To evaluate the potential of mirabegron, a selective β3-adrenoceptor agonist, for treatment of overactive bladder (OAB) symptoms.
To evaluate the potential of mirabegron, a selective β3-adrenoceptor agonist, for treatment of overactive bladder (OAB) symptoms.
A multicenter, randomized, double-blind, double-dummy, parallel group, placebo and active-controlled, Phase 2, proof-of-concept study was conducted. Eligible patients (n = 314) were enrolled into a single-blind, 2-week placebo run-in period followed by a randomized, double-blind, placebo-controlled treatment period. Patients received mirabegron 100 or 150 mg twice-daily (BID), placebo or tolterodine 4 mg extended release (ER) once-daily for 4 weeks. Primary endpoint was change from baseline to end-of-treatment in mean number of micturition episodes per 24 hr. Secondary endpoints included changes in mean volume voided per micturition; mean number of urinary incontinence, urgency urinary incontinence, and urgency episodes per 24 hr; severity of urgency; nocturia, and quality of life measures. Safety parameters included adverse events, laboratory tests, electrocardiogram parameters and post-void residual volume.
Mirabegron 100 and 150 mg BID resulted in a statistically significant improvement versus placebo in mean change from baseline to end-of-treatment in the primary endpoint of micturition frequency (2.2 micturitions/24 hr vs. 1.2 micturitions/24 hr for both doses, adjusted P ≤ 0.01 for both comparisons). Mirabegron had a statistically significant effect versus placebo for most secondary endpoints, including quality of life variables. Despite a small increase in pulse rate, mirabegron demonstrated good safety and tolerability.
Mirabegron was efficacious and well tolerated in patients with OAB symptoms and heralds the first of a new class of oral pharmacological therapy for OAB for more than 30 years. Neurourol. Urodynam. 32:1116–1122, 2013. © 2013 Wiley Periodicals, Inc.
Overactive bladder (OAB) is a disorder of the filling phase of the bladder, characterized by symptoms of urgency, urinary frequency and nocturia, with or without urgency incontinence in the absence of any other underlying pathology. It is a highly prevalent disorder estimated to affect 50–100 million people worldwide. OAB has been proposed to be consequent upon increased afferent activity, decreased inhibitory control, and increased sensitivity of the detrusor muscle to efferent stimulation. Current pharmacotherapy for OAB consists primarily of antimuscarinics which also affect the salivary gland, intestine, and eye, producing undesirable side effects such as dry mouth, constipation, and blurred vision. Together with an often insufficient response to treatment, these side effects lead to the low compliance seen with antimuscarinic therapy.
The β-adrenoceptor is classified into β1, β2, and β3 subtypes. The β3 subtype, first identified in adipose tissue, has also been identified in bladder smooth muscle tissue (detrusor muscle). In the human bladder, the β3-adrenoceptor subtype was identified to promote detrusor relaxation and urine storage.[6-8] β3-adrenoceptor mRNA is predominantly expressed in the human urinary bladder, with 97% of the total β-adrenoceptor mRNA expressed by the β3 subtype and only 1.5% and 1.4% expressed by the β1 and β2 subtypes, respectively. These observations suggest that drugs acting at β3-adrenoceptors may have therapeutic potential.[9, 10]
The results of an initial Phase 2 clinical trial of mirabegron (clinicaltrials.gov: NCT01604928; formerly referred to as YM178, Astellas Pharma, Inc., Northbrook, IL) in patients with OAB are presented here.
Men and women ≥18 years of age were enrolled in the study. Patients had symptoms of OAB (urinary frequency and urgency with or without urgency incontinence) for ≥3 months; a frequency of micturition on average ≥8 times/24 hr; and ≥3 episodes of urgency (grade 3 or 4), with or without incontinence, during the 3-day micturition diary period.
Major exclusion criteria included clinically significant outflow obstruction; significant post-void residual (PVR) volume (>200 ml); incontinence where stress was the predominant factor; indwelling catheters or intermittent self-catheterization; neurological causes for abnormal detrusor activity; diabetic neuropathy; symptomatic bladder disorders, bladder stones, previous pelvic radiation therapy or previous or current malignant disease of the pelvic organs; contraindications for anticholinergics such as uncontrolled narrow angle glaucoma, other recognized pathologies affecting the urinary or colorectal systems; non-drug treatment including electro-stimulation therapy; use of other urinary incontinence medications; known or suspected hypersensitivity to tolterodine, other anticholinergics, mirabegron, lactose, or any of the excipients; clinically significant cardiovascular or cerebrovascular disease; any other condition making the patient unsuitable for the study (as deemed by the investigator).
