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Low-dose Desmopressin Orally Disintegrating Tablet: Suggested Clinically Meaningful Benefit in Patients with Nocturia Due to Nocturnal Polyuria
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Neuro-urology
Low-dose Desmopressin Orally Disintegrating Tablet: Suggested Clinically Meaningful Benefit in Patients with Nocturia Due to Nocturnal Polyuria Jeffrey P. Weiss a, Egbert A. van der Meulen b, Kristian Vinter Juul b,* a
Department of Urology, SUNY Downstate Medical School, Brooklyn, New York, USA; b Ferring Pharmaceuticals, Copenhagen S, Denmark
Article info
Abstract
Article history: Accepted November 7, 2018
Background: Clinical benefit has not been evaluated much in patients with nocturia. Objective: To assess the clinical benefit of desmopressin orally disintegrating tablet (ODT) in women (25 mg) and men (50 mg) with nocturia due to nocturnal polyuria (NP). Design, setting, and patients: Patients with NP from two randomised, placebo-controlled trials in men (CS41) and women (CS40) with two or more nocturnal voids per night were included. Outcome measurements and statistical analysis: Change from baseline in nocturnal voids, 33% and 50% responder status (average reduction of 33% and 50%, respectively, in the mean number of nocturnal voids vs baseline), and percentage of nights with at most one void or no voids (ie, complete response) during 3-mo treatment period were assessed for clinical benefit. Two-sided test (5% significance level) was used for all endpoints. Results and limitations: Demographics and baseline characteristics of patients in CS41 (N = 230) and CS40 (N = 232) were similar. A greater reduction in the mean number of nocturnal voids was seen with desmopressin ODT in men (treatment difference [TD]: 0.37 voids) compared with women (TD: 0.29 voids). For 33% and 50% responder status, TD with ODT versus placebo were 21% and 12%, respectively, in men, and 12% and 17%, respectively, in women. For the number of nights with at most one void, TDs were 11% and 13% (p < 0.009 for both) for men and women, respectively. For complete response, TD was significant in men (TD: 9%, p < 0.001). Limitations inherent in this analysis were evident as the data for cotreatments (baseline) and quality of life were not collected. Conclusions: A stronger treatment effect with desmopressin ODT versus placebo and the magnitude of differences are indicative of clinical benefit in patients with NP. Patient summary: We looked at the clinical benefit of desmopressin ODT in patients with nocturnal polyuria. We conclude that clinical benefit was observed with desmopressin ODT in these patients. © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Associate Editor: Malte Rieken Keywords: Clinical benefit Desmopressin Desmopressin orally disintegrating tablet Nocturnal polyuria
* Corresponding author. Ferring Pharmaceuticals, Kay Fiskers Plads 11, Copenhagen S, Denmark. Tel. +45 28787544; Fax: +45 28176548. E-mail address: [email protected] (K.V. Juul).
https://doi.org/10.1016/j.euf.2018.11.001 2405-4569/© 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Weiss JP, et al. Low-dose Desmopressin Orally Disintegrating Tablet: Suggested Clinically Meaningful Benefit in Patients with Nocturia Due to Nocturnal Polyuria. Eur Urol Focus (2018), https://doi.org/10.1016/j. euf.2018.11.001
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1.
Introduction
Among the various lower urinary tract symptoms (LUTS), nocturia can be considered as the most prevalent and bothersome symptom [1], occurring in both men and women, and also being associated with advancing age. Nocturia defined as “waking to pass urine during the main sleep period” [2], is essentially linked to disturbed sleep. In this context, it has previously been observed that nocturia has detrimental impact on the quality of life (QoL) and overall health of patients mainly due to sleep fragmentation [3,4], especially when two or more nocturnal voids are experienced. Clinically relevant nocturia (two or more voids per night) affects only 2–16.6% of young men (20–40 yr) and 4.4–18% of young women. However, in older (>70 yr) men and women, the rate varies between 29% and 59.3% and between 28.3% and 61.5%, respectively [1]. The treatment of nocturia is generally two pronged where behavioural interventions (restricting fluid intake, alarm therapy, etc.) are combined with pharmacological treatments such as a-blockers, 5-a-reductase inhibitors, and phosphodiesterase inhibitors [5]. However, the current treatment approach is constrained due to the complex and multifactorial aetiology of nocturia [6], making the choice of treatment difficult and often ineffective. Traditionally, treatment strategy is targeted to primarily address LUTS rather than nocturnal polyuria (NP), the commonest underlying pathophysiology in nocturia [7]. NP, sometimes defined as “excessive urine production during the patient’s main sleep period”, is reported to be present in 83% of patients with nocturia [2] and is known to result from decreased secretion of the antidiuretic hormone arginine vasopressin. Desmopressin, a synthetic vasopressin analogue, is the only drug approved for the treatment of nocturia due to NP [8], and is devoid of unwanted vasopressor and uterotonic effects [9]. To maximise the benefit, in terms of both bioavailability and minimising water intake for drug administration, desmopressin is formulated as an orally disintegrating tablet (ODT) [10]. Desmopressin ODT has been studied separately in the sex-specific pivotal trials CS41 and CS40 in patients with nocturia, where 87% had NP (defined as nocturnal polyuria index [NPi] >33%). In both the trials, statistically significant efficacy results were obtained for the coprimary endpoints, i.e., “change from baseline in the mean number of nocturnal voids” and “33% responder status”. However, it has been questioned whether the treatment effect size versus placebo reached clinical significance along with statistical significance [11,12]. This may be a consequence of lifestyle and behavioural interventions, particularly restricted fluid intake, which masks the actual clinical benefit, as reported in the urological conditions [13]. Additionally, the high placebo effect may be due to no placebo or an active run-in period before randomisation, regression to the mean, and multiple questionnaires and diaries. In addition to these factors, efficacy is further constrained by the lack of clearly defined clinically meaningful benefit in nocturia, also limiting the drug development programmes and drug approvals.
Ideally, efficacious treatment should result not only in statistically significant, but also in clinically meaningful reduction in the number of nocturnal voiding, which matter most to the patients [14]. This is because the magnitude of actual treatment effect (ie, treatment effect size) determines the likely impact of the results of the trial on the current clinical practice [15]. However, surprisingly, the current research focuses mainly on statistical significance. Therefore, it would be interesting to look at the available data for desmopressin ODT in the context of clinical benefit in the NP patients, the ideal population benefitting with antidiuretics. Here, we present the results from a post-hoc analysis of two pivotal desmopressin ODT trials (CS40 and CS41). This analysis aimed to evaluate the clinically meaningful sex-specific treatment benefit of recently approved low-doses of desmopressin ODT (25 mg in women [CS40] and 50 mg in men [CS41]) in patients with nocturia due to NP. 2.
