Faculty Bibliography

PURPOSE/OBJECTIVE:Antidiuretic therapy with desmopressin for nocturia has been hampered by formulations with high doses, low bioavailability and variable pharmacokinetics. AV002 (SER120), a novel, emulsified, microdose desmopressin nasal spray, with a permeation enhancer (cylcopentadecanolide), was developed to have pharmacokinetic characteristics suitable for nocturia treatment. METHODS:Twelve healthy subjects participated in an open-label, dose-escalating study. Water-loaded subjects were sequentially dosed every 48 h with AV002 0.5, 1.0, 2.0 μg and 0.12 μg desmopressin subcutaneous (SC) bolus injection. RESULTS:and area under the curve showed dose proportionality. Coefficient of variation for AV002 was similar to that observed for the SC dose. Bioavailability of AV002 was approximately 8% compared to SC injection. AV002 demonstrated pharmacodynamic effects within 20 min of dosing and showed increasing magnitude and duration with escalating doses. AV002 2.0 μg had maximum median urine osmolality of 629 mOsm/kg and median urine output ≤2 mL/min for 5-6 h. CONCLUSIONS:AV002 demonstrated rapid absorption, high bioavailability, limited duration of action, and low coefficient of variation, suggesting it may be a suitable formulation for nocturia treatment. Trial registration not required (single-center, phase 1).

Introduction & Objectives: To evaluate the efficacy and safety of AV002 by age and gender in patients with nocturia. Material(s) and Method(s): This was a pooled analysis of two double-blind phase 3 trials (NCT01357356, NCT01900704). Studies were approved by an institutional review board. Patients >=50 years with >=2 voids/night were randomized to AV002 1.66 mcg, 0.83 mcg, or placebo and treated for 12 weeks. The co-primary efficacy endpoints (based on patient voiding diaries)were percent of patients with >=50% reduction in mean number of nocturic voids/night (>=50% responders)and mean change in number of nocturic voids/night. Safety endpoints included serum sodium and adverse events (AEs). No fluid restrictions or behavioral modifications were implemented. Data were analyzed by gender and age (< or >=65 years). Result(s): The intent-to-treat (ITT)population (>=3 days of diary data)included 1333 patients: 761 males (302 <65 years; 459 >=65 years)and 572 females (304 <65 years; 268 >=65 years). AV002 1.66 mcg significantly increased percent of responders and decreased number of nocturic voids/night compared with placebo for all age and gender subgroups (Tables 1 and 2). Compared with placebo, AV002 0.83 mcg significantly decreased number of nocturic voids/night for all subgroups and significantly increased percent of responders for patients >=65 years and for males. For patients <65 years and for females, the percent of responders was numerically higher in the AV002 0.83 mcg group compared with placebo; however, the difference was not statistically significant, possibly due to a high response rate in the placebo group. AV002 was well tolerated and there were no differences in AEs between AV002 and placebo. Hyponatremia (serum sodium <=125 mmol/mL)occurred in 5 patients (4 male, 1 female; all >=65 years)receiving 1.66 mcg AV002 (1.1%), 1 patient (1 male >=65 years)receiving placebo (0.2%), and no patients receiving AV002 0.83 mcg. In all, 4 of 5 patients with hyponatremia received steroids within days of the event because of a later-reported protocol deviation; systemic and inhaled glucocorticoids are now contraindicated in the US label. [Table Presented]Conclusions: AV002 1.66 mcg was effective and well tolerated for the treatment of nocturia for all age and gender subgroups. The risk of hyponatremia was low, even without fluid restrictions or behavioral modifications.