This was a multinational, multicenter, randomized, double-blind, double-dummy, parallel group, placebo and active-controlled Phase 2 proof-of-concept study. Patients were enrolled into a single-blind, 2-week placebo run-in period and then randomized, using an interactive voice response system, to 4 weeks of double-blind treatment with mirabegron 100 or 150 mg twice daily (BID), placebo, or tolterodine 4 mg extended release (ER) once-daily (QD).
The study was conducted in accordance with Good Clinical Practice guidelines and the principles of the Declaration of Helsinki (1996). The study protocol and amendment, and informed consent form were reviewed and approved by the local Independent Ethics Committees before initiation of the study. Patients provided written informed consent before any study procedures were performed.
There were six study visits: visit 1 (screening); visit 2 (baseline) after the placebo run-in period; visits 3, 4, and 5 after 1, 2, and 4 weeks of double-blind treatment; and visit 6 after a 2-week placebo follow-up period.
At visit 1, patients received a micturition diary which was to be completed during the 3-day period preceding all visits after screening. At visit 2, diary scores were checked against inclusion criteria to confirm study eligibility. For each micturition or incontinence episode, patients were asked to rate the degree of associated urgency on a 5-point categorical scale (0, no urgency; 1, mild urgency; 2, moderate urgency; 3, severe urgency; and 4, urgency incontinence).
Since OAB symptoms have a significant impact on quality of life, the impact of treatment on quality of life was assessed. Patients' perception of their bladder condition was evaluated once per visit, starting at visit 2, by completing the statement “my bladder condition …” with one of the following: “does not cause me any problems,” “causes me some very minor problems,” “causes me some minor problems,” “causes me some moderate problems,” causes me severe problems,” or “causes me many severe problems.” Patients' assessment of treatment benefit was also evaluated once per visit, starting at visit 2, with the question “has the treatment been of any benefit to you?” and three possible responses of “no,” “yes, a little,” or “yes, very much.”
Adverse events were assessed and blood pressure and pulse rate were measured at each study visit. Twelve-lead ECGs were carried out at visits 1 and 5 (and visit 6 if the visit 5 result was clinically significantly different from baseline). Blood and urine samples for safety assessments (hematology, biochemistry, urinalysis, and urine culture) were collected by a central laboratory at visits 1, 3, 4, 5, and 6, and PVR was assessed by ultrasonography or bladder scan at visits 1, 5, and 6.
The primary efficacy endpoint was change from baseline to end-of-treatment in mean number of micturitions per 24 hr. Secondary endpoints included changes from baseline to end-of-treatment in mean volume voided per micturition; mean number of urinary incontinence and urgency urinary incontinence episodes, and urgency episodes per 24 hr; severity of urgency; nocturia; and patients' perception of bladder condition and treatment benefit. Safety endpoints were incidence and severity of adverse events, and changes from baseline to end-of-treatment in vital signs, laboratory tests, ECG parameters, and PVR.
As this was the first efficacy study for mirabegron in OAB, no accurate estimate of inter-patient standard deviation was available; therefore, no formal sample size calculation was done. It was estimated that 244 patients should be randomized in order to have a sample size of at least 200 patients (50 patients in each of the placebo, mirabegron 100 and 150 mg BID and tolterodine ER 4 mg QD groups). These numbers were chosen based on medical grounds.
To obtain an estimate of the power of the study, the inter-patient standard deviation from a large phase 3 European study of an antimuscarinic treatment in the same indication and with the same primary endpoint was utilized. In that study, the inter-patient standard deviation of the primary variable, change from baseline to endpoint in mean number of micturition per 24 hr, was estimated to be approximately 3.3. A sample size of 50 patients in each group provided 80% power to detect a difference in means of approximately 1.9 for the primary endpoint and 1.3 for the secondary endpoints using a 2-group t-test with a 0.05 2-sided significance level.
