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

INTRODUCTION: Intra-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. METHODS: In 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. RESULTS: Of 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. CONCLUSIONS: Following 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.

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).

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. CLINICALTRIALSGOV IDENTIFIER: NCT03378076.

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.

Final results of the phase 1/2, open-label clinical study of intravenous recombinant human N-acetyl-α-d-glucosaminidase (SBC-103) in children with mucopolysaccharidosis IIIB.

Mucopolysaccharidosis IIIB is caused by a marked decrease in N-acetyl-α-d-glucosaminidase (NAGLU) enzyme activity, which leads to the accumulation of heparan sulfate in key organs, progressive brain atrophy, and neurocognitive decline. In this open-label study, 11 eligible patients aged 2 to <12 years (developmental age ≥ 1 year) were sequentially allocated to recombinant human NAGLU enzyme (SBC-103) in 3 staggered- and escalating-dose groups (0.3 mg/kg [n = 3], 1.0 mg/kg [n = 4], or 3.0 mg/kg [n = 4]) by intravenous infusion every 2 weeks for 24 weeks, followed by a 4-week interruption (Part A), treatment at 1.0 and/or 3.0 mg/kg every 2 weeks starting at week 28 (Part B), and treatment at 5.0 or 10.0 mg/kg every 2 weeks (Part C) for approximately 2 total years in the study. The primary objective of the study was safety and tolerability evaluation; secondary objectives included evaluation of SBC-103 effects on total heparan sulfate levels in cerebrospinal fluid (CSF), brain structural magnetic resonance imaging (cortical gray matter volume), and neurocognitive status (age equivalent/developmental quotient). During the study, 13 treatment-emergent serious adverse events (SAEs) occurred in 3 patients; 32 infusion-associated reactions (IARs) occurred in 8 patients. Most AEs were mild and intravenous treatment with SBC-103 was well tolerated. Mean (SD) changes from baseline at 52 weeks in Part C for the 5.0 and 10.0 mg/kg doses, respectively, were: -4.7% (8.3) and - 4.7% (14.7) for heparan sulfate levels in CSF, -8.1% (3.5) and - 10.3% (9.4) for cortical gray matter volume, +2.3 (6.9) points and +1.0 (9.2) points in cognitive age equivalent and -8.9 (10.2) points and -14.4 (9.2) points in developmental quotient. In summary, SBC-103 was generally well tolerated. Changes in heparan sulfate levels in CSF were small and were not maintained from earlier study time points, there was no clear evidence overall of clinically meaningful improvement in neurocognitive function at the higher doses investigated, and no dose-dependent effects were observed.

Ventricular remodeling and survival are more favorable for myocarditis than for idiopathic dilated cardiomyopathy in childhood: an outcomes study from the Pediatric Cardiomyopathy Registry.

BACKGROUND: Myocarditis is a cause of a new-onset dilated cardiomyopathy phenotype in children, with small studies reporting high rates of recovery of left ventricular (LV) function. METHODS AND RESULTS: The presenting characteristics and outcomes of children with myocarditis diagnosed clinically and with biopsy confirmation (n=119) or with probable myocarditis diagnosed clinically or by biopsy alone (n=253) were compared with children with idiopathic dilated cardiomyopathy (n=1123). Characteristics at presentation were assessed as possible predictors of outcomes. The distributions of time to death, transplantation, and echocardiographic normalization in the biopsy-confirmed myocarditis and probable myocarditis groups did not differ (P≥0.5), but both groups differed significantly from the idiopathic dilated cardiomyopathy group (all P≤0.003). In children with myocarditis, lower LV fractional shortening z-score at presentation predicted greater mortality (hazard ratio, 0.85; 95% confidence interval, 0.73 to 0.98; P=0.03) and greater LV posterior wall thickness predicted transplantation (hazard ratio, 1.17; 95% confidence interval, 1.02 to 1.35; P=0.03). In those with decreased LV fractional shortening at presentation, independent predictors of echocardiographic normalization were presentation with an LV end-diastolic dimension z-score >2 (hazard ratio, 0.36; 95% confidence interval, 0.22 to 0.58; P<0.001) and greater septal wall thickness (hazard ratio, 1.16; 95% confidence interval, 1.01 to 1.34; P=0.04). CONCLUSIONS: Children with biopsy-confirmed or probable myocarditis had similar proportions of death, transplantation, and echocardiographic normalization 3 years after presentation and better outcomes than those of children with idiopathic dilated cardiomyopathy. In children with myocarditis who had impaired LV ejection at presentation, rates of echocardiographic normalization were greater in those without LV dilation and in those with greater septal wall thickness at presentation. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00005391.

