Tara L. Frenkl

A Multicenter, Double-Blind, Randomized, Placebo Controlled Trial of a Neurokinin-1 Receptor Antagonist for Overactive Bladder

PURPOSE Neurokinin-1 receptor dependent mechanisms may regulate urinary frequency and urgency. We conducted this study to assess the efficacy and tolerability of the neurokinin-1 receptor antagonist serlopitant vs placebo or tolterodine in patients with overactive bladder. MATERIALS AND METHODS This randomized, double-blind, 69-center trial enrolled adults with overactive bladder (8 or more average daily micturitions and 1 or more daily urge incontinence episodes). After a 1-week placebo run-in the patients were randomized to 8 weeks of daily 0.25, 1 or 4 mg serlopitant, 4 mg tolterodine extended release or placebo. Patients kept 7-day voiding diaries. The primary end point was change from baseline in micturitions per day. Secondary end points included urgency, total incontinence, urge incontinence episodes and incidence of dry mouth. RESULTS Of 557 patients randomized 476 completed the trial and had valid efficacy data for analysis. Mean change from baseline in daily micturitions was significantly greater for 0.25 (-1.1) and 4 mg (-1.1) serlopitant, and for tolterodine (-1.5) than for placebo (-0.5), but not for 1 mg serlopitant (-0.8). No serlopitant dose response was demonstrated. Tolterodine was numerically superior to all doses of serlopitant in mean micturitions per day and secondary end points. The incidence of dry mouth on serlopitant (3.3%) was comparable to placebo (4.6%) and lower than tolterodine (8.8%). Serlopitant was generally well tolerated. CONCLUSIONS Serlopitant (0.25 and 4 mg) significantly decreased the primary end point of daily micturitions but not the secondary end points compared with placebo. Serlopitant was generally well tolerated. Thus, NK-1 receptor antagonists may have a role in the treatment of overactive bladder but this compound does not offer advantages in efficacy compared to tolterodine.

Discovery of Vibegron: A Potent and Selective β3 Adrenergic Receptor Agonist for the Treatment of Overactive Bladder.

The discovery of vibegron, a potent and selective human β3-AR agonist for the treatment of overactive bladder (OAB), is described. An early-generation clinical β3-AR agonist MK-0634 (3) exhibited efficacy in humans for the treatment of OAB, but development was discontinued due to unacceptable structure-based toxicity in preclinical species. Optimization of a series of second-generation pyrrolidine-derived β3-AR agonists included reducing the risk for phospholipidosis, the risk of formation of disproportionate human metabolites, and the risk of formation of high levels of circulating metabolites in preclinical species. These efforts resulted in the discovery of vibegron, which possesses improved druglike properties and an overall superior preclinical profile compared to MK-0634. Structure-activity relationships leading to the discovery of vibegron and a summary of its preclinical profile are described.

Perioperative use of etoricoxib reduces pain and opioid side-effects after total abdominal hysterectomy: a double-blind, randomized, placebo-controlled phase III study.