Patients and methods
The previously published phase 3 pivotal trials were designed as randomised, double-blind, placebo-controlled, parallel-group, multicentre clinical trials including adult men (CS41; NCT01262456) [11] and women (CS40; NCT01223937) [12] with two or more nocturnal voids per night, as documented in a 3-d sleep/voiding diary. Key exclusion criteria were evidence of severe daytime voiding dysfunction (urgency incontinence [more than one episode per day] or urgency [more than one episode per day] or frequency [more than eight daytime voids per day]), polydipsia, and hyponatraemia (serum sodium <135 mmol/l) [11,12]. Briefly, patients were randomised (stratified by age <65 and 65 yr) to receive either desmopressin ODT (women, 25 mg [CS40] and men, 50 mg [CS41]), administered sublingually, or placebo once daily, 1 h prior to bedtime. All patients received behavioural intervention, i.e., emptying their bladder before going to the bed and limiting fluid intake at bedtime. This post-hoc analysis included selective population from these two trials, i.e., patients with nocturia due to NP. The NP patients comprised patients with baseline NPi >33%. Further, nocturnal void was defined as a void occurring from 5 min after going to bed with the intention to sleep until rising in the morning. The coprimary endpoints for both the previous studies were the change from baseline in nocturnal voids averaged over the treatment period, and 33% responder status (defined as an average reduction of 33% in the mean number of nocturnal voids compared with baseline over the treatment period) were evaluated for clinical benefit in this post -hoc analysis. Additionally, for this post-hoc analysis, 50% responder status (defined as an average reduction of 50% in the mean number of nocturnal voids compared with baseline over the treatment period) and percentage of nights with at most one void or no voids during the treatment period (ie, complete response) were also evaluated. The voiding data were captured in a 3-d sleep/voiding diary, and assessments were made at the visits at week 1 and months 1, 2, and 3. This post-hoc analysis was performed using the modified intentionto-treat analysis set and comprised all randomised patients who received at least one dose of the study drug. The analyses were performed by sex (men and women) and not on the pooled data considering sex-specific doses. A two-sided test (5% significance level) was used for all the endpoints. Average change from baseline to the end of the 3-mo treatment period and percentage of nights with at most one void or no voids (complete response) were analysed using an analysis of covariance. The analysis was adjusted for baseline number of voids, age (<65 or 65 yr), and treatment. Further, the responder status averaged over the
Please cite this article in press as: Weiss JP, et al. Low-dose Desmopressin Orally Disintegrating Tablet: Suggested Clinically Meaningful Benefit in Patients with Nocturia Due to Nocturnal Polyuria. Eur Urol Focus (2018), https://doi.org/10.1016/j. euf.2018.11.001
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treatment period was analysed using the Cochran–Mantel–Haenszel method, stratified by age and expressed in terms of difference in responder probabilities between the treatment groups. Change in the mean number of nocturnal voids per night from baseline was presented using cumulative distribution function (CDF) plots. Missing values were maintained as missing, and sensitivity analysis was performed to assess the impact of missing data.
3.
Results
The patient disposition is presented in Supplementary Table 1, and baseline demographics and clinical characteristics of this post-hoc analysis population are presented in Table 1. Overall, the demographics and baseline characteristics were similar across the treatment groups in both the trials. A greater reduction was noted in the mean number of nocturnal voids with desmopressin ODT versus placebo in both men and women. The treatment difference (TD) or the effect size compared with placebo was 0.37 voids (p < 0.001) in men and 0.29 voids (p < 0.05) in women (Table 2). The assessed parameters such as percentage of nights with at most one void or no voids improved with desmopressin ODT versus placebo. Further, the 33% and 50%
responder status, defined as an average reduction of 33% and 50%, respectively, in the mean number of nocturnal voids compared with baseline over the treatment period, also improved with desmopressin ODT versus placebo during the 3-mo treatment period in both men and women with nocturia due to NP. Regarding the percentage of nights with no voids, i.e., complete response, the TD between desmopressin ODT and placebo was significant in men (TD: 9%, p < 0.001). Further, for the percentage of nights with at most one void, the differences between desmopressin ODT and placebo were 11% and 13% (p < 0.009 for both) for men and women, respectively (Fig. 1). There was a higher probability of achieving 33% and 50% responder status with desmopressin ODT versus placebo in both men and women, respectively. For the 33% responder status, the TD with desmopressin ODT compared with placebo was 21% (p < 0.001) in men and 12% (p < 0.05) in women. Similarly, for the 50% responder status, the TD compared with placebo was 12% (p = 0.055) in men and 17% (p < 0.05) in women (Fig. 2). CDF plots for the mean change from baseline in the number of nocturnal voids followed a similar trend in both men and women treated with desmopressin ODT (Fig. 3A and 3 B).
Table 1 – Demographics and baseline characteristics of patients with nocturnal polyuria. CS41 (men; N = 230)
CS40 (women; N = 232)
Desmopressin ODT (N = 102)Placebo (N = 128)Total (N = 230)Desmopressin ODT (N = 118)Placebo (N = 114)Total (N = 232) Age (yr) Mean SD 60.1 13.75 Age category, N (%) 57 (55.9) <65 yr 65 yr 45 (44.1) BMI (kg/m2) 29.3 4.97 Mean SD Ethnicity, N (%) Hispanic or Latino 17 (16.7) Not Hispanic or Latino85 (83.3) No. of nocturnal voids, N (%) <2 – 54 (52.9) 2–3 32 (31.4) 3–4 4–5 11 (10.8) 3 (2.9) 5–6 2 (2.0) 6–7 >7 – Time to first void (min) 139.7 52.02 Mean SD No. of daytime voids 5.6 1.29 Mean SD Nocturnal urine volume (ml) Mean SD 658.0 351.04 NPi (%) 48.5 10.69 Mean SD No. of nocturnal voids 3.0 0.89 Mean SD Percentage of nights with at most one nocturnal void Mean SD 0.3 3.30 Percentage of nights with no nocturnal voids 0.00 0.00 Mean SD
61.4 14.42
60.8 14.11
59.0 14.65
60.3 14.23
59.6 14.43
63 (49.2) 65 (50.8)
120 (52.2) 110 (47.8)
64 (54.2) 54 (45.8)
57 (50.0) 57 (50.0)
121 (52.2) 111 (47.8)
29.2 5.29
29.2 5.14
31.4 7.02
29.5 6.53
30.5 6.84
19 (14.8) 109 (85.2)
36 (15.7) 194 (84.4)
23 (19.5) 95 (80.5)
16 (14.0) 98 (86.0)
39 (16.8) 193 (83.2)
1 (0.8) 60 (46.9) 45 (35.2) 19 (14.8) 3 (2.3) – –
1 (0.4) 114 (49.6) 77 (33.5) 30 (13.0) 6 (2.6) 2 (0.9) –
– 63 (53.4) 45 (38.1) 9 (7.6) – – 1 (0.9)
– 61 (53.5) 42 (36.8) 9 (7.9) – 1 (0.9) 1 (0.9)
– 124 (53.5) 87 (37.5) 18 (7.8) – 1 (0.4) 2 (0.9)
144.5 56.65
142.4 54.58
145.5 54.85
139.9 56.73
142.8 55.73
5.6 1.17
5.6 1.22
5.7 1.25
5.4 1.25
5.6 1.26
654.3 310.59
655.9 328.41 663.9 325.41
630.6 346.02
647.6 335.38
48.9 11.32
48.7 11.03
47.6 10.10
49.4 12.70
48.5 11.46
3.0 0.83
3.0 0.85
2.9 0.91
2.9 0.81
2.9 0.86
1.0 9.30
0.7 7.27
1.1 6.06
0.3 3.12
0.7 4.85
0.00 0.00
0.00 0.00
0.00 0.00
0.00 0.00
0.00 0.00
BMI = body mass index; N = number of patients; NPi = nocturnal polyuria index; ODT = orally disintegrating tablet; SD = standard deviation; % = percentage of patients.
