​3.8, and 5.4 ​± ​4.0 ​s lower at the three respective follow-up timepoints, although these changes did not reach statistical significance (p ​= ​0.0530, p ​= ​0.0599, and p ​= ​0.1793 respectively). The 40m-FPWT time did not significantly improve. ConclusionThese data indicate improvement in chair stand performance through 12 weeks post-injection and sustained improvement in participant-reported physical function through 24-week follow-up in adults with bilateral painful knee OA treated with TA-ER.

A Randomized, Open-Label, Single-Dose Study to Assess Safety and Systemic Exposure of Triamcinolone Acetonide Extended-Release in Patients With Hip Osteoarthritis.

IntroductionIntra-articular (IA) corticosteroids, including triamcinolone acetonide (TA), are a recommended treatment for hip osteoarthritis. We compared the safety and systemic exposure of TA extended-release (TA-ER) versus TA crystalline suspension (TAcs) in patients with hip osteoarthritis.MethodsIn this phase 2, randomized, multicenter, open-label, single-dose study (NCT03382262), patients with hip osteoarthritis were randomly assigned 1:1 to receive single IA injections of TA-ER 32 mg or TAcs 40 mg. Safety assessments included treatment-emergent adverse events (TEAEs). Blood samples were collected for pharmacokinetic (PK) analysis up to day 85. PK parameters included area under the concentration–time curve, total body drug clearance, maximum concentration (Cmax), mean residence time, half-life, and time to maximum concentration.ResultsOf 30 patients (TA-ER: n = 15; TAcs: n = 15) randomized and included in the Safety Population, 25 patients were evaluated in the PK Population. TEAEs were reported in four of 15 (26.7%) patients who received TA-ER and in seven of 15 (46.7%) patients who received TAcs. The most common TEAEs included arthralgia and headache. All TEAEs were of grade 1 or 2 in severity. TA-ER produced substantially lower peak plasma TA concentrations compared with TAcs (Cmax geometric mean: 890.4 vs. 5549.4 pg/ml), and these were less variable with TA-ER versus TAcs. Similarly, overall TA systemic exposure was substantially lower for TA-ER versus TAcs, with gradual elimination from systemic circulation through day 85.ConclusionsFollowing a single IA injection in the hip, TA-ER was generally well tolerated, with a safety profile comparable to that of TAcs. Systemic TA exposure was markedly lower in TA-ER-treated patients, consistent with the PK profile observed in knee osteoarthritis.Clinicaltrials.gov identifier: NCT03382262.

Improved Treatment Effect of Triamcinolone Acetonide Extended-Release in Patients with Concordant Baseline Pain Scores on the Average Daily Pain and Western Ontario and McMaster Universities Osteoarthritis Index Pain Scales.

IntroductionA phase 3 randomized controlled study comparing triamcinolone acetonide extended-release (TA-ER) to conventional TA crystalline suspension (TAcs) reported variable efficacy results. Enrollment criteria may have contributed to this discrepancy, as moderate-to-severe average daily pain (ADP) was required at baseline, whereas no limitations were placed on Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC-A) pain severity. We conducted a post hoc sensitivity analysis to compare treatment effects in patients reporting moderate-to-severe osteoarthritis (OA) pain on both scales.MethodsParticipants > 40 years old with symptomatic knee OA were randomly assigned to a single intra-articular injection of TA-ER 32 mg, TAcs 40 mg, or saline-placebo and followed for 24 weeks. Patient-reported ADP, WOMAC-A, rescue medication usage, and adverse events (AEs) were assessed. Participants who reported moderate-to-severe OA pain at baseline using both instruments (ADP ≥ 5 to ≤ 9, maximum 10 and WOMAC-A ≥ 2, maximum 4) were categorized as “concordant” pain reporters; patients with baseline moderate-to-severe OA on ADP only were termed “discordant” pain reporters.ResultsTwo-hundred-ninety-two concordant pain reporters of 484 total subjects received TA-ER 32 mg (n = 95), TAcs 40 mg (n = 100), or saline-placebo (n = 97). Baseline characteristics and AE profiles of the concordant and discordant pain responders were consistent with the full analysis population. Among concordant pain reporters, TA-ER significantly (p < 0.05) improved ADP scores vs. TAcs (weeks 5–19; area-under-the-effect [AUE]weeks1–12; AUEweeks1–24) and saline-placebo (weeks 1–20; AUEweeks1–12; AUEweeks1–24). At week 12, a higher proportion reported no knee pain (ADP = 0) with TA-ER (~ 28%) vs. TAcs (~ 8%). TA-ER significantly improved WOMAC-A vs. TAcs at weeks 4, 8, and 12, with significant reduction in rescue medication usage observed with TA-ER from weeks 2 to 20 vs. TAcs.ConclusionsIn patients reporting moderate-to-severe knee OA pain at baseline based on concordant ADP and WOMAC-A scores, TA-ER provided statistically significant pain relief for ≥ 12 weeks compared with conventional TAcs.Trial RegistrationClinicalTrials.gov Identifier: NCT02357459.