Introduction & Objectives: Nocturia is a highly prevalent medical condition. Approximately 80% of patients with nocturia (average of >=2 nocturnal voids)have nocturnal polyuria (NP), and 21% also have overactive bladder (OAB). These patients report sleep disruption and negative effect on nighttime symptoms. First-line therapies for OAB, have limited efficacy in treating nocturia. Combination therapy with an antimuscarinic and an antidiuretic may provide better relief of nocturia for patients with this multifactorial pathophysiology. AV002 is an emulsified microdose desmopressin nasal spray indicated for the treatment of nocturia due to NP and may be suitable concomitant therapy for these patients. Material(s) and Method(s): Data from a subgroup of OAB patients with concomitant NP enrolled in two double-blind Phase 3 trials of AV002 for treatment of nocturia were pooled. Studies were approved by an institutional review board. Patients with >=2 nocturic voids for >=6 months received AV002 1.66 mcg, AV002 0.83 mcg, or placebo every night for 12 weeks. No fluid restrictions or behavioral modifications were required. Efficacy endpoints, based on patient voiding diaries, included first uninterrupted sleep period (FUSP; elapsed time from bedtime to first nocturic void). Patients in one trial also completed the validated Impact of Nighttime Urination (INTU)questionnaire to assess changes in quality of life (QoL; range, 0-100; 0, no impact; 100, greatest impact). Result(s): Of 1045 randomized NP patients, 275 with OAB were included in the FUSP analysis. Of these, 136 patients from one study were included in the INTU analysis. Baseline and change from baseline for FUSP and INTU are shown in Table 1. After 12 weeks of treatment, FUSP was extended to 4.0 hours and 3.9 hours in the AV002 1.66 mcg and 0.83 mcg groups, respectively (change from baseline, p<0.05 vs. placebo for each AV002 group). INTU overall impact scores were significantly improved in patients receiving AV002 compared with placebo. [Table Presented]Conclusions: AV002 treatment over 12 weeks significantly extended FUSP and improved INTU (QoL)scores compared with placebo in OAB patients with nocturia due to NP. AV002 may be an appropriate treatment for nocturia in patients with OAB and nocturia due to NP.

OBJECTIVE:This study assessed stress urinary incontinence (SUI) outcomes after sling excision for urinary tract perforation or vaginal exposure, and compared the outcomes of concomitant versus staged autologous fascia pubovaginal sling (AFPVS). METHODS:A retrospective chart review of all patients who underwent midurethral sling (MUS) excision for urinary tract perforation or vaginal exposure at a tertiary referral center between 2010 and 2015 was performed. Therapeutic strategies were categorized as concomitant AFPVS, staged AFPVS, and no anti-incontinence procedure. RESULTS:In all, 32 patients were included for analysis: 13 with vaginal tape exposure (40.6%) and 19 with urinary tract tape exposure (59.4%). In patients who had SUI prior to sling excision (43.8%), the rate of resolved or improved SUI postoperatively was higher in the concomitant AFPVS group than in those who underwent sling excision alone (83.3% vs 12.5%, respectively; P = 0.03). Of 18 patients with no SUI prior to sling excision, 12 experienced recurrent SUI after sling removal (66.7%). The rate of recurrent SUI was lower in patients with vaginal MUS exposure than urinary tract MUS perforation, but this did not reach statistical significance (57.1% vs 72.7%, respectively; P = 0.63). The rates of resolved SUI after AFPVS were comparable in patients with concomitant and staged AFPVS (66.7% vs 71.4%, respectively; P = 0.99). CONCLUSIONS:Many patients with MUS perforations or exposures will have SUI at initial presentation or develop SUI after removal of the synthetic sling. The decision to perform a concomitant AFPVS or to stage the surgical management of SUI can be individualized.

OBJECTIVE:To evaluate the effect of radiation on male stress urinary incontinence (SUI) and to assess the relative value of preoperative urodynamic (UDS) testing in radiated vs nonradiated men with SUI. METHODS:A retrospective chart review of all male patients with SUI who underwent UDS testing from 2010 to 2016 was performed. The impact of UDS findings on treatment decision making was assessed. UDS parameters and treatment patterns of radiated vs nonradiated patients were compared as well as the fates of storage symptoms in each group. RESULTS:Two hundred seven men were identified that underwent UDS with a clinical diagnosis of SUI. Sixty-five out of 207 (31.4%) were exposed to radiation as a treatment modality for prostate cancer. All patients that underwent UDS testing moved on to surgical correction of SUI, and the UDS findings did not alter plan to treat SUI in any patients. Men who were radiated prior to surgical correction of SUI were more likely to have detrusor overactivity (70% vs 38%, P <.0001) and had lower maximum cystometric capacity (255 vs 307.4 mL, P = .01) when compared to nonradiated on UDS. After artificial urinary sphincter or sling implantation, the proportion of patients requiring overactive bladder medications was higher in radiated vs nonradiated men (44.3% vs 25.3%; P = .01). CONCLUSION/CONCLUSIONS:Radiation therapy appears to increase the likelihood of bladder dysfunction in male patients with SUI. The UDS findings did not alter the plan to treat SUI in any patients in our series, and its role before SUI surgery in male patients, including those receiving radiation, may be limited.