Association of left ventricular dilation at listing for heart transplant with postlisting and early posttransplant mortality in children with dilated cardiomyopathy.

BACKGROUND: In patients with dilated cardiomyopathy, the magnitude of cardiac remodeling often correlates with the clinical severity of heart failure. We sought to determine whether measures of left ventricular (LV) dilation and systolic dysfunction in children with dilated cardiomyopathy at the time of listing for cardiac transplantation are associated with survival while waiting for and early after transplant. METHODS AND RESULTS: We analyzed echocardiographic data obtained within 6 months of listing for heart transplant and clinical data from 261 children with dilated cardiomyopathy who were included in both the Pediatric Cardiomyopathy Registry and the Pediatric Heart Transplant Study. Median time to listing after diagnosis was 1.9 months and to transplant after listing was 0.8 months. There were 42 deaths (29 waiting and 13 within 6 months after transplant). We found a significant age-dependent association of LV end-diastolic dimension z score (n=204, 31 deaths) with death controlling for race, transplant status, and medical insurance. The association was strongest for infants younger than 6 months at diagnosis (hazard ratio 1.47, P=0.008) and was not significant in children older than 5 years at diagnosis. A similar interaction was identified between age and LV end-systolic dimension z score (P=0.04). Neither LV function nor mass was associated with death, overall, or in subgroups. CONCLUSIONS: The severity of LV dilation at listing for heart transplant is associated with outcome in infants and young children with dilated cardiomyopathy, whereas the severity of LV systolic dysfunction is not. These findings should be considered in risk stratification of these children at listing.

Cluster analysis and lower urinary tract symptoms in men: findings from the Boston Area Community Health Survey.

OBJECTIVES: To classify lower urinary tract symptoms (LUTS) in a large, representative sample of men in the USA by means of cluster analysis and to investigate risk factors and comorbidities associated with the resulting cluster patterns. SUBJECTS AND METHODS: A combination of hierarchical and non-hierarchical cluster methods was used to assign men with LUTS in the Boston Area Community Health (BACH) study to symptom-based categories or clusters. Of the 2301 men in the BACH study, those reporting one or more of 14 common LUTS (1592 men) were included in the analysis. The prevalence and frequency of symptoms in each cluster was assessed, in addition to the demographic, lifestyle risk factors, comorbidities, quality of life, and interference with activities of daily living associated with each cluster. We used anova methods for assessing cluster effects on continuous variables, and cross-classification and chi-square tests for categorical measures. Internal validity of the cluster solution was tested by means of a split-half replication, and external validity by comparison with previously published data. RESULTS: Five clusters were identified among symptomatic men. About half of the symptomatic men were assigned to Cluster 1, which included individuals with a low prevalence and frequency of urological symptoms and a correspondingly low level of interference with activities of daily living. There were intermediate levels of symptom frequency and prevalence in Clusters 2-4, which were characterized by mixed patterns of voiding, storage and postvoiding symptoms. Cluster 5 consisted of predominantly older men (mean age 58.9 years), with a high prevalence and frequency of urological symptoms with a mean (SD) number of symptoms of 9.9 (2.1), and with elevated levels of comorbid cardiovascular disease (P < 0.001). These men also had higher rates of kidney and bladder infections and previous urological surgery. Men with increased waist circumference and more sedentary lifestyles were over-represented in the more symptomatic clusters. CONCLUSION: Cluster analysis provides an empirically based method for categorizing men with LUTS. These findings provide a new framework for examining aetiological pathways and mechanisms, the potential impact of and consequences for comorbid conditions, and for assessing prognosis and outcomes associated with common urological disorders.

