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.

INTRODUCTION: A 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. METHODS: Participants > 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. RESULTS: Two-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. CONCLUSIONS: In 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 REGISTRATION: ClinicalTrials.gov Identifier: NCT02357459.

Osteoarthritis is a chronic condition that greatly impacts patients. Pain is the most common symptom of osteoarthritis. Clinical trials evaluating the effects of new drugs to treat osteoarthritis pain frequently use scales to rate overall pain following treatment. Patients may rate their pain using a number that best describes their pain, with the lowest number typically meaning "no pain," and the highest number typically meaning "pain as bad as you can imagine." Other rating scales may be used to rate pain in situations commonly associated with osteoarthritis.Results from a large clinical trial demonstrated that injection of an extended-release steroid significantly reduced pain compared with a conventional steroid injection on only one of the two pain-reporting scales used in the trial. A closer look found that some patients reported their pain differently on the two rating scales at the start of the trial, with some reporting moderate-to-severe pain using one questionnaire and mild pain using the other. Here, we focused on those patients who reported having moderate-to-severe osteoarthritis knee pain on both pain scales at the start and found that the pain relief benefit associated with the extended-release steroid injection was greatly improved compared with the conventional steroid injection with both measures. Patients receiving the extended-release steroid injection also decreased their use of rescue medication for pain relief.

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 OBJECTIVES: Osteoarthritis (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. METHODS: In 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. RESULTS: Among 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. CONCLUSION: These 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 NUMBER: NCT03382262 (December 22, 2017 retrospectively registered).

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.

INTRODUCTION: In 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. METHODS: Patients (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. RESULTS: The 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). CONCLUSIONS: In 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. FUNDING: Flexion Therapeutics, Inc., Burlington, MA, USA. Plain language summary available for this article.

Efficacy of Triamcinolone Acetonide Extended-Release in Participants with Unilateral Knee Osteoarthritis: A Post Hoc Analysis.

INTRODUCTION: Osteoarthritis (OA) is common and its prevalence is increased in military service members. In a phase 3 randomized controlled trial (NCT02357459), a single intra-articular injection of an extended-release formulation of triamcinolone acetonide (TA-ER) in participants with unilateral or bilateral knee OA demonstrated substantial improvement in pain and symptoms. Bilateral knee pain has emerged as a confounding factor in clinical trials when evaluating the effect of a single intra-articular injection. Furthermore, unilateral disease is frequently first to emerge in active military personnel secondary to prior traumatic joint injury. In this post hoc analysis, we assessed efficacy and safety of TA-ER in a subgroup of participants with unilateral knee OA. METHODS: Participants ≥ 40 years of age with symptomatic knee OA were randomized to a single intra-articular injection of TA-ER 32 mg, TA crystalline suspension (TAcs) 40 mg, or saline-placebo. Average daily pain (ADP)-intensity and rescue medication use were collected at each of weeks 1-24 postinjection; Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)-A (pain), WOMAC-B (stiffness), WOMAC-C (function), and Knee Injury and Osteoarthritis Outcome Score Quality of Life (KOOS-QoL) were collected at weeks 4, 8, 12, 16, 20, and 24 postinjection. Adverse events (AEs) were assessed throughout the study. Participants with unilateral knee OA were selected for this analysis. RESULTS: Of 170 participants with unilateral OA (TA-ER, N = 51; saline-placebo, N = 60; TAcs, N = 59), 42% were male and 89% were white. TA-ER significantly (p < 0.05) improved ADP-intensity vs. saline-placebo (weeks 1-24) and TAcs (weeks 4-21). TA-ER significantly (p < 0.05) improved WOMAC-A vs. saline-placebo (all time points) and TAcs (weeks 4, 8, 12, 24). Consistent outcomes were observed for rescue medication, WOMAC-B, WOMAC-C, and KOOS-QoL. AEs were similar in frequency/type across treatments. CONCLUSION: TA-ER provided 5-6 months' pain relief that consistently exceeded saline-placebo and TAcs, suggesting that TA-ER injected intra-articularly into the affected knee may be an effective non-opioid treatment option. Although the participants included in this analysis did not fully represent the diverse demographics of active service members, the substantial unmet medical need in the military population suggests that TA-ER may be an important treatment option; additional studies of TA-ER in active military patients are needed. TRIAL REGISTRATION: ClinicalTrials.gov NCT02357459. FUNDING: Flexion Therapeutics, Inc. Plain language summary available for this article.