Please cite this article in press as: Weiss JP, et al. Low-dose Desmopressin Orally Disintegrating Tablet: Suggested Clinically Meaningful Benefit in Patients with Nocturia Due to Nocturnal Polyuria. Eur Urol Focus (2018), https://doi.org/10.1016/j. euf.2018.11.001
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Table 2 – Change from baseline in mean number of nocturnal voids. CS41 (Men)
CS40 (Women)
Desmopressin ODT Change from baseline Treatment difference 95% CI p value
1.26 0.37 ( 0.59, <0.001
Placebo
Desmopressin ODT
0.89
1.47 0.29 ( 0.51, 0.008
0.15)
Placebo 1.18
0.08)
CI = confidence interval; ODT = orally disintegrating tablet.
4.
Discussion
Nocturia is a widespread problem with significant impact on QoL, yet there are large unmet needs. The available treatments are often ineffective due to unclear or undiagnosed underlying pathophysiology, and no consensus around the treatment effect size, i.e., the minimal clinically important difference (MCID), which should be based on both clinician’s and patients’ perspective rather than just the statistical significance. The present post-hoc analysis underlines the clinical benefit of the proposed dosages of desmopressin ODT in men and women with nocturia due to NP. The findings from other trials in this indication are being discussed vis-à-vis to quantify the MCID—how much is good enough. This post-hoc analysis included NP patient from the larger population included in the two pivotal trials, i.e., 230 of 266 (86.5%) in CS41 and 232 of 262 (88.5%) in CS 40, who had nocturia due to NP, as this population is anticipated to provide deeper insights into the treatment benefit of desmopressin ODT, considering that it is an antidiuretic therapy.
70
Percentage of nights
60 50
The results from this post-hoc analysis demonstrated a significant mean reduction of more than one nocturnal void with desmopressin ODT, with treatment effect size favouring desmopressin ODT in both men and women. Some benefit was also noted in the placebo group, probably due to restricted water intake at bedtime and other lifestyle modifications, masking the detection of the actual therapeutic response [16]. Despite this, the pre-post difference of 1.3–1.5 voids was suggestive of clinical benefit with desmopressin ODT versus placebo, supported by evidence published earlier, wherein a change from baseline in nocturia episodes in the range of 1.7 to 1.2 voids was considered to be reasonably clinically meaningful [17]. Further, the frequency of nocturnal voids was reduced to less than two voids per night in both men and women, which is lower than the threshold for significant bother/substantially reduced QoL in this indication [18]. Additionally, our findings are consistent with the results from the larger population in CS41, CS40, and another study where treatment with desmopressin ODT resulted in rapid, clinically relevant reductions in the mean number of nocturnal voids versus placebo in patients with nocturia
Treatment difference = 13 (4, 21) p = 0.005 Treatment difference = 11 (3, 20) p = 0.008
58
45
44
Treatment difference = 9 (4, 14) p ≤ 0.001
40 32 30
Treatment difference = 4 (-3, 11) p = 0.221 19
20
15
15 7
10 0 Desmopressin ODT (50 μg)
Placebo
CS41 (men)
Desmopressin ODT (25 μg)
Placebo
CS40 (women)
% nights with at most one nocturnal void
Desmopressin ODT (50 μg)
Placebo
CS41 (men)
Desmopressin ODT (25 μg)
Placebo
CS40 (women)
% nights with no nocturnal voids
Fig. 1 – Patients with percentage of nights with no voids (complete response) or at most one void. Adjusted treatment difference (95% confidence intervals) are presented. ODT = orally disintegrating tablet.
Please cite this article in press as: Weiss JP, et al. Low-dose Desmopressin Orally Disintegrating Tablet: Suggested Clinically Meaningful Benefit in Patients with Nocturia Due to Nocturnal Polyuria. Eur Urol Focus (2018), https://doi.org/10.1016/j. euf.2018.11.001
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Treatment difference = 21 (9, 34) p ≤ 0.001
Treatment difference = 12 (0, 24) p = 0.047 Treatment difference = 17 (4, 30) p = 0.010
76
80 Percentage of responders
70 70
63
60
Treatment difference = 12 (-0, 25) p = 0.055
58
47
50
41
40
40 28
30 20 10 0 Desmopressin ODT (50 μg)
Placebo
CS41 (men)
Desmopressin ODT (25 μg)
Placebo
CS40 (women)
33% responder rate
Desmopressin ODT (50 μg)
Placebo
CS41 (men)
Desmopressin ODT (25 μg)
Placebo
CS40 (women)
50% responder rate
Fig. 2 – Responder status. Adjusted treatment difference (95% confidence intervals) are presented. ODT = orally disintegrating tablet.
[10,11,12]. Based upon patient perception and considerable effect on QoL, even a small change might be relevant for a person and vice versa. For example, for “responders” it may be a clinically useful reduction, while for others it may not be a change or may result in marginal reduction only [16]. Even though the other outcomes, such as complete response, number of nights with at most one void, and 50% responder status, were not the primary endpoints, their relevance cannot be ignored since these aspects are important for the overall improvement in patient QoL. The present post-hoc analysis supports the clinical benefit with desmopressin ODT since 41% men (p = 0.055 vs placebo) and 58% women (p = 0.010 vs placebo) treated with desmopressin ODT had 50% responder status, with an improvement of 12– 17% compared with placebo. This is consistent with another study where 33% of the patients in the desmopressin and 11% in the placebo arm (p = 0.0014) achieved a clinically significant response (50% reduction in the mean number of nocturnal voids); clinical benefit was 20% higher with desmopressin tablets [19]. Thus, the magnitude and direction of effect with desmopressin ODT versus placebo in our study commensurate with the clinical benefit evident in other studies [19,20]. Treatment benefit with desmopressin ODT versus placebo was more evident in men than in women in terms of complete response, i.e., nights with no voids, a critical parameter. Desmopressin ODT provided >50% and >20% benefit over and above placebo with a TD of 4–9% in men and women, respectively, in terms of complete response, though the overall benefit was greater in women. Having nights with no voids is suggestive of compete resolution of the symptom being treated (ie, nocturia) for those nights.