Do urological symptoms cluster among women? Results from the Boston Area Community Health Survey.

OBJECTIVES: To conduct a cluster analysis of urological symptoms among women in the Boston Area Community Health (BACH) Survey, to describe the distribution of urological symptoms within each cluster, and to determine whether comorbidities, demographic characteristics, and lifestyle factors were associated with cluster membership. SUBJECTS AND METHODS: The BACH Survey is a racially and ethnically diverse random sample (3205 women) of community-dwelling residents of Boston, MA, USA, aged 30-79 years. Fourteen urological symptoms measured by participant self-report (using previously validated scales) were included in this analysis. Cluster analyses were conducted using hierarchical and non-hierarchical (k-means) methods. Within clusters, demographic characteristics, risk factors for urological symptoms and the interference of symptoms with daily activities were also assessed. RESULTS: Three-quarters of the sample reported at least one urological symptom; four symptom clusters were identified. Most symptomatic women (54%) were assigned to Cluster 1, which was characterized by storage symptoms (nocturia and urinary frequency) with an accompanying low prevalence of other urological symptoms; a second cluster was distinguished by frequency symptoms. Clusters 3 and 4 were characterized by a high prevalence of urinary incontinence and had increased interference scores and more symptoms overall (including voiding and post-voiding symptoms) than the other two clusters. Cluster 4 (8% of symptomatic women) was characterized by a high prevalence of nearly all urological symptoms and the highest interference score. In this most symptomatic cluster, body size and waist circumference were markedly higher, as was the prevalence of diabetes, hypertension and cardiovascular disease than in the other cluster groups or asymptomatic women. Women in Cluster 4 were more likely to be surgically menopausal, or to have had other forms of urogynaecological surgeries than women in the other clusters. CONCLUSION: Four distinct clusters of urological symptoms were identified among symptomatic women in the BACH Survey, two of which had a high prevalence of urinary incontinence. These cluster patterns provide a novel, empirically-based framework for investigating aetiological mechanisms and management outcomes for common urological symptoms in women.

Beyond the cluster: methodological and clinical implications in the Boston Area Community Health survey and EPIC studies.

OBJECTIVE: To test the replicability and robustness of findings about urological symptoms in men and women, classified using an objective statistical method, cluster analysis, by planned sensitivity analyses conducted within and across two large, epidemiological studies of lower urinary tract symptoms. METHODS: Sensitivity analyses were used to assess the effects of: (i) the number of urological symptoms included in the cluster analysis; (ii) the use of ordinal vs dichotomous scaling of responses; (iii) the type of cluster analysis used (hierarchical vs non-hierarchical; random vs nonrandom seeds); and (iv) the distance metric (median difference vs root mean square) of the resulting clusters. These sensitivity analyses were conducted independently in each of the two studies, with results systematically compared using Cramer's V statistic. Contingency tables were also used to assess the frequency of transitions or change in classification from one method to another. RESULTS: There were marked similarities in the cluster profiles in men and women across the two studies. For both men and women, the largest clusters consisted of low-frequency, single-symptom profiles, with urinary frequency and urgency symptoms reported by both genders. There was a multiple, mixed and highly symptomatic cluster profile in both genders in the Boston Area Community Health (BACH) and EPIC studies. The sensitivity analyses showed stability across both BACH and EPIC studies, and varying cluster methods and solutions (Cramer's V, 0.37-0.93). CONCLUSION: Sensitivity analyses show that cluster profiles are quite robust from EPIC to BACH, and that gender profiles within studies are relatively consistent across the methods and variables examined. Further studies are needed to investigate the mechanisms of action and clinical management implications of these findings.