Abstract Objective: To evaluate the effects of two different doses of etoricoxib delivered perioperatively compared with placebo and standard pain management on pain at rest, pain with mobilization, and use of additional morphine/opioids postoperatively. Research design and methods: In this double-blind, placebo-controlled, randomized clinical trial, we evaluated postoperative pain following total abdominal hysterectomy over 5 days in patients receiving placebo or etoricoxib administered 90 min prior to surgery and continuing postoperatively. Patients were randomly assigned to receive either placebo (n = 144), etoricoxib 90 mg/day (n = 142), or etoricoxib 120 mg/day (n = 144). Average Pain Intensity at Rest over days 1–3 (0- to 10-point numerical rating scale [NRS]) was the primary efficacy endpoint. Secondary endpoints included Average Pain Intensity upon Sitting, Standing, and Walking over days 1–3 (0- to 10-point NRS) as well as Average Total Daily Dose of Morphine over days 1–3. Clinical trial registration: This trial is registered on www.clinicaltrials.gov (NCT00788710). Results: The least squares (LS) means (95% CI) for the primary endpoint were 3.26 (2.96, 3.55); 2.46 (2.16, 2.76); and 2.40 (2.11, 2.69) for placebo, etoricoxib 90 mg, and etoricoxib 120 mg, respectively, significantly different for both etoricoxib doses versus placebo (p < 0.001). Patients on etoricoxib 90 mg and 120 mg required ∼30% less morphine per day than those on placebo (p < 0.001), which led to more rapid bowel recovery in the active treatment groups by ∼10 hours vs. placebo. A greater proportion of patients on etoricoxib (10–30% greater than placebo) achieved mild levels of pain with movement, defined as pain ≤3/10. Limitations: A key limitation for this study was that movement-evoked pain measurements were not designated as primary endpoints. Conclusion: In patients undergoing total abdominal hysterectomy, etoricoxib 90 mg and 120 mg dosed preoperatively and then continued postoperatively significantly reduces both resting and movement-related pain, as well as reduced opioid (morphine) consumption that led to more rapid bowel recovery.

Pharmacological Characterization of a Novel Beta 3 Adrenergic Agonist, Vibegron: Evaluation of Antimuscarinic Receptor Selectivity for Combination Therapy for Overactive Bladder

Although the physiologic role of muscarinic receptors in bladder function and the therapeutic efficacy of muscarinic antagonists for the treatment of overactive bladder are well established, the role of β3-adrenergic receptors (β3ARs) and their potential as therapeutics is just emerging. In this manuscript, we characterized the pharmacology of a novel β3AR agonist vibegron (MK-4618, KRP-114V) and explored mechanistic interactions of β3AR agonism and muscarinic antagonism in urinary bladder function. Vibegron is a potent, selective full β3AR agonist across species, and it dose dependently increased bladder capacity, decreased micturition pressure, and increased bladder compliance in rhesus monkeys. The relaxation effect of vibegron was enhanced when combined with muscarinic antagonists, but differentially influenced by muscarinic receptor subtype selectivity. The effect was greater when vibegron was co-administered with tolterodine, a nonselective antagonist, compared with coadministration with darifenacin, a selective M3 antagonist. Furthermore, a synergistic effect for bladder strip relaxation was observed with the combination of a β3AR agonist and tolterodine in contrast to simple additivity with darifenacin. To determine expression in rhesus bladder, we employed a novel β3AR agonist probe, [3H]MRL-037, that selectively labels β3 receptors in both urothelium and detrusor smooth muscle. Vibegron administration caused a dose-dependent increase in circulating glycerol and fatty acid levels in rhesus and rat in vivo, suggesting these circulating lipids can be surrogate biomarkers. The translation of our observation to the clinic has yet to be determined, but the combination of β3AR agonists with M2/M3 antimuscarinics has the potential to redefine the standard of care for the pharmacological treatment of overactive bladder.

Evaluation of an experimental urodynamic platform to identify treatment effects: A randomized, placebo-controlled, crossover study in patients with overactive bladder†‡

To evaluate a urodynamic platform designed to identify treatment effects in small numbers of patients after a short duration of treatment using a medication with known efficacy in overactive bladder (OAB).

ROLE OF URODYNAMICS ON CLINICAL DECISION-MAKING IN PATIENTS WITH URINARY INCONTINENCE AND VOIDING DYSFUNCTION

analysis, we used the prolapse (POPDI) and urinary (UDI) subscales of the PFDI. We used Wilcoxon ranked test and McNemar test for repeated parametric and categorical variables, respectively. RESULTS: Thirty-three women with a mean age of 79 years (65-90) were included in the analysis. The median follow-up was 9 months (3-23 months). Prior to surgery, the median POP-Q stage was 3 (range 2-4). Nearly all (91%) had some incontinence symptoms, and 80% reported symptoms of stress urinary incontinence (SUI). Preoperative urodynamic diagnoses included: urodynamic stress incontinence (USI)