Further, this also translates into sound sleep, i.e., no sleep fragmentation during these nights, thus, indicative of better QoL. Similar results were seen in another study where patients treated with nasal desmopressin acetate had 5% more nights with no nocturnal voids, yielding a clinically meaningful benefit versus placebo [20]. Regarding percentage of nights with at most one void (partial response), desmopressin ODT provided >27% and >22% benefit over and above placebo with a TD of 11–13% in men and women, respectively, and similar to complete response, the overall benefit was greater in women. This translates into a reduction in nocturnal voids (less than two voids per night) below the threshold associated with significant bother/substantially reduced QoL [18]. Our findings are consistent with another study where nasal desmopressin acetate provided 10–15% higher partial response versus placebo [20]. The findings from this post-hoc analysis also reiterate the good efficacy of low-dose desmopressin ODT in women, highlighting sex specificity of desmopressin ODT, and can be attributed to higher levels of vasopressin receptor expression in women [21,22]. Although, our findings are suggestive of the clinically meaningful benefit of recently approved dosages of desmopressin ODT, i.e., 50 mg in men and 25 mg in women in the NP population, the results of this post-hoc analysis should be interpreted with caution due to certain limitations. This is because the two pivotal trials (CS41 and CS40) were designed and powered to determine the statistical significance of the coprimary endpoints in these trials and not for the additional endpoints evaluated in this analysis. Additionally, considering the post-hoc nature of this analysis, assessment and interpretation of the additional endpoints
Please cite this article in press as: Weiss JP, et al. Low-dose Desmopressin Orally Disintegrating Tablet: Suggested Clinically Meaningful Benefit in Patients with Nocturia Due to Nocturnal Polyuria. Eur Urol Focus (2018), https://doi.org/10.1016/j. euf.2018.11.001
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Fig. 3 – Cumulative distribution function for the mean change in the number of nocturnal voids from baseline to month 3 in (A) men (CS41) and (B) women (CS40). ODT = orally disintegrating tablet.
are limited by the type of data collection required, i.e., in terms of timing and frequency. Thus, QoL data in terms of sleep quality, and reduction in falls or fractures and fatigue could not be captured in this post-hoc analysis. Further, data regarding the cotreatments received by the patients at baseline were not collected.
Study concept and design: Weiss, van der Meulen, Juul. Acquisition of data : van der Meulen, Juul. Analysis and interpretation of data: Weiss, van der Meulen, Juul. Drafting of the manuscript: Weiss, van der Meulen, Juul. Critical revision of the manuscript for important intellectual content: Weiss, van der Meulen, Juul. Statistical analysis: van der Meulen. Obtaining funding: None.
5.
Conclusions
Our findings may help guide further research and explore the important aspect of MCID in terms of not only the number of voids, but also appropriate patient-reported outcomes, with pointers to QoL and quality of sleep.
Administrative, technical, or material support: None. Supervision: None. Other: None. Financial disclosures: Kristian Vinter Juul certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents
Author contributions: Kristian Vinter Juul had full access to all the data
filed, received, or pending), are the following: Jeffrey P. Weiss is a consultant
in the study and takes responsibility for the integrity of the data and the
for Ferring, Vantia, Symptelligence, and Wellesley. Kristian Vinter Juul and
accuracy of the data analysis.
Egbert A. van der Meulen are employees of Ferring.
Please cite this article in press as: Weiss JP, et al. Low-dose Desmopressin Orally Disintegrating Tablet: Suggested Clinically Meaningful Benefit in Patients with Nocturia Due to Nocturnal Polyuria. Eur Urol Focus (2018), https://doi.org/10.1016/j. euf.2018.11.001
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Funding/Support and role of the sponsor: This study was supported by
7
[11] Weiss JP, Herschorn S, Albei CD, van der Meulen EA. Efficacy and
Ferring Pharmaceuticals A/S.
safety of low dose desmopressin orally disintegrating tablet in men
Acknowledgements: The authors acknowledge the medical writing sup-
placebo controlled, parallel group study. J Urol 2013;190:965–72.
with nocturia: results of a multicenter, randomized, double-blind, port provided by Sakshi Jindal and Dr. Payal Bhardwaj of Tata Consultancy Services, funded by Ferring Pharmaceuticals.
[12] Sand PK, Dmochowski RR, Reddy J, van der Meulen EA. Efficacy and safety of low dose desmopressin orally disintegrating tablet inwomen with nocturia: results of a multicenter, randomized, double-blind, placebo controlled, parallel group study. J Urol 2013;190:958–64. [13] Lee S, Malhotra B, Creanga D, Carlsson M, Glue P. A meta-analysis of
Appendix A. Supplementary data
the placebo response in antimuscarinic drug trials for overactive bladder. BMC Med Res Methodol 2009;9:55.
Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j.euf. 2018.11.001.
[14] Smith AL, Wein AJ. Outcomes of pharmacological management of nocturia with non-antidiuretic agents: does statistically significant equal clinically significant? BJU Int 2011;107:1550–4. [15] Ranganathan P, Pramesh CS, Buyse M. Common pitfalls in statistical analysis: P values, statistical significance and confidence intervals.