Safety and Systemic Exposure of Triamcinolone Acetonide Following Ultrasound-Guided Intra-Articular Injection of Triamcinolone Extended-Release or Standard Triamcinolone Acetonide in Patients with Shoulder Osteoarthritis: An Open-Label, Randomized Study.

Background and ObjectivesOsteoarthritis (OA) is a major public health burden. While knee and hip joints are most commonly affected, the glenohumoral (shoulder) joint is also frequently involved. We evaluated the pharmacokinetics and safety/tolerability of triamcinolone acetonide extended-release (TA-ER) and triamcinolone acetonide crystalline suspension (TAcs) in patients with shoulder OA.MethodsIn this phase 2, randomized, open-label, single-dose study (NCT03382262), adults with moderately-to-severely symptomatic shoulder OA for ≥ 6 months randomly received a single ultrasound-guided intra-articular (IA) injection of TA-ER 32 mg or TAcs 40 mg. Safety was evaluated throughout 12 weeks post-injection; blood samples for pharmacokinetic evaluations were collected pre-injection and through Day 85 post-injection.ResultsAmong 25 randomized patients, 12 received TA-ER and 13 received TAcs. Most patients were female (60%), and all had moderate (72%) or severe (28%) shoulder OA. Adverse events (AEs) were reported by four (33%) patients following TA-ER and three (23%) following TAcs injection. No AE was serious or led to study discontinuation. Systemic exposure following TAcs was approximately 1.5-fold higher than that following TA-ER injection (geometric mean [GM] AUC0–last 873,543 vs 557,602 h × pg/mL). GM Cmax was also higher in TAcs- than TA-ER-treated patients (2034 vs 1283 pg/mL). Bioequivalence testing confirmed lower systemic TA exposure following TA-ER than TAcs IA injection.ConclusionThese pharmacokinetic data confirm protracted release of TA from TA-ER following IA injection in patients with shoulder OA. Lower peak and systemic TA exposure following TA-ER suggests TA-ER could potentially confer an improved systemic safety profile over TAcs.Trial Registration NumberNCT03382262 (December 22, 2017 retrospectively registered).

Interim results: the effect of intra-articular extended-release triamcinolone acetonide on OARSI-recommended physical performance measures in adults with bilateral symptomatic knee OA

Purpose: Triamcinolone acetonideextended-release (TA-ER) is a polylactic-co-glycolic acid (PLGA) microspherepreparation of triamcinolone acetonide, FDA-approved for treatment of knee paindue to OA. Following intra-articular injection with TA-ER, triamcinoloneacetonide has been found to persist in the synovial fluid through 16-weekfollow-up. While the efficacy of TA-ER on reducing pain due to knee OA has beenreported, the effects on physical performance have not been fully investigated.Given the incomplete association between reduction in pain and reduction in functionallimitations, the primary aim of this study was to demonstrate theeffects of intra-articular injection of TA-ER on OARSI-recommended physicalperformance measures (30-second chair stand test, stair ascent time, and 40mfast-paced walking time) in adults with bilateral symptomatic knee OA.

Fitbit Analysis Shows Enhanced Mobility Of Knee Osteoarthritis Patients Treated With Triamcinolone Acetonide Extended Release