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

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.

Multicenter Study Validating Accuracy of a Continuous Respiratory Rate Measurement Derived From Pulse Oximetry: A Comparison With Capnography.

BACKGROUND: Intermittent measurement of respiratory rate via observation is routine in many patient care settings. This approach has several inherent limitations that diminish the clinical utility of these measurements because it is intermittent, susceptible to human error, and requires clinical resources. As an alternative, a software application that derives continuous respiratory rate measurement from a standard pulse oximeter has been developed. We sought to determine the performance characteristics of this new technology by comparison with clinician-reviewed capnography waveforms in both healthy subjects and hospitalized patients in a low-acuity care setting. METHODS: Two independent observational studies were conducted to validate the performance of the Medtronic Nellcor Respiration Rate Software application. One study enrolled 26 healthy volunteer subjects in a clinical laboratory, and a second multicenter study enrolled 53 hospitalized patients. During a 30-minute study period taking place while participants were breathing spontaneously, pulse oximeter and nasal/oral capnography waveforms were collected. Pulse oximeter waveforms were processed to determine respiratory rate via the Medtronic Nellcor Respiration Rate Software. Capnography waveforms reviewed by a clinician were used to determine the reference respiratory rate. RESULTS: A total of 23,243 paired observations between the pulse oximeter-derived respiratory rate and the capnography reference method were collected and examined. The mean reference-based respiratory rate was 15.3 ± 4.3 breaths per minute with a range of 4 to 34 breaths per minute. The Pearson correlation coefficient between the Medtronic Nellcor Respiration Rate Software values and the capnography reference respiratory rate is reported as a linear correlation, R, as 0.92 ± 0.02 (P < .001), whereas Lin's concordance correlation coefficient indicates an overall agreement of 0.85 ± 0.04 (95% confidence interval [CI] +0.76; +0.93) (healthy volunteers: 0.94 ± 0.02 [95% CI +0.91; +0.97]; hospitalized patients: 0.80 ± 0.06 [95% CI +0.68; +0.92]). The mean bias of the Medtronic Nellcor Respiration Rate Software was 0.18 breaths per minute with a precision (SD) of 1.65 breaths per minute (healthy volunteers: 0.37 ± 0.78 [95% limits of agreement: -1.16; +1.90] breaths per minute; hospitalized patients: 0.07 ± 1.99 [95% limits of agreement: -3.84; +3.97] breaths per minute). The root mean square deviation was 1.35 breaths per minute (healthy volunteers: 0.81; hospitalized patients: 1.60). CONCLUSIONS: These data demonstrate the performance of the Medtronic Nellcor Respiration Rate Software in healthy subjects and patients hospitalized in a low-acuity care setting when compared with clinician-reviewed capnography. The observed performance of this technology suggests that it may be a useful adjunct to continuous pulse oximetry monitoring by providing continuous respiratory rate measurements. The potential patient safety benefit of using combined continuous pulse oximetry and respiratory rate monitoring warrants assessment.

Number needed to treat for subglottic secretion drainage technology as a ventilator-associated pneumonia prevention strategy.

The number needed to treat can be calculated for ventilator-associated pneumonia reduction strategies such as subglottic secretion drainage technology based on previous work establishing its relative risk reduction. Assuming an incidence of 4%, employing subglottic secretion drainage in 33 patients will prevent one case of ventilator-associated pneumonia, and thus potentially 4 cases annually in an average hospital in the United States. With a previously described limit of £300 ($470 USD) additional cost per 10 days of ventilation as a threshold of investment for technologies to reduce ventilator-associated pneumonia, subglottic secretion drainage technology is both clinically and cost effective.

Hospital stay and mortality are increased in patients having a "triple low" of low blood pressure, low bispectral index, and low minimum alveolar concentration of volatile anesthesia.