BACKGROUND:Nocturia is considered to be a very bothersome lower urinary tract disorder. Yet, to date, the economic burden attributable to this poor health condition remains less well known. OBJECTIVE:To compare differences in health care resource utilization (HCRU), health care costs, and work productivity in adult patients with differing frequencies of nocturia episodes (i.e., < 2 vs. ≥ 2 nocturia episodes per night). METHODS:Adult patients with nocturia enrolled in an integrated proprietary database were recruited to complete a survey on their demographics, nocturia characteristics, and work productivity. Using patients' survey data and health care claims from the previous 6 months, those with < 2 (n = 197; 21.9%) versus ≥ 2 (n = 702; 78.1%) nocturia episodes per night were compared for differences in HCRU, health care costs, and work productivity after adjusting for potential confounders. HCRU was reported as the mean number per patient per month (PPPM) for outpatient visits (all types), physician office visits, and prescriptions filled and the proportion of patients with ≥1 hospitalization or emergency department visit in the previous 6 months. Health care costs were reported as mean PPPM. Work productivity was assessed via patient survey and reported as a mean percentage for absenteeism, presenteeism, overall work impairment, and activity impairment during the past week. RESULTS:899 adult patients (mean age = 71.4 years; 57.2% men) were enrolled and analyzed. Compared with patients with <2 nocturia episodes per night, patients with ≥ 2 nocturia episodes had more outpatient health care visits (unadjusted mean visits PPPM: 2.1 vs. 1.6; P < 0.001; adjusted mean visits PPPM: 2.1 vs. 1.6; P = 0.017), office visits (unadjusted and adjusted mean visits PPPM: 0.9 vs. 0.7; P < 0.001), and prescriptions filled (unadjusted mean prescription fills PPPM: 3.1 vs. 2.1; P < 0.001; adjusted mean prescription fills PPPM: 3.2 vs. 2.2; P = 0.027). Patients with ≥ 2 nocturia episodes per night also displayed significantly higher outpatient health care costs (unadjusted mean PPPM costs: $676 vs. $516; P = 0.028; adjusted mean PPPM costs: $678 vs. $506; P = 0.017). In terms of work productivity impairment, patients with ≥ 2 nocturia episodes per night experienced higher rates of unadjusted (20% vs. 10%; P = 0.002) and adjusted presenteeism (20% vs. 10%; P = 0.004) and unadjusted (20% vs. 10%; P = 0.002) and adjusted overall work impairment (20% vs. 10%; P = 0.001). CONCLUSIONS:Study findings demonstrate that nocturia was associated with higher outpatient encounters and related costs in the presence of a greater occurrence of nocturic episodes. DISCLOSURES/UNASSIGNED:This study was funded by Allergan plc, Dublin, Ireland. Neither honoraria nor payments were provided for authorship. Dmochowski is a consultant and speaker for Allergan plc and a consultant for Serenity Pharmaceuticals. Brucker is a consultant and speaker for Allergan plc, a consultant for Watkins-Conti and Avadel, and an investigator for Medtronic and Ipsen. Cole is a consultant for Allergan plc and an employee of Sharp Rees-Stealy Medical Group. Kawahara and Pulicharam are full-time employees of DaVita Medical Group. Burk is a consultant for Allergan plc and a health outcomes consultant. Tung is an employee of Allergan plc. Hale has served as a consultant/advisor to and has received research funding from Allergan plc. The data from this manuscript were previously presented in poster format by Steve Kawahara at the Academy of Managed Care & Specialty Pharmacy Annual Meeting; April 19-22, 2016; San Francisco, CA.