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Perspect Clin Res 2015;6:116–7. [16] Marshall SD, Raskolnikov D, Blanker MH, et al. Nocturia: current levels of evidence and recommendations from the international consultation on male lower urinary tract symptoms. Urology 2015;85:1291–9. [17] Bone, Reproductive and Urologic Drugs Advisory Committee (BRUDAC). FDA briefing document. October 19, 2016. https://www.fda. gov/downloads/AdvisoryCommittees/ CommitteesMeetingMaterials/Drugs/ ReproductiveHealthDrugsAdvisoryCommittee/UCM525329.pdf. [18] Tikkinen KA, Johnson TM, Tammela TL, et al. Nocturia frequency, bother, and quality of life: how often is too often? A populationbased study in Finland. Eur Urol 2010;57:488–96. [19] van Kerrebroeck P, Rezapour M, Cortesse A, Thüroff J, Riis A, Norgaard JP. Desmopressin in the treatment of nocturia: a double-blind, placebo-controlled study. Eur Urol 2007;52:221–9. [20] Noctiva (desmopressin acetate) nasal spray. Summary review for regulatory action. September 04, 2018. https://www.accessdata. fda.gov/drugsatfda_docs/summary_review/2017/ 201656Orig1s000SumR.pdf. [21] Yamaguchi O, Nishizawa O, Juul KV, Nørgaard JP. Gender difference in efficacy and dose response in Japanese patients with nocturia treated with four different doses of desmopressin orally disintegrating tablet in a randomized, placebo-controlled trial. BJU Int 2013;111:474–84. [22] Juul KV, Klein BM, Sandström R, Erichsen L, Nørgaard JP. Gender
domized, double-blind, placebo-controlled trial. Neurourol Urodyn
difference in antidiuretic response to desmopressin. Am J Physiol
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Please cite this article in press as: Weiss JP, et al. Low-dose Desmopressin Orally Disintegrating Tablet: Suggested Clinically Meaningful Benefit in Patients with Nocturia Due to Nocturnal Polyuria. Eur Urol Focus (2018), https://doi.org/10.1016/j. euf.2018.11.001
available at www.sciencedirect.com journal homepage: www.europeanurology.com/eufocus
Neuro-urology
Low-dose Desmopressin Orally Disintegrating Tablet: Suggested Clinically Meaningful Benefit in Patients with Nocturia Due to Nocturnal Polyuria Jeffrey P. Weiss a, Egbert A. van der Meulen b, Kristian Vinter Juul b,* a
Department of Urology, SUNY Downstate Medical School, Brooklyn, New York, USA; b Ferring Pharmaceuticals, Copenhagen S, Denmark
Article info
Abstract
Article history: Accepted November 7, 2018
Background: Clinical benefit has not been evaluated much in patients with nocturia. Objective: To assess the clinical benefit of desmopressin orally disintegrating tablet (ODT) in women (25 mg) and men (50 mg) with nocturia due to nocturnal polyuria (NP). Design, setting, and patients: Patients with NP from two randomised, placebo-controlled trials in men (CS41) and women (CS40) with two or more nocturnal voids per night were included. Outcome measurements and statistical analysis: Change from baseline in nocturnal voids, 33% and 50% responder status (average reduction of 33% and 50%, respectively, in the mean number of nocturnal voids vs baseline), and percentage of nights with at most one void or no voids (ie, complete response) during 3-mo treatment period were assessed for clinical benefit. Two-sided test (5% significance level) was used for all endpoints. Results and limitations: Demographics and baseline characteristics of patients in CS41 (N = 230) and CS40 (N = 232) were similar. A greater reduction in the mean number of nocturnal voids was seen with desmopressin ODT in men (treatment difference [TD]: 0.37 voids) compared with women (TD: 0.29 voids). For 33% and 50% responder status, TD with ODT versus placebo were 21% and 12%, respectively, in men, and 12% and 17%, respectively, in women. For the number of nights with at most one void, TDs were 11% and 13% (p < 0.009 for both) for men and women, respectively. For complete response, TD was significant in men (TD: 9%, p < 0.001). Limitations inherent in this analysis were evident as the data for cotreatments (baseline) and quality of life were not collected. Conclusions: A stronger treatment effect with desmopressin ODT versus placebo and the magnitude of differences are indicative of clinical benefit in patients with NP. Patient summary: We looked at the clinical benefit of desmopressin ODT in patients with nocturnal polyuria. We conclude that clinical benefit was observed with desmopressin ODT in these patients. © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Associate Editor: Malte Rieken Keywords: Clinical benefit Desmopressin Desmopressin orally disintegrating tablet Nocturnal polyuria
* Corresponding author. Ferring Pharmaceuticals, Kay Fiskers Plads 11, Copenhagen S, Denmark. Tel. +45 28787544; Fax: +45 28176548. E-mail address: [email protected] (K.V. Juul).
https://doi.org/10.1016/j.euf.2018.11.001 2405-4569/© 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Weiss JP, et al. Low-dose Desmopressin Orally Disintegrating Tablet: Suggested Clinically Meaningful Benefit in Patients with Nocturia Due to Nocturnal Polyuria. Eur Urol Focus (2018), https://doi.org/10.1016/j. euf.2018.11.001
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1.
Introduction
Among the various lower urinary tract symptoms (LUTS), nocturia can be considered as the most prevalent and bothersome symptom [1], occurring in both men and women, and also being associated with advancing age. Nocturia defined as “waking to pass urine during the main sleep period” [2], is essentially linked to disturbed sleep. In this context, it has previously been observed that nocturia has detrimental impact on the quality of life (QoL) and overall health of patients mainly due to sleep fragmentation [3,4], especially when two or more nocturnal voids are experienced. Clinically relevant nocturia (two or more voids per night) affects only 2–16.6% of young men (20–40 yr) and 4.4–18% of young women. However, in older (>70 yr) men and women, the rate varies between 29% and 59.3% and between 28.3% and 61.5%, respectively [1]. The treatment of nocturia is generally two pronged where behavioural interventions (restricting fluid intake, alarm therapy, etc.) are combined with pharmacological treatments such as a-blockers, 5-a-reductase inhibitors, and phosphodiesterase inhibitors [5]. However, the current treatment approach is constrained due to the complex and multifactorial aetiology of nocturia [6], making the choice of treatment difficult and often ineffective. Traditionally, treatment strategy is targeted to primarily address LUTS rather than nocturnal polyuria (NP), the commonest underlying pathophysiology in nocturia [7]. NP, sometimes defined as “excessive urine production during the patient’s main sleep period”, is reported to be present in 83% of patients with nocturia [2] and is known to result from decreased secretion of the antidiuretic hormone arginine vasopressin. Desmopressin, a synthetic vasopressin analogue, is the only drug approved for the treatment of nocturia due to NP [8], and is devoid of unwanted vasopressor and uterotonic effects [9]. To maximise the benefit, in terms of both bioavailability and minimising water intake for drug administration, desmopressin is formulated as an orally disintegrating tablet (ODT) [10]. Desmopressin ODT has been studied separately in the sex-specific pivotal trials CS41 and CS40 in patients with nocturia, where 87% had NP (defined as nocturnal polyuria index [NPi] >33%). In both the trials, statistically significant efficacy results were obtained for the coprimary endpoints, i.e., “change from baseline in the mean number of nocturnal voids” and “33% responder status”. However, it has been questioned whether the treatment effect size versus placebo reached clinical significance along with statistical significance [11,12]. This may be a consequence of lifestyle and behavioural interventions, particularly restricted fluid intake, which masks the actual clinical benefit, as reported in the urological conditions [13]. Additionally, the high placebo effect may be due to no placebo or an active run-in period before randomisation, regression to the mean, and multiple questionnaires and diaries. In addition to these factors, efficacy is further constrained by the lack of clearly defined clinically meaningful benefit in nocturia, also limiting the drug development programmes and drug approvals.