PURPOSE: In knee osteoarthritis (OAK), walking >6000 steps/day can prevent functional limitation (White DK. Arthritis Care Res. 2014;66:1328). Intra-articular triamcinolone acetonide extended-release (TA-ER) is approved for OAK pain. This Phase 3b study assessed safety and an exploratory endpoint of mobility (steps/day) in patients treated with TA-ER. METHODS: OAK patients aged ≥40 years, symptomatic ≥6 months, with Western Ontario and McMaster Universities Osteoarthritis Index pain (WOMAC-A) score ≥6, and index-knee pain >15 days during the past month received TA-ER on Day 1. Movements were analyzed with a Fitbit® device (≥7 days prior to Day 1 to end of Week 12). RESULTS: A total of 208 patients were treated with TA-ER; 67.8% had moderate-severe OAK, mean age of 60.8 years, and mean body mass index (BMI) of 31.4 kg/m2. Baseline mean WOMAC pain score was 2.17. Mobility improved as seen by increases in weekly mean steps/day. 73 of 203 patients (36%) with sufficient step data at baseline had <6000 steps. Of these, 42 (57.5%) had ≥1 post-baseline week with average daily steps >6000; 19 (26.0%) had ≥50% of their follow-up with >6000 steps. Patients treated with TA-ER had mean changes from baseline in WOMAC pain scores of −1.4, −1.2, and −0.8 at Weeks 4, 8, and 12, respectively. A significantly greater change in steps from baseline was associated with decreases in WOMAC pain scores, male sex, lower BMI, lower baseline GPAQ average MET, and lower baseline steps/day. For every 1-unit decrease (from baseline) in mean WOMAC pain, mean steps/day increased by 339 (Figure 1). CONCLUSIONS: OAK patients given TA-ER had increased mobility (≥6000 steps/day) as measured by fitness monitor which was associated with a decrease in pain. Limitations were incomplete adherence to monitor usage and a no comparator open-label design. Fitness monitors are a feasible tool to measure patient mobility and understand pain and function.

Effect Of Triamcinolone Acetonide Extended-release On Synovial Inflammation In Patients With Osteoarthritis Of The Knee

PURPOSE: Synovitis is common in osteoarthritis of the knee (OAK) and is associated with pain and disease severity. This open-label phase 3b study is evaluating the effect of an intra-articular (IA) injection of triamcinolone acetonide extended release (TA-ER) on synovial tissue volume (STV), pain, and function (NCT03529942). A prespecified analysis of the primary endpoint is reported. METHODS: STV was determined using gadolinium MRI; synovitis was defined as pre-treatment STV ≥3000 mm3 (3 mL). All patients (pts) received TA-ER 32 mg at baseline (BL) and were assessed at Weeks 6, 12, 18, and 24. MRIs were repeated at Weeks 6 and 24. Interim analysis was performed for the primary efficacy endpoint, mean standardized change from BL in STV at 6 weeks. Planned enrollment was based on earlier studies. RESULTS: We enrolled 116 OAK pts with typical OA characteristics (Table); 89 (77%) demonstrated synovitis at BL. STV was significantly reduced from BL at 6 weeks (P<0.001; Fig. 1A). The primary endpoint was met: standardized least squares mean change in STV was −1.13 (95% CI, −1.35 to −0.91; P<0.001). Western Ontario and McMaster Universities Osteoarthritis Index (pain) was significantly reduced at 6 weeks in all pts (Fig. 1B). 24 (20.7%) pts experienced ≥1 treatment-emergent adverse event (TEAE); 6 (5.2%) pts had ≥1 index-knee TEAE. All TEAEs were mild or moderate; none were treatment related. CONCLUSIONS: At 6 weeks, a single TA-ER IA injection markedly reduced STV in pts with synovitis at BL. Marked symptomatic improvement was observed in all pts at 6 weeks following TA-ER.

Fitbit®-derived evidence of enhanced mobility of patients with knee osteoarthritis treated with triamcinolone acetonide extended release: Results from a phase 3B, single-ARM, open-label study

Purpose: Repeated treatment with intra-articular corticosteroid is often used to manage recurrent osteoarthritis (OA) symptoms. Triamcinolone acetonide extended-release (TA-ER) is an intra-articular injection approved for the treatment of pain in patients with knee OA. We conducted a Phase 3b, single-arm, open-label study and assessed safety and exploratory efficacy endpoints in patients with knee OA treated with repeat administration of TA-ER (NCT03046446). This analysis assessed the clinical benefit of treatment based on patient mobility defined as numbers of steps per day.

Concordance of baseline pain measures (across two reporting instruments) influences treatment effect: post hoc analysis of a phase 3 randomized controlled trial of triamcinolone acetonide extended-release in patients with knee osteoarthritis

Purpose: In a Phase 3 randomized controlled study, differing efficacy Results were observed when triamcinolone acetonide extended-release (TA-ER) was compared to conventional TA crystalline suspension (TAcs) with two different pain measures, average daily pain (ADP) using a 0-10 numeric rating scale (NRS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC-A subscale). Trial enrollment criteria may have contributed to this discrepancy, as a moderate-to-severe ADP score of ≥5 to ≤9 was required at baseline whereas no limitations were placed on baseline WOMAC-A score (0-4 Likert).