Changes from baseline to end-of-treatment in mean number of micturitions per 24 hr (primary analysis) were assessed using a mixed model with treatment group as a fixed factor and center as a random factor. The baseline value of mean number of micturitions per 24 hr was included in the models as a covariate. Comparison of the mirabegron doses to placebo was tested at the 2-sided significance level of 0.05 taking into account a Bonferroni–Holm adjustment for multiplicity. This analysis was also performed for the secondary efficacy variables. The percentages of patients responding for micturition frequency, incontinence, urgency, and nocturia episodes per 24 hr were compared between the treatment groups using logistic regression in which the dependent variable was dichotomous (i.e., patients were responders or non-responders) and the mean number of episodes (micturitions, incontinence, urgency incontinence, or nocturia) were covariates in the model. For micturition frequency, a responder was defined as a patient with a mean number of micturitions per 24 hr <8 during a specified diary period. For symptom urgency (severity ≥3), incontinence and nocturia, a responder was defined a patient with ≥1 episode of the symptom at baseline and no episodes of that symptom during a specified diary period. Frequencies and percentages for patients' assessment of bladder condition and treatment benefit at end-of-treatment were calculated; logistic regression was performed for comparisons versus placebo. Safety variables were analyzed descriptively.
A total of 314 patients were enrolled in the study and 262 were randomized (the 52 patients who were not randomized failed to satisfy the inclusion criteria at randomization). Two hundred sixty patients received at least 1 dose of study medication and had any data reported after the first dose (safety analysis set); of these, 255 patients also had primary efficacy data at baseline and at least one post-baseline visit (full analysis set). The proportion of patients who discontinued the study was 7% and was comparable across treatment groups (Fig. 1). The study groups were comparable with respect to demographic characteristics, type of OAB, and prior drug therapy (Table I). Across treatment groups, >99% of patients were White and >85% were females; mean duration of exposure to study medication was approximately 30 days; and compliance ranged from 98.5% to 99.4%.
|Characteristic||PBO (N = 64)||MIRA, 100 mg BID (N = 65)||MIRA, 150 mg BID (N = 63)||TOL, 4 mg ER QD (N = 63)|
|Age—year, mean ± SD||55.2 ± 13.3||58.4 ± 13.9||55.4 ± 13.5||59.0 ± 13.3|
|Male||11 (17.2)||10 (15.4)||8 (12.7)||9 (14.3)|
|Female||53 (82.8)||55 (84.6)||55 (87.3)||54 (85.7)|
|Asian||0 (0.0)||0 (0.0)||1 (1.6)||0 (0.0)|
|Black||0 (0.0)||0 (0.0)||0 (0.0)||0 (0.0)|
|White||63 (98.4)||65 (100.0)||62 (98.4)||63 (100.0)|
|Other||1 (1.6)||0 (0.0)||0 (0.0)||0 (0.0)|
|Type of incontinence—n (%)|
|Urgency incontinence only||29 (45.3)||25 (38.5)||27 (42.9)||29 (46.0)|
|Mixed incontinencea||14 (21.9)||17 (26.2)||18 (28.6)||16 (25.4)|
|Without incontinence||21 (32.8)||23 (35.4)||18 (28.6)||18 (28.6)|
|Prior drug therapy—n (%)|
|Yes, at least 1 effective||12 (18.8)||22 (33.8)||17 (27.0)||21 (33.3)|
|Yes, none effective||22 (34.4)||15 (23.1)||13 (20.6)||18 (28.6)|
|No||30 (46.9)||28 (43.1)||33 (52.4)||24 (38.1)|
|Non-drug therapy—n (%)||17 (26.6)||6 (9.2)||26 (41.3)||26 (41.3)|
For the primary efficacy endpoint, change from baseline to end-of-treatment in mean number of micturitions per 24 hr, mirabegron 100 and 150 mg BID both resulted in a statistically significant reduction (improvement) in micturition frequency of 2.2 micturitions per 24 hr compared to a reduction of 1.2 micturitions per 24 hr in the placebo group (P ≤ 0.01 for both comparisons). A reduction of 1.5 micturitions per 24 hr was noted for tolterodine ER 4 mg QD (not significant versus placebo) (Table II).