Ideally, efficacious treatment should result not only in statistically significant, but also in clinically meaningful reduction in the number of nocturnal voiding, which matter most to the patients [14]. This is because the magnitude of actual treatment effect (ie, treatment effect size) determines the likely impact of the results of the trial on the current clinical practice [15]. However, surprisingly, the current research focuses mainly on statistical significance. Therefore, it would be interesting to look at the available data for desmopressin ODT in the context of clinical benefit in the NP patients, the ideal population benefitting with antidiuretics. Here, we present the results from a post-hoc analysis of two pivotal desmopressin ODT trials (CS40 and CS41). This analysis aimed to evaluate the clinically meaningful sex-specific treatment benefit of recently approved low-doses of desmopressin ODT (25 mg in women [CS40] and 50 mg in men [CS41]) in patients with nocturia due to NP. 2.
Patients and methods
The previously published phase 3 pivotal trials were designed as randomised, double-blind, placebo-controlled, parallel-group, multicentre clinical trials including adult men (CS41; NCT01262456) [11] and women (CS40; NCT01223937) [12] with two or more nocturnal voids per night, as documented in a 3-d sleep/voiding diary. Key exclusion criteria were evidence of severe daytime voiding dysfunction (urgency incontinence [more than one episode per day] or urgency [more than one episode per day] or frequency [more than eight daytime voids per day]), polydipsia, and hyponatraemia (serum sodium <135 mmol/l) [11,12]. Briefly, patients were randomised (stratified by age <65 and 65 yr) to receive either desmopressin ODT (women, 25 mg [CS40] and men, 50 mg [CS41]), administered sublingually, or placebo once daily, 1 h prior to bedtime. All patients received behavioural intervention, i.e., emptying their bladder before going to the bed and limiting fluid intake at bedtime. This post-hoc analysis included selective population from these two trials, i.e., patients with nocturia due to NP. The NP patients comprised patients with baseline NPi >33%. Further, nocturnal void was defined as a void occurring from 5 min after going to bed with the intention to sleep until rising in the morning. The coprimary endpoints for both the previous studies were the change from baseline in nocturnal voids averaged over the treatment period, and 33% responder status (defined as an average reduction of 33% in the mean number of nocturnal voids compared with baseline over the treatment period) were evaluated for clinical benefit in this post -hoc analysis. Additionally, for this post-hoc analysis, 50% responder status (defined as an average reduction of 50% in the mean number of nocturnal voids compared with baseline over the treatment period) and percentage of nights with at most one void or no voids during the treatment period (ie, complete response) were also evaluated. The voiding data were captured in a 3-d sleep/voiding diary, and assessments were made at the visits at week 1 and months 1, 2, and 3. This post-hoc analysis was performed using the modified intentionto-treat analysis set and comprised all randomised patients who received at least one dose of the study drug. The analyses were performed by sex (men and women) and not on the pooled data considering sex-specific doses. A two-sided test (5% significance level) was used for all the endpoints. Average change from baseline to the end of the 3-mo treatment period and percentage of nights with at most one void or no voids (complete response) were analysed using an analysis of covariance. The analysis was adjusted for baseline number of voids, age (<65 or 65 yr), and treatment. Further, the responder status averaged over the
Please cite this article in press as: Weiss JP, et al. Low-dose Desmopressin Orally Disintegrating Tablet: Suggested Clinically Meaningful Benefit in Patients with Nocturia Due to Nocturnal Polyuria. Eur Urol Focus (2018), https://doi.org/10.1016/j. euf.2018.11.001
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treatment period was analysed using the Cochran–Mantel–Haenszel method, stratified by age and expressed in terms of difference in responder probabilities between the treatment groups. Change in the mean number of nocturnal voids per night from baseline was presented using cumulative distribution function (CDF) plots. Missing values were maintained as missing, and sensitivity analysis was performed to assess the impact of missing data.
3.
Results
The patient disposition is presented in Supplementary Table 1, and baseline demographics and clinical characteristics of this post-hoc analysis population are presented in Table 1. Overall, the demographics and baseline characteristics were similar across the treatment groups in both the trials. A greater reduction was noted in the mean number of nocturnal voids with desmopressin ODT versus placebo in both men and women. The treatment difference (TD) or the effect size compared with placebo was 0.37 voids (p < 0.001) in men and 0.29 voids (p < 0.05) in women (Table 2). The assessed parameters such as percentage of nights with at most one void or no voids improved with desmopressin ODT versus placebo. Further, the 33% and 50%
responder status, defined as an average reduction of 33% and 50%, respectively, in the mean number of nocturnal voids compared with baseline over the treatment period, also improved with desmopressin ODT versus placebo during the 3-mo treatment period in both men and women with nocturia due to NP. Regarding the percentage of nights with no voids, i.e., complete response, the TD between desmopressin ODT and placebo was significant in men (TD: 9%, p < 0.001). Further, for the percentage of nights with at most one void, the differences between desmopressin ODT and placebo were 11% and 13% (p < 0.009 for both) for men and women, respectively (Fig. 1). There was a higher probability of achieving 33% and 50% responder status with desmopressin ODT versus placebo in both men and women, respectively. For the 33% responder status, the TD with desmopressin ODT compared with placebo was 21% (p < 0.001) in men and 12% (p < 0.05) in women. Similarly, for the 50% responder status, the TD compared with placebo was 12% (p = 0.055) in men and 17% (p < 0.05) in women (Fig. 2). CDF plots for the mean change from baseline in the number of nocturnal voids followed a similar trend in both men and women treated with desmopressin ODT (Fig. 3A and 3 B).