Vibegron (RVT-901/MK-4618/KRP-114V) Administered Once Daily as Monotherapy or Concomitantly with Tolterodine in Patients with an Overactive Bladder: A Multicenter, Phase IIb, Randomized, Double-blind, Controlled Trial

BACKGROUND Antimuscarinics have shown modest efficacy with unwanted side effects in patients with overactive bladder (OAB). Efficacy of vibegron, a new β3-adrenergic receptor agonist, for OAB is unknown. OBJECTIVE To evaluate the efficacy of once-daily oral vibegron in OAB patients (primary), and its safety, tolerability, and efficacy when administered alone or concomitantly with tolterodine (secondary). DESIGN, SETTING, AND PARTICIPANTS International, phase IIb, randomized, double-blind, placebo- and active comparator-controlled, two-part superiority trial (2011-2013) in OAB-wet or OAB-dry patients aged 18-75 yr (NCT01314872). INTERVENTIONS Part 1: once-daily oral vibegron monotherapy (3 [V3], 15 [V15], 50 [V50], or 100 [V100] mg), tolterodine extended release 4mg (TER4), or placebo for 8 wk, or combination V50/TER4 for 4 wk and then V50 for 4 wk; part 2: V100/TER4, V100, TER4, or placebo for 4 wk. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Average daily micturitions at week 8 of part 1 (primary); urge incontinence episodes, total incontinence episodes, and urgency episodes (secondary). RESULTS AND LIMITATIONS Overall, 1395 patients were randomized. From baseline to week 8, V50 and V100 significantly decreased average daily micturitions (least square mean difference [95% confidence interval], -0.64 [-1.11, -0.18]; p=0.007 and -0.91 [-1.37, -0.44]; p<0.001, respectively) and the number of urge incontinence episodes (-0.72 [-1.11, -0.33] and -0.71 [-1.10, -0.32], respectively; both p<0.001) versus placebo. All vibegron doses were well tolerated. The incidence of dry mouth was higher with TER4 than with vibegron monotherapy. Results are limited by the relatively short treatment duration. CONCLUSIONS Once-daily V50 and V100 improved OAB symptoms; vibegron was well tolerated as monotherapy and concomitantly with tolterodine. Further development is warranted. PATIENT SUMMARY Antimuscarinics, commonly used to treat overactive bladder, produce modest efficacy and unwanted side effects. In this study, a different type of drug (vibegron) was efficacious and safe, alone or with an antimuscarinic (tolterodine).

An Open-Label, Randomized, Two-Period Crossover Study of the NuvaRing Applicator in Healthy Women [8N]

INTRODUCTION: NuvaRing®, a contraceptive vaginal ring, is inserted by the user with her fingers. An applicator has been developed as an optional insertion aid. This study assessed performance, tolerability, and safety of a new applicator. METHODS: Women aged 18–45 years not currently using NuvaRing® were enrolled at 2 centers in this 2-period crossover study. Women were randomly assigned to either applicator or fingers in the first period and the other method in the second. For both periods, the ring was in place for 24–72 h; questionnaires were administered immediately following ring insertion and at removal. The second period occurred 48–72 h after removal of the first ring. RESULTS: 164 women (mean age 30.2 years) were randomized: 163 completed the applicator period, 162 completed the fingers period. Insertion was 100% successful with both methods. Ring expulsion occurred in 1 and 2 women, respectively, with applicator and fingers. Among randomized subjects, 8.6% and 4.3%, respectively, reported at least 1 treatment-related adverse event (AE); all were mild and were mostly considered related to the ring rather than the insertion method. Five AEs (4 events [2.5%] of vulvovaginal pain, 1 episode [0.6%] of abdominal cramping) were considered related to the applicator. The 4 AEs of mild pain (eg, “pinching”) lasted less than 1 minute and resolved spontaneously. Bleeding did not occur during or up to 15 h following applicator use; mild events occurred more commonly during follow-up after applicator use (3.1% and 0.6%, respectively). CONCLUSION: The NuvaRing® Applicator is an effective and well-tolerated optional NuvaRing® insertion aid.