AIMS/OBJECTIVE:To perform a systematic review of studies reporting the outcomes of AMS-800 artificial urinary sphincter (AUS) implantation in female patients with stress urinary incontinence (SUI) resulting from intrinsic sphincter deficiency (ISD). METHODS:A systematic literature search of the Medline and Embase databases was performed in June 2018 in accordance with the PRISMA statement. No time limit was used. The protocol was registered in PROSPERO (CRD42018099612). Study selection and data extraction were performed by two independent reviewers. RESULTS:Of 886 records screened, 17 were included. All were retrospective or prospective non-comparative case series. One study reported on vaginal AUS implantation, 11 on open AUS implantation, two on laparoscopic AUS implantation, two on robot-assisted AUS implantation and one compared open and robot-assisted implantations. The vast majority of patients had undergone at least one anti-incontinence surgical procedure prior to AUS implantation (69.1-100%). The intraoperative bladder neck injury rates ranged from 0% to 43.8% and the intraoperative vaginal injury rates ranged from 0 to 25%. After mean follow-up periods ranging from 5 to 204 months, the complete continence rates ranged from 61.1% to 100%. The rates of explantation, erosion and mechanical failure varied from 0% to 45.3%, 0% to 22.2% and 0% to 44.1%, respectively. CONCLUSIONS:AMS-800 AUS can provide excellent functional outcomes in female patients with SUI resulting from ISD but at the cost of a relatively high morbidity. High level of evidence studies are needed to help better define the role of AUS in the female SUI armamentarium.

OBJECTIVE:To characterize the current evaluation, and efficacy of treatments in patients with the primary complaint of nocturia. METHODS:A retrospective chart review was performed of new patient encounters seen in a tertiary urology practice from May 2010 to September 2016 with the primary diagnosis of nocturia (ICD-9 788.43 and ICD-10 R35.1). RESULTS:595 patients were identified. 403 met inclusion criteria. The median patient reported that nocturia episodes were 4 (1-20). 192 patients (48%) reported previous treatment for nocturia. After the index visit, a bladder diary (BD) was utilized in 50% of patients, with a 62% (n = 124) completion rate at follow-up visit. On BD analysis, the most common etiologies of nocturia were nocturnal polyuria 76% (n = 90) and overactive bladder in 21% (n = 26). Patient reported improvement with therapy after BD completion was 46% (n = 34), similar to patients without voiding diaries (43% improvement, n = 153). Anticholinergics and alpha blockers were the most commonly recommended drug, but no specific medication was associated with nocturia improvement. Oral desmopressin was used in 5% of patients. CONCLUSION/CONCLUSIONS:Nocturia is a common condition and very commonly patients have sought treatment prior to presentation. Bladder diaries were recommended to half of the patients. Patient reported that improvement did not seem to correlate with completion of a bladder diary. Though most patients had NP the use of desmopressin was very low. Current treatments used in managing nocturia may lack efficacy.

OBJECTIVES/OBJECTIVE:Stress urinary incontinence is highly prevalent and sling surgery has increased since 2000. Urethrolysis traditionally had been standard management of complications after anti-incontinence surgery; however, partial excision is a less aggressive option. This study describes the different populations in a contemporary cohort that undergo sling excision and urethrolysis and their surgical outcomes. METHODS:Chart analysis was performed on patients assigned Current Procedural Terminology codes for removal or revision of sling for stress incontinence, urethrolysis, or revision of graft at our institution from 2010 to 2015. Demographics, indications, outcomes, and subsequent treatment were evaluated. RESULTS:A total of 110 patients underwent surgery and were included. Partial excision was performed on 82 patients and urethrolysis on 28 patients. About 32.7% had prior revision, and median length to revision was 3.1 years. Overall success was 75.0% for urethrolysis and 86.6% for partial excision. Without concomitant sling placement, stress incontinence developed in 25.0% of urethrolysis and 21.6% of partial excision patients. New onset overactive bladder symptoms developed in 21.4% of urethrolysis patients and 7.3% of partial excision, which was significantly different (P = 0.039). CONCLUSIONS:Both approaches had good success, 75.0% for formal urethrolysis and 86.6% for partial excision. New onset urgency was lower for partial excision, but rates of all other complications were similar. These procedures are often used for different patient populations, and thus, outcomes are not meant to be directly compared. Future work on sling revision should report these procedures separately.