Table 1 – Demographics and baseline characteristics of patients with nocturnal polyuria. CS41 (men; N = 230)
CS40 (women; N = 232)
Desmopressin ODT (N = 102)Placebo (N = 128)Total (N = 230)Desmopressin ODT (N = 118)Placebo (N = 114)Total (N = 232) Age (yr) Mean SD 60.1 13.75 Age category, N (%) 57 (55.9) <65 yr 65 yr 45 (44.1) BMI (kg/m2) 29.3 4.97 Mean SD Ethnicity, N (%) Hispanic or Latino 17 (16.7) Not Hispanic or Latino85 (83.3) No. of nocturnal voids, N (%) <2 – 54 (52.9) 2–3 32 (31.4) 3–4 4–5 11 (10.8) 3 (2.9) 5–6 2 (2.0) 6–7 >7 – Time to first void (min) 139.7 52.02 Mean SD No. of daytime voids 5.6 1.29 Mean SD Nocturnal urine volume (ml) Mean SD 658.0 351.04 NPi (%) 48.5 10.69 Mean SD No. of nocturnal voids 3.0 0.89 Mean SD Percentage of nights with at most one nocturnal void Mean SD 0.3 3.30 Percentage of nights with no nocturnal voids 0.00 0.00 Mean SD
61.4 14.42
60.8 14.11
59.0 14.65
60.3 14.23
59.6 14.43
63 (49.2) 65 (50.8)
120 (52.2) 110 (47.8)
64 (54.2) 54 (45.8)
57 (50.0) 57 (50.0)
121 (52.2) 111 (47.8)
29.2 5.29
29.2 5.14
31.4 7.02
29.5 6.53
30.5 6.84
19 (14.8) 109 (85.2)
36 (15.7) 194 (84.4)
23 (19.5) 95 (80.5)
16 (14.0) 98 (86.0)
39 (16.8) 193 (83.2)
1 (0.8) 60 (46.9) 45 (35.2) 19 (14.8) 3 (2.3) – –
1 (0.4) 114 (49.6) 77 (33.5) 30 (13.0) 6 (2.6) 2 (0.9) –
– 63 (53.4) 45 (38.1) 9 (7.6) – – 1 (0.9)
– 61 (53.5) 42 (36.8) 9 (7.9) – 1 (0.9) 1 (0.9)
– 124 (53.5) 87 (37.5) 18 (7.8) – 1 (0.4) 2 (0.9)
144.5 56.65
142.4 54.58
145.5 54.85
139.9 56.73
142.8 55.73
5.6 1.17
5.6 1.22
5.7 1.25
5.4 1.25
5.6 1.26
654.3 310.59
655.9 328.41 663.9 325.41
630.6 346.02
647.6 335.38
48.9 11.32
48.7 11.03
47.6 10.10
49.4 12.70
48.5 11.46
3.0 0.83
3.0 0.85
2.9 0.91
2.9 0.81
2.9 0.86
1.0 9.30
0.7 7.27
1.1 6.06
0.3 3.12
0.7 4.85
0.00 0.00
0.00 0.00
0.00 0.00
0.00 0.00
0.00 0.00
BMI = body mass index; N = number of patients; NPi = nocturnal polyuria index; ODT = orally disintegrating tablet; SD = standard deviation; % = percentage of patients.
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Table 2 – Change from baseline in mean number of nocturnal voids. CS41 (Men)
CS40 (Women)
Desmopressin ODT Change from baseline Treatment difference 95% CI p value
1.26 0.37 ( 0.59, <0.001
Placebo
Desmopressin ODT
0.89
1.47 0.29 ( 0.51, 0.008
0.15)
Placebo 1.18
0.08)
CI = confidence interval; ODT = orally disintegrating tablet.
4.
Discussion
Nocturia is a widespread problem with significant impact on QoL, yet there are large unmet needs. The available treatments are often ineffective due to unclear or undiagnosed underlying pathophysiology, and no consensus around the treatment effect size, i.e., the minimal clinically important difference (MCID), which should be based on both clinician’s and patients’ perspective rather than just the statistical significance. The present post-hoc analysis underlines the clinical benefit of the proposed dosages of desmopressin ODT in men and women with nocturia due to NP. The findings from other trials in this indication are being discussed vis-à-vis to quantify the MCID—how much is good enough. This post-hoc analysis included NP patient from the larger population included in the two pivotal trials, i.e., 230 of 266 (86.5%) in CS41 and 232 of 262 (88.5%) in CS 40, who had nocturia due to NP, as this population is anticipated to provide deeper insights into the treatment benefit of desmopressin ODT, considering that it is an antidiuretic therapy.
70
Percentage of nights
60 50
The results from this post-hoc analysis demonstrated a significant mean reduction of more than one nocturnal void with desmopressin ODT, with treatment effect size favouring desmopressin ODT in both men and women. Some benefit was also noted in the placebo group, probably due to restricted water intake at bedtime and other lifestyle modifications, masking the detection of the actual therapeutic response [16]. Despite this, the pre-post difference of 1.3–1.5 voids was suggestive of clinical benefit with desmopressin ODT versus placebo, supported by evidence published earlier, wherein a change from baseline in nocturia episodes in the range of 1.7 to 1.2 voids was considered to be reasonably clinically meaningful [17]. Further, the frequency of nocturnal voids was reduced to less than two voids per night in both men and women, which is lower than the threshold for significant bother/substantially reduced QoL in this indication [18]. Additionally, our findings are consistent with the results from the larger population in CS41, CS40, and another study where treatment with desmopressin ODT resulted in rapid, clinically relevant reductions in the mean number of nocturnal voids versus placebo in patients with nocturia
Treatment difference = 13 (4, 21) p = 0.005 Treatment difference = 11 (3, 20) p = 0.008
58
45
44
Treatment difference = 9 (4, 14) p ≤ 0.001
40 32 30
Treatment difference = 4 (-3, 11) p = 0.221 19
20
15
15 7
10 0 Desmopressin ODT (50 μg)
Placebo
CS41 (men)
Desmopressin ODT (25 μg)
Placebo
CS40 (women)
% nights with at most one nocturnal void
Desmopressin ODT (50 μg)
Placebo
CS41 (men)
Desmopressin ODT (25 μg)
Placebo
CS40 (women)
% nights with no nocturnal voids
Fig. 1 – Patients with percentage of nights with no voids (complete response) or at most one void. Adjusted treatment difference (95% confidence intervals) are presented. ODT = orally disintegrating tablet.
Please cite this article in press as: Weiss JP, et al. Low-dose Desmopressin Orally Disintegrating Tablet: Suggested Clinically Meaningful Benefit in Patients with Nocturia Due to Nocturnal Polyuria. Eur Urol Focus (2018), https://doi.org/10.1016/j. euf.2018.11.001
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Treatment difference = 21 (9, 34) p ≤ 0.001
Treatment difference = 12 (0, 24) p = 0.047 Treatment difference = 17 (4, 30) p = 0.010
76
80 Percentage of responders
70 70
63
60
Treatment difference = 12 (-0, 25) p = 0.055
58
47
50
41
40
40 28
30 20 10 0 Desmopressin ODT (50 μg)
Placebo
CS41 (men)
Desmopressin ODT (25 μg)
Placebo
CS40 (women)
33% responder rate
Desmopressin ODT (50 μg)
Placebo
CS41 (men)
Desmopressin ODT (25 μg)
Placebo
CS40 (women)
50% responder rate
Fig. 2 – Responder status. Adjusted treatment difference (95% confidence intervals) are presented. ODT = orally disintegrating tablet.