Safety and efficacy of the NuvaRing® Applicator in healthy females: a multicenter, open-label, randomized, 2-period crossover study.

INTRODUCTION We assessed performance and safety of the NuvaRing® Applicator. METHODS We randomized women (18-45 years) to insert a placebo ring using the applicator or fingers-only and then vice versa. We assessed outcomes post-insertion and then 24-72 h later. RESULTS Insertion was 100% successful using both methods (applicator, n=163; fingers-only, n=162). A total of 8.6% (applicator) and 4.3% (fingers-only) of subjects reported at least 1 treatment-related adverse event (AE); all were mild. Subjects reported 5 applicator-related AEs (vulvovaginal pain, 4; abdominal cramping, 1). There was no vaginal bleeding within 15 h post-applicator use. Ring expulsions were rare (applicator, 1; fingers-only, 2). CONCLUSION NuvaRing Applicator is effective and well-tolerated (NCT02275546).

Authors' response to Cartwright R, Renganathan A, Cardozo C. Letter to the editor re: Frenkl TL, Railkar R, Palcza J, et al. variability of urodynamic parameters in patients with overactive bladder. Neurourol urodyn 2011;31:605†‡

Our urodynamic studies sought to enroll patients that were comparable to patients enrolled in traditional Phase II and Phase III OAB studies, which in turn are intended to reflect the broader OAB population. Eligibility was based on clinical history and bladder diary criteria of frequency and urge incontinence. It is known that only about half of patients with clinical OAB, both with and without urgency incontinence, demonstrate detrusor overactivity on urodynamics. Concentrating research efforts on detrusor overactivity alone would exclude half of the relevant population of patients. Furthermore, determination of detrusor overactivity on cystometrograms is not trivial, and changes in detrusor overactivity that are associated with symptom improvement have not been defined in the literature. For these reasons, detrusor overactivity was neither necessary for inclusion in the studies nor was it a primary endpoint, and meaningful conclusions regarding detrusor overactivity could not be drawn from these particular data sets. In contrast to the current status of detrusor overactivity, maximum bladder capacity, measured by cystometry or voided volume, is relevant to the OAB patient whether or not detrusor overactivity is present on urodynamics. An increase in bladder capacity would not only result in less frequency but may also reflect an improvement in urgency as urgency is also a driver for other lower urinary tract symptoms with a proven direct causative effect to reduce intervoid intervals. We refute the notion that patients enrolled in both studies were ‘‘entirely unrepresentative of typical overactive bladder patients’’ based solely on the baseline average maximum bladder capacity. First, patients were included only if they had a clinical history of overactive bladder and met the traditional bladder diary criteria used in clinical trials of overactive bladder. Second, MCC in similar ranges have been reported in multiple urodynamic trials of overactive bladder patients. We acknowledge that variability will exist among every cohort and our cohort is on the lower range of the spectrum but there is no valid reason to conclude that the patients included in these studies were not representative of the OAB population. We fully agree that patient-important outcomes should be a priority in drug development and this is supported by the inclusion of patient-reported outcomes in most Phase II and III clinical trials. As acknowledged in our article, a urodynamic trial is not intended to replace large-scale studies measuring patient-important outcomes. Rather, urodynamic trials would compliment these large-scale studies by providing a potential physiologic explanation for the observed therapeutic benefit. Drug development for OAB requires reliable, rapid methods to show biological activity for new compounds in humans beyond establishing drug exposure. Using a rapid and sensitive urodynamics assessment, platform should speed drug development and allow later stages of development to focus on the appropriate dose range for compounds showing some evidence of activity. In this way, our pharmacological platform will increase the likelihood of improving therapeutic options in this field. Some drugs may be effective in OAB that do not act via a mechanism that is detectable with any urodynamic endpoint. This platform is suitable for use with molecules with a strong biological hypothesis to benefit patients through appropriate mechanisms, but not all.