|PBO||MIRA, 100 mg BID||MIRA, 150 mg BID||TOL, 4 mg ER QD|
|Micturitions/24 hr||N = 64||N = 65||N = 63||N = 63|
|Baseline value (±SD)||12.34 (3.51)||11.30 (2.65)||12.25 (3.62)||11.00 (3.06)|
|Adjusted mean CFB||−1.175||−2.191||−2.206||−1.487|
|Est. difference from placebo||−1.016**||−1.031**||−0.399|
|95% CIs||−1.673, −0.357||−1.688, −0.372||−1.055, 0.258|
|Mean volume voided/micturition (ml)||N = 64||N = 65||N = 63||N = 63|
|Baseline value (±SD)||151.8 (58.3)||164.7 (62.9)||150.7 (53.5)||179.9 (65.2)|
|Adjusted mean CFB||10.483||26.041||32.733||23.768|
|Est. difference from placebo||15.56||22.25*||13.10|
|95% CIs||−0.136, 31.252||6.480, 38.020||−2.705, 28.909|
|Incontinence episodes/24 hr||N = 41||N = 37||N = 41||N = 41|
|Baseline value (±SD)||2.41 (1.69)||2.50 (2.53)||3.57 (3.47)||2.95 (2.52)|
|Adjusted mean CFB||−1.011||−2.167||−1.579||−1.647|
|Est. difference from placebo||−1.156*||−0.568||−0.612|
|95% CIs||−1.934, −0.377||−1.338, 0.202||−1.343, 0.120|
|Nocturia episodes/24 hr||N = 57||N = 58||N = 54||N = 58|
|Baseline value (±SD)||1.88 (1.16)||1.84 (0.97)||1.92 (1.008)||1.84 (1.08)|
|Adjusted mean CFB||−0.22||−0.608||−0.391||−0.407|
|Est. difference from placebo||−0.388*||−0.171||−0.196|
|95% CIs||−0.652, −0.123||−0.440, 0.099||−0.467, 0.075|
|Urgency incontinence episodes/24 hr||N = 40||N = 37||N = 39||N = 39|
|Baseline value (±SD)||2.10 (1.54)||2.41 (2.50)||3.47 (3.39)||2.70 (2.11)|
|Adjusted mean CFB||−1.09||−2.058||−1.443||−1.529|
|Est. difference from placebo||−0.968*||−0.353||−0.44|
|95% CIs||−1.729, −0.206||−1.122, 0.415||−1.163, 0.284|
|Urgency episodes/24 hr (severity ≥3)||N = 64||N = 65||N = 62||N = 63|
|Baseline value (±SD)||5.88 (3.40)||5.52 (3.47)||6.58 (4.34)||5.55 (3.64)|
|Adjusted mean CFB||−1.03||−2.298||−2.302||−2.085|
|Est. difference from placebo||−1.268*||−1.271*||−1.087|
|95% CIs||−2.316, −0.219||−2.337, −0.205||−2.112, −0.060|
The percentage of patients classified as responders for micturition frequency at end-of-treatment was 12.5% for the placebo group, 32.3% and 22.2%, respectively, for the mirabegron 100 and 150 mg BID groups and 27.0% for the tolterodine ER 4 mg QD group.
Mirabegron 100 and 150 mg BID showed statistically significant reductions from baseline to end-of-treatment in urgency episodes (2.3 for both doses vs. 1.0 for placebo; P ≤ 0.05 for both comparisons). Mirabegron 150 mg BID also resulted in a statistically significant increase versus placebo from baseline to end-of-treatment in mean volume voided per micturition (32.7 ml vs. 10.5 ml, P ≤ 0.05). Compared with placebo, mirabegron 100 mg BID resulted in statistically significant improvements in incontinence episodes (2.2 episodes/24 hr vs. 1.0 episodes/24 hr, P ≤ 0.01); urgency incontinence episodes (2.1 episodes/24 hr vs. 1.1 episodes/24 hr, P ≤ 0.05); and nocturia episodes (0.6 episodes/24 hr vs. 0.2 episodes/24 hr, P ≤ 0.01) (Table II). Efficacy was apparent as early as 2 weeks after commencing therapy. There were no statistically significant differences between tolterodine ER 4 mg QD and placebo for any of the secondary endpoints (Table II). For most variables, the de-challenge in the placebo follow-up period confirmed the existence of a mirabegron treatment effect in the double-blind treatment period.
The percentage of patients classified as responders for the placebo, mirabegron 100 and 150 mg BID and tolterodine ER 4 mg QD groups at end-of-treatment was 34.1%, 64.9%, 46.3%, and 34.1%, respectively for incontinence episodes; 6.3%, 18.5%, 14.5%, and 12.7%, respectively for urgency episodes; and 1.8%, 10.3%, 5.6% and 15.5%, respectively for nocturia episodes.