[10,11,12]. Based upon patient perception and considerable effect on QoL, even a small change might be relevant for a person and vice versa. For example, for “responders” it may be a clinically useful reduction, while for others it may not be a change or may result in marginal reduction only [16]. Even though the other outcomes, such as complete response, number of nights with at most one void, and 50% responder status, were not the primary endpoints, their relevance cannot be ignored since these aspects are important for the overall improvement in patient QoL. The present post-hoc analysis supports the clinical benefit with desmopressin ODT since 41% men (p = 0.055 vs placebo) and 58% women (p = 0.010 vs placebo) treated with desmopressin ODT had 50% responder status, with an improvement of 12– 17% compared with placebo. This is consistent with another study where 33% of the patients in the desmopressin and 11% in the placebo arm (p = 0.0014) achieved a clinically significant response (50% reduction in the mean number of nocturnal voids); clinical benefit was 20% higher with desmopressin tablets [19]. Thus, the magnitude and direction of effect with desmopressin ODT versus placebo in our study commensurate with the clinical benefit evident in other studies [19,20]. Treatment benefit with desmopressin ODT versus placebo was more evident in men than in women in terms of complete response, i.e., nights with no voids, a critical parameter. Desmopressin ODT provided >50% and >20% benefit over and above placebo with a TD of 4–9% in men and women, respectively, in terms of complete response, though the overall benefit was greater in women. Having nights with no voids is suggestive of compete resolution of the symptom being treated (ie, nocturia) for those nights.
Further, this also translates into sound sleep, i.e., no sleep fragmentation during these nights, thus, indicative of better QoL. Similar results were seen in another study where patients treated with nasal desmopressin acetate had 5% more nights with no nocturnal voids, yielding a clinically meaningful benefit versus placebo [20]. Regarding percentage of nights with at most one void (partial response), desmopressin ODT provided >27% and >22% benefit over and above placebo with a TD of 11–13% in men and women, respectively, and similar to complete response, the overall benefit was greater in women. This translates into a reduction in nocturnal voids (less than two voids per night) below the threshold associated with significant bother/substantially reduced QoL [18]. Our findings are consistent with another study where nasal desmopressin acetate provided 10–15% higher partial response versus placebo [20]. The findings from this post-hoc analysis also reiterate the good efficacy of low-dose desmopressin ODT in women, highlighting sex specificity of desmopressin ODT, and can be attributed to higher levels of vasopressin receptor expression in women [21,22]. Although, our findings are suggestive of the clinically meaningful benefit of recently approved dosages of desmopressin ODT, i.e., 50 mg in men and 25 mg in women in the NP population, the results of this post-hoc analysis should be interpreted with caution due to certain limitations. This is because the two pivotal trials (CS41 and CS40) were designed and powered to determine the statistical significance of the coprimary endpoints in these trials and not for the additional endpoints evaluated in this analysis. Additionally, considering the post-hoc nature of this analysis, assessment and interpretation of the additional endpoints
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Fig. 3 – Cumulative distribution function for the mean change in the number of nocturnal voids from baseline to month 3 in (A) men (CS41) and (B) women (CS40). ODT = orally disintegrating tablet.
are limited by the type of data collection required, i.e., in terms of timing and frequency. Thus, QoL data in terms of sleep quality, and reduction in falls or fractures and fatigue could not be captured in this post-hoc analysis. Further, data regarding the cotreatments received by the patients at baseline were not collected.
Study concept and design: Weiss, van der Meulen, Juul. Acquisition of data : van der Meulen, Juul. Analysis and interpretation of data: Weiss, van der Meulen, Juul. Drafting of the manuscript: Weiss, van der Meulen, Juul. Critical revision of the manuscript for important intellectual content: Weiss, van der Meulen, Juul. Statistical analysis: van der Meulen. Obtaining funding: None.
5.
Conclusions
Our findings may help guide further research and explore the important aspect of MCID in terms of not only the number of voids, but also appropriate patient-reported outcomes, with pointers to QoL and quality of sleep.
Administrative, technical, or material support: None. Supervision: None. Other: None. Financial disclosures: Kristian Vinter Juul certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents
Author contributions: Kristian Vinter Juul had full access to all the data
filed, received, or pending), are the following: Jeffrey P. Weiss is a consultant
in the study and takes responsibility for the integrity of the data and the
for Ferring, Vantia, Symptelligence, and Wellesley. Kristian Vinter Juul and
accuracy of the data analysis.
Egbert A. van der Meulen are employees of Ferring.
Please cite this article in press as: Weiss JP, et al. Low-dose Desmopressin Orally Disintegrating Tablet: Suggested Clinically Meaningful Benefit in Patients with Nocturia Due to Nocturnal Polyuria. Eur Urol Focus (2018), https://doi.org/10.1016/j. euf.2018.11.001
EUF-631; No. of Pages 7 E U RO P E A N U RO L O GY F O C U S X X X ( 2 018 ) X X X– X X X
Funding/Support and role of the sponsor: This study was supported by
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[11] Weiss JP, Herschorn S, Albei CD, van der Meulen EA. Efficacy and
Ferring Pharmaceuticals A/S.
safety of low dose desmopressin orally disintegrating tablet in men
Acknowledgements: The authors acknowledge the medical writing sup-
placebo controlled, parallel group study. J Urol 2013;190:965–72.
with nocturia: results of a multicenter, randomized, double-blind, port provided by Sakshi Jindal and Dr. Payal Bhardwaj of Tata Consultancy Services, funded by Ferring Pharmaceuticals.
[12] Sand PK, Dmochowski RR, Reddy J, van der Meulen EA. Efficacy and safety of low dose desmopressin orally disintegrating tablet inwomen with nocturia: results of a multicenter, randomized, double-blind, placebo controlled, parallel group study. J Urol 2013;190:958–64. [13] Lee S, Malhotra B, Creanga D, Carlsson M, Glue P. A meta-analysis of
Appendix A. Supplementary data
the placebo response in antimuscarinic drug trials for overactive bladder. BMC Med Res Methodol 2009;9:55.
Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j.euf. 2018.11.001.
[14] Smith AL, Wein AJ. Outcomes of pharmacological management of nocturia with non-antidiuretic agents: does statistically significant equal clinically significant? BJU Int 2011;107:1550–4. [15] Ranganathan P, Pramesh CS, Buyse M. Common pitfalls in statistical analysis: P values, statistical significance and confidence intervals.
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Please cite this article in press as: Weiss JP, et al. Low-dose Desmopressin Orally Disintegrating Tablet: Suggested Clinically Meaningful Benefit in Patients with Nocturia Due to Nocturnal Polyuria. Eur Urol Focus (2018), https://doi.org/10.1016/j. euf.2018.11.001