Expanding the Potential of Nonoperative Therapies In Advanced Knee Osteoarthritis: Treatment Response to Repeat Administration Triamcinolone Acetonide Extended-Release Is Similar Across Kellgren-Lawrence Grades 2-4

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 &gt;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. [Table: see text][Figure: see text]

Rescue Analgesic Medication Use by Patients Treated with Triamcinolone Acetonide Extended-Release for Knee Osteoarthritis Pain: Pooled Analysis of Three Phase 2/3 Randomized Clinical Trials.

IntroductionIn clinical trials for knee osteoarthritis (OAK), rescue medication is commonly provided to manage uncontrolled index-knee pain. The impact of treatment on rescue medication utilization provides important information on the robustness of analgesic effect. In randomized controlled OAK trials (NCT01487161, NCT02116972, NCT02357459), intra-articular (IA) triamcinolone acetonide extended-release (TA-ER) demonstrated substantial, prolonged analgesia versus saline-placebo and TA crystalline solution (TAcs) as assessed by patient-reported pain scales. This pooled analysis assessed the impact of TA-ER on rescue medication use.MethodsPatients (N = 798) with OAK (American College of Rheumatology criteria; Kellgren–Lawrence grade 2/3) and baseline average daily pain intensity score ≥ 5 to ≤ 9 (0–10 numeric rating scale) received a single IA injection of TA-ER (N = 324), saline-placebo (N = 262), or TAcs (N = 212). Acetaminophen/paracetamol tablets were provided to treat uncontrolled pain (knee or otherwise). Rescue medication consumption was monitored through a daily diary; pill counts were confirmed at the clinical site. Differences in rescue medication use were measured by least-squares mean (LSM) differences, number of rescue medication tablets used per day, and in area under the effect (AUE) curves of rescue medication tablets used per week.ResultsThe overall number of rescue medication tablets used per day through week 24 was significantly less (p ≤ 0.05) for TA-ER versus saline-placebo (LSM difference, − 0.43) and TAcs (− 0.24). Rescue medication use was significantly (p ≤ 0.05) lower following TA-ER versus saline-placebo across weeks 1–12 (AUEweeks1–12; LSM difference, − 24.5) and weeks 1–24 (AUEweeks1–24; − 51.6) and versus TAcs across weeks 1–12 (AUEweeks1–12; − 21.1).ConclusionsIn patients with painful OAK, reduced rescue medication use may be a potential benefit of TA-ER and further supports its analgesic efficacy. Additional research is needed to assess whether TA-ER impacts the use of other common oral analgesics (nonsteroidal anti-inflammatory drugs, opioids) for patients with OAK.FundingFlexion Therapeutics, Inc., Burlington, MA, USA.Plain Language SummaryPlain language summary available for this article.

Safety and systemic exposure of triamcinolone acetonide following intra-articular injection of triamcinolone acetonide extended-release or standard triamcinolone in patients with hip osteoarthritis

Safety and systemic exposure of triamcinolone acetonide following intra-articular injection of triamcinolone acetonide extended-release or standard triamcinolone in patients with hip osteoarthritis

Repeat administration of triamcinolone acetonide extended-release affords consistent, clinically relevant improvements in pain: results from a phase 3B, single-arm, open-label study

Repeat administration of triamcinolone acetonide extended-release affords consistent, clinically relevant improvements in pain: results from a phase 3B, single-arm, open-label study

(404) Concordance of Baseline Pain Measures Influences Treatment Effect: Post-Hoc Analysis of 3 Randomized Controlled Trials of Triamcinolone Acetonide Extended-Release in Patients with Knee Osteoarthritis