The percentage of patients classified as “responders” at end-of-treatment (defined as improvement of at least one category compared to baseline) for patients' perception of their bladder condition was higher for mirabegron than placebo (53%, 55%, and 68% for placebo, mirabegron 100 and 150 mg BID, respectively; P < 0.05 for mirabegron 150 mg BID vs. placebo). Similarly, 17%, 28%, and 33% of patients in the placebo, mirabegron 100 and 150 mg BID groups, respectively, reported improvement of at least two categories at end-of-treatment compared to baseline (P < 0.05 for mirabegron 150 mg BID vs. placebo). The difference in the proportion of responders (improvement of at least one category) was also statistically significant for tolterodine ER 4 mg QD versus placebo (60% vs. 53%, P < 0.05).
The percentage of patients classified as “responders” at end-of-treatment (defined as improvement of at least one category compared to baseline) for patients' assessment of treatment benefit was higher for mirabegron than placebo at 50%, 60%, and 71% for placebo, mirabegron 100 and 150 mg BID, respectively (P < 0.05 vs. placebo for both comparisons). The difference in the proportion of responders was also statistically significant for tolterodine ER 4 mg QD versus placebo (75% vs. 50%, P < 0.001).
The incidence of treatment-related adverse events was comparable for the mirabegron and placebo treatment groups (Table III). The rate of discontinuation due to adverse events was low at 1.5% (placebo), 4.6% (mirabegron 100 mg BID), 7.7% (mirabegron 150 mg BID), and 3.1% (tolterodine ER 4 mg QD). In total, 11 patients discontinued due to adverse events after they had entered the double-blind treatment period. Adverse events leading to discontinuation were angina pectoris (considered serious) in one patient in the placebo group; and exanthema, fatigue (considered serious, but deemed not related to treatment), nausea and dizziness, each occurring in one patient in the mirabegron 100 mg group. A further seven patients in the mirabegron 150 mg group discontinued due to adverse events; one due to palpitations, vertigo, blurred vision and dry mouth; one due to nausea, dizziness and hot flush; one due to rash and increased ALAT and ASAT; and one patient each due to vomiting, allergic dermatitis, urticaria, and rash (considered serious). Except for the case of fatigue, all were considered to be possibly or probably related to study medication. There were no serious adverse events in mirabegron-treated patients and no deaths during the study.
|System organ class preferred term||PBO (N = 66)||MIRA, 100 mg BID (N = 65)||MIRA, 150 mg BID (N = 65)||TOL, 4 mg ER QD (N = 64)|
|Overall||16 (24.2)||12 (18.5)||16 (24.6)||17 (26.6)|
|Cardiac disorders||3 (4.5)||0 (0.0)||3 (4.6)||1 (1.6)|
|Palpitations||1 (1.5)||0 (0.0)||3 (4.6)||0 (0.0)|
|Ear and labyrinth disorders||2 (3.0)||0 (0.0)||1 (1.5)||0 (0.0)|
|Vertigo||2 (3.0)||0 (0.0)||1 (1.5)||0 (0.0)|
|Eye disorders||0 (0.0)||0 (0.0)||2 (3.1)||0 (0.0)|
|Gastrointestinal disorders||2 (3.0)||4 (6.2)||9 (13.8)||11 (17.2)|
|Diarrhea||0 (0.0)||1 (1.5)||0 (0.0)||2 (3.1)|
|Dry mouth||1 (1.5)||0 (0.0)||4 (6.2)||3 (4.7)|
|Nausea||0 (0.0)||1 (1.5)||1 (1.5)||2 (3.1)|
|Vomiting||0 (0.0)||1 (1.5)||3 (4.6)||0 (0.0)|
|General disorders and administration site conditions||3 (4.5)||0 (0.0)||2 (3.1)||1 (1.6)|
|Fatigue||2 (3.0)||0 (0.0)||0 (0.0)||0 (0.0)|
|Infections and infestations||2 (3.0)||1 (1.5)||0 (0.0)||1 (1.6)|
|Investigations||2 (3.0)||1 (1.5)||2 (3.1)||1 (1.6)|
|Musculoskeletal and connective tissue disorders||2 (3.0)||1 (1.5)||0 (0.0)||1 (1.6)|
|Nervous system disorders||4 (6.1)||4 (6.2)||5 (7.7)||7 (10.9)|
|Dizziness||0 (0.0)||1 (1.5)||3 (4.6)||1 (1.6)|
|Headache||2 (3.0)||3 (4.6)||3 (4.6)||4 (6.3)|
|Skin and subcutaneous tissue disorders||0 (0.0)||4 (6.2)||2 (3.1)||2 (3.1)|
|Exanthem||0 (0.0)||2 (3.1)||0 (0.0)||0 (0.0)|
|Vascular disorders||0 (0.0)||2 (3.1)||0 (0.0)||2 (3.1)|
Mirabegron 150 mg BID caused a small (5 beats per minute [bpm]) mean increase from baseline in pulse rate. The effects of mirabegron 100 mg BID and tolterodine ER 4 mg QD on pulse rate (observed increases of −0.7 to 1.4 bpm) were not clinically relevant. There were also no clinically relevant effects on systolic and diastolic blood pressures, ECG, laboratory parameters, physical examination findings, or PVR.