BACKGROUND: Low mean arterial pressure (MAP) and deep hypnosis have been associated with complications and mortality. The normal response to high minimum alveolar concentration (MAC) fraction of anesthetics is hypotension and low Bispectral Index (BIS) scores. Low MAP and/or BIS at lower MAC fractions may represent anesthetic sensitivity. The authors sought to characterize the effect of the triple low state (low MAP and low BIS during a low MAC fraction) on duration of hospitalization and 30-day all-cause mortality. METHODS: Mean intraoperative MAP, BIS, and MAC were determined for 24,120 noncardiac surgery patients at the Cleveland Clinic, Cleveland, Ohio. The hazard ratios associated with combinations of MAP, BIS, and MAC values greater or less than a reference value were determined. The authors also evaluated the association between cumulative triple low minutes, and excess length-of-stay and 30-day mortality. RESULTS: Means (±SD) defining the reference, low, and high states were 87 ± 5 mmHg (MAP), 46 ± 4 (BIS), and 0.56 ± 0.11 (MAC). Triple lows were associated with prolonged length of stay (hazard ratio 1.5, 95% CI 1.3-1.7). Thirty-day mortality was doubled in double low combinations and quadrupled in the triple low group. Triple low duration ≥60 min quadrupled 30-day mortality compared with ≤15 min. Excess length of stay increased progressively from ≤15 min to ≥60 min of triple low. CONCLUSIONS: The occurrence of low MAP during low MAC fraction was a strong and highly significant predictor for mortality. When these occurrences were combined with low BIS, mortality risk was even greater. The values defining the triple low state were well within the range that many anesthesiologists tolerate routinely.

Broadly applicable risk stratification system for predicting duration of hospitalization and mortality.

BACKGROUND: Hospitals are increasingly required to publicly report outcomes, yet performance is best interpreted in the context of population and procedural risk. We sought to develop a risk-adjustment method using administrative claims data to assess both national-level and hospital-specific performance. METHODS: A total of 35,179,507 patient stay records from 2001-2006 Medicare Provider Analysis and Review (MEDPAR) files were randomly divided into development and validation sets. Risk stratification indices (RSIs) for length of stay and mortality endpoints were derived from aggregate risk associated with individual diagnostic and procedure codes. Performance of RSIs were tested prospectively on the validation database, as well as a single institution registry of 103,324 adult surgical patients, and compared with the Charlson comorbidity index, which was designed to predict 1-yr mortality. The primary outcome was the C statistic indicating the discriminatory power of alternative risk-adjustment methods for prediction of outcome measures. RESULTS: A single risk-stratification model predicted 30-day and 1-yr postdischarge mortality; separate risk-stratification models predicted length of stay and in-hospital mortality. The RSIs performed well on the national dataset (C statistics for median length of stay and 30-day mortality were 0.86 and 0.84). They performed significantly better than the Charlson comorbidity index on the Cleveland Clinic registry for all outcomes. The C statistics for the RSIs and Charlson comorbidity index were 0.89 versus 0.60 for median length of stay, 0.98 versus 0.65 for in-hospital mortality, 0.85 versus 0.76 for 30-day mortality, and 0.83 versus 0.77 for 1-yr mortality. Addition of demographic information only slightly improved performance of the RSI. CONCLUSION: RSI is a broadly applicable and robust system for assessing hospital length of stay and mortality for groups of surgical patients based solely on administrative data.

Update on best practice recommendations for anesthetic perioperative care and pain management in weight loss surgery, 2004-2007.

To reevaluate and update evidence-based best practice recommendations published in 2004 for anesthetic perioperative care and pain management in weight loss surgery (WLS), we performed a systematic search of English-language literature on anesthetic perioperative care and pain management in WLS published between April 2004 and May 2007 in MEDLINE and the Cochrane Library. We identified relevant abstracts by using key words, retrieved full text articles, and stratified the resulting evidence according to systems used in established evidence-based models. We updated prior evidence-based best practice recommendations based upon interim literature. In instances of controversial or inadequate scientific evidence, the task force reached consensus recommendations following evaluation of the best available information and expert opinion. The search yielded 1,788 abstracts, with 162 potentially relevant titles; 45 were reviewed in detail. Despite more information on perioperative management of patients with obstructive sleep apnea (OSA), evidence to support preoperative testing and treatment or to guide perioperative monitoring is scarce. New evidence on appropriate intraoperative dosing of muscle relaxants allows for greater precision in their use during WLS. A novel application of alpha-2 agonists for perioperative anesthetic care is emerging. Key elements that may enhance patient safety include integration of the latest evidence on WLS, obesity, and collaborative multidisciplinary care into clinical care. However, large gaps remain in the evidence base.