Knee osteoarthritis (OA) is a painful condition and intra-articular corticosteroids (IACS) are often used to manage OA pain. In Phase 2/3 clinical studies, triamcinolone acetonide extended-release (TA-ER) demonstrated sustained, clinically meaningful pain relief compared with saline-placebo using general Average Daily Pain (ADP)-intensity scores, and compared with saline-placebo and TA crystalline solution (TAcs) using disease-specific Western Ontario and McMaster Universities OA Index (WOMAC-A) measures. As patients may report baseline pain differently using ADP and WOMAC-A measures, we evaluated whether discordant baseline pain reporting influenced measured outcomes. A post hoc analysis of pooled data from 3 Phase 2/3 studies (NCT01487161, NCT02116972, NCT02357459) was conducted to assess treatment effects for patients who reported moderate-to-severe pain at baseline on both pain measures (concordant pain reporters; ADP ≥5 to ≤9 & WOMAC-A ≥2) versus those that reported it only on ADP (discordant pain reporters; ADP ≥5 to ≤9 & WOMAC-A

Correction to: Triamcinolone Acetonide Extended-Release: A Review in Osteoarthritis Pain of the Knee.

The original article has been corrected.

Triamcinolone Acetonide Extended-Release: A Review in Osteoarthritis Pain of the Knee.

Triamcinolone acetonide extended-release (ER) 32 mg (Zilretta®) is approved in the USA for the management of osteoarthritis (OA) pain of the knee and is administered as a single, 5 mL intra-articular (IA) injection. Although the therapeutic effects from IA corticosteroids are typically short-lived, triamcinolone acetonide ER is formulated in poly (lactic-co-glycolic acid) (PLGA) microspheres that slowly release triamcinolone acetonide in the synovium, enabling their prolonged presence in the joint. This reduces systemic exposure and lessens corticosteroid-related systemic adverse reactions, such as blood glucose elevations. In a 24-week, randomized, phase III clinical trial, triamcinolone acetonide ER 32 mg significantly improved mean average daily pain intensity in patients with knee OA relative to placebo, and pain, stiffness and physical function (according to WOMAC criteria) relative to placebo and triamcinolone acetonide crystalline suspension (CS). Triamcinolone acetonide ER was generally well tolerated, with a tolerability profile similar to that of triamcinolone acetonide CS and placebo. Findings from a single-arm phase IIIb study indicated that a repeat administration of triamcinolone acetonide ER may be similarly efficacious to an initial injection without having deleterious effects on cartilage or other aspects of joint structure. Thus, triamcinolone acetonide ER expands the treatment options available for the management of OA pain of the knee.

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

IntroductionThe 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.MethodsIn 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.ResultsA 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.ConclusionsRepeat 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 InformationClinicalTrials.gov identifier: NCT03046446.FundingFlexion Therapeutics, Inc.Plain Language SummaryPlain language summary available for this article.Electronic supplementary materialThe online version of this article (10.1007/s40744-019-0140-z) contains supplementary material, which is available to authorized users.

Physical and Chemical Compatibility of Extended-Release Triamcinolone Acetonide (TA-ER) with Common Local Anesthetics

IntroductionIntra-articular (IA) corticosteroids are used extensively for the treatment of patients with knee osteoarthritis pain. In clinical practice, local anesthetics are frequently combined with corticosteroids prior to IA injection to provide rapid-onset analgesia. From this common practice there is no evidence to suggest that the addition of local anesthetics to corticosteroid preparations, including triamcinolone acetonide (TA), alters the physical properties or efficacy of the corticosteroid. Triamcinolone acetonide extended-release (TA-ER, formerly FX006) is a novel, microsphere-based TA formulation that demonstrated analgesic efficacy in phase 2 and 3 randomized controlled trials.MethodsThe current study assessed the compatibility of TA-ER and lidocaine, ropivacaine, and/or bupivacaine in vitro. The TA-ER and local anesthetic mixtures were assayed for changes in syringeability, pH, particle size, percentage free drug, purity, and appearance compared with TA-ER alone.ResultsBy these measures, the combination of local anesthetics with TA-ER did not negatively impact the chemical or physical properties of TA-ER when compared to TA-ER controls.ConclusionThese results demonstrate that lidocaine, bupivacaine, and ropivacaine are physically and chemically compatible with TA-ER, suggesting that local anesthetic solutions can be added to TA-ER preparations in clinical practice without adversely affecting TA-ER in vitro product characteristics.FundingFlexion Therapeutics, Inc.

A randomized, phase IIa study to assess the systemic exposure of triamcinolone acetonide following injection of extended-release triamcinolone acetonide or traditional triamcinolone acetonide into both knees of patients with bilateral knee osteoarthritis.