Mirabegron activates β3-adrenoceptors in the detrusor muscle to actively relax precontracted human detrusor muscle strips and thereby promote filling of the bladder and hence urine storage.[14, 15] These pre-clinical results prompted the current proof-of-concept study in which total daily doses of 200 and 300 mg (100 and 150 mg BID, respectively) were evaluated for clinical effectiveness close to the maximum tolerable dose (previously shown to be 240 mg with multiple dose administration under fasting conditions). The proof-of-concept was successfully proven in this study. Since no difference in efficacy was seen between the 100 and 150 mg BID mirabegron doses, we conclude that a total daily dose of 200 mg provides maximum therapeutic efficacy. However, it should be noted that the size of effect observed for tolterodine ER in this study was smaller than seen previously.
Through stimulation of β3 receptors and relaxation of the bladder during filling, mirabegron demonstrated improvement in OAB symptoms by utilizing pathways distinct to that of antimuscarinics. Mirabegron produced consistently positive effects compared with placebo on the various symptoms of OAB. In addition, more mirabegron-treated patients became continent and experienced improvement in quality of life parameters, providing further evidence that treatment with mirabegron may provide a clinically meaningful benefit to patients with OAB symptoms. A higher responder rate for micturition frequency in the mirabegron 100 mg group compared with the mirabegron 150 mg group is of no significance and can be explained by the fact that the baseline value for micturition frequency is lower in the 100 mg than in the 150 mg mirabegron groups (Table II).
Mirabegron exhibited a good balance between efficacy and tolerability which could potentially improve treatment compliance compared to what is seen with antimuscarinics and the incidence of adverse events with mirabegron was intermediate between that seen with placebo and tolterodine (active control) with no clinically meaningful increase in PVR. The incidence of dry mouth was low and when it occurred, was often milder with mirabegron (3.1% for the combined groups) than tolterodine (4.7%). This observation is important since dry mouth is consistently the most common complaint with antimuscarinic therapy. At the efficacy plateau of 200 mg daily, the side effect profile of mirabegron was similar to that of placebo. While there appeared to be a small mean increase from baseline in pulse rate in the mirabegron (150 mg BID) group, this was not associated with a clinically significant increase in cardiovascular adverse events such as tachycardia and palpitations. Moreover, there was no clinically relevant effect of treatment on blood pressure, ECG parameters, laboratory safety parameters, or physical examination findings.
Existing antimuscarinic therapy has the disadvantage of a high prevalence of unpleasant and sometimes intolerable side effects. Mirabegron is effective in the treatment of the symptoms of OAB, with treatment effects that are similar to those seen with conventional antimuscarinic therapy. Moreover, it has a good safety profile and improved tolerability, and is thus the first in this new class of oral pharmacological therapy for OAB for over 30 years. The results of larger phase 3 placebo-controlled studies are awaited for more definitive conclusions.
The study was designed by the authors from Astellas Pharma in collaboration with the other authors. Data were collected by the investigators at the study center and were monitored and analyzed by personnel at Astellas. All of the authors participated in the interpretation of the data and writing of the manuscript. Emad Siddiqui BSc, MBBS, MRCS, MD (Astellas Pharma Europe Ltd, Middlesex, UK), Yolanda Cartwright, PhD (Ledell, Inc.) and Envision Scientific Solutions provided assistance with the preparation of the manuscript. All authors reviewed the manuscript drafts and contributed to revision of the manuscript. The decision to submit the article for publication was made by all of the authors. The study and medical writing support was funded by Astellas Pharma.