Background:Intra-articular corticosteroids are commonly used for pain relief in patients with knee osteoarthritis. Simultaneous intra-articular corticosteroid (CS) knee injections may be beneficial for the ~80–90% of patients who present with, or develop, bilateral knee osteoarthritis, but concurrent injections may increase systemic CS exposure and data on safety/tolerability are lacking. Triamcinolone acetonide extended release (TA-ER) has shown decreased systemic triamcinolone acetonide exposure compared with traditional triamcinolone acetonide crystalline suspension (TAcs) after a single knee injection in patients with knee osteoarthritis. This phase IIa study was designed to assess the safety and systemic triamcinolone acetonide exposure following injections of TA-ER or TAcs into each knee of patients with bilateral knee osteoarthritis.Methods:Patients (⩾40 years) meeting American College of Rheumatology criteria for knee osteoarthritis in both knees received concurrent single intra-articular injections of TA-ER 32 mg or TAcs 40 mg into each knee (total: 64 mg and 80 mg, respectively) and were followed for 6 weeks. Safety was evaluated based on treatment-emergent adverse events (TEAEs). Blood samples for pharmacokinetic analysis were collected pre-injection, and at the following postinjection time points: 1, 2, 3, 4, 5, 6, 8, 10, 12, and 24 h, and days 8, 15, 29, and 43.Results:Baseline characteristics were balanced between patients randomly assigned to TA-ER (n = 12) or TAcs (n = 12). Both treatments were well tolerated with comparable TEAE profiles. Peak plasma triamcinolone acetonide concentrations (Cmax) were lower following bilateral TA-ER injections [geometric mean, 2277.7 pg/ml (95% CI, 1602.13–3238.04)] compared with bilateral TAcs injections [7394.7 pg/ml (2201.06–24,843.43)], with median times to Cmax (Tmax) of 4.5 and 6.5 h, respectively.Conclusions:In patients with bilateral knee osteoarthritis, intra-articular injection of TA-ER into both knees was well tolerated. Consistent with pharmacokinetic profiles observed after a single knee injection, plasma triamcinolone acetonide concentrations were lower after bilateral TA-ER injections compared with the higher and more variable concentrations observed after bilateral TAcs injections.ClinicalTrials.gov identifier:NCT03378076

Local Effects Following Single and Repeat Intra-Articular Injections of Triamcinolone Acetonide Extended-Release: Results from Three Nonclinical Toxicity Studies in Dogs.

IntroductionSingle intra-articular (IA) injections of poly(lactic-co-glycolic acid) (PLGA) microsphere-based triamcinolone acetonide extended-release (TA–ER; formerly FX006) demonstrated sustained, clinically relevant benefits in patients with knee osteoarthritis. The local effects of TA–ER were assessed in normal canine knees in three nonclinical studies.MethodsKnees were evaluated for up to 6 weeks or 9 months after a single injection of TA–ER (2.1/6.25/18.75 mg TA), or TA crystalline suspension (TAcs, 18.75 mg TA), and for up to 6 months after three injections (every 1 or 3 months) of TA–ER (6.25/18.75 mg TA) or TAcs (18.75 mg). Vehicle-diluent, blank microspheres, and untreated knees were used as controls. Plasma and synovial fluid (SF) TA concentrations and standard histopathological assessment of the synovium were conducted. Articular cartilage morphology was assessed via modified Mankin scoring.ResultsPlasma and SF concentrations indicated prolonged dose-dependent TA joint residency with TA–ER compared with TAcs. Effects in articular cartilage were dose- and time-dependent and consistent with known effects of corticosteroids in the normal knee. Loss of Safranin O staining occurred, indicative of a reduction in cartilage matrix proteoglycan, and recovered in a similar manner for TA–ER and TAcs across all studies. Structural lesions were infrequent and generally comparable in severity between TA–ER and TAcs but slightly higher in incidence for TA–ER. Focal/multifocal foreign-body responses (FBR) to PLGA were observed in the superficial layer of the synovium, peaking after 4–6 weeks, with significant recovery or complete resolution by month 6.ConclusionsThese findings suggest that the effects of IA injections of TA–ER on cartilage are predominantly transient, and comparable to those observed with TAcs in the normal canine knee joint. These mild effects in the normal joint differ from the beneficial effects observed with TA–ER and other corticosteroids in disease models. The synovial FBR to PLGA microspheres was focal and transient.FundingFlexion Therapeutics, Inc.Plain Language SummaryPlain language summary available for this article.Electronic supplementary materialThe online version of this article (10.1007/s40744-018-0125-3) contains supplementary material, which is available to authorized users.