European Urology

1. Introduction

To the best of our knowledge, publications of confirmatory clinical trials in children suffering from nonneurogenic overactive bladder (OAB) and urinary incontinence demonstrating superiority of antimuscarinics over placebo are still missing. On the other hand, antimuscarinics—for example, propiverine hydrochloride (in the following referred to as propiverine)—are very well-established in these children as well as in children suffering from neurogenic detrusor overactivity [1], [2], [3], [4], [5], and [6]. Reflecting this fact, the International Consultation on Incontinence (ICI) recommends antimuscarinic treatment for this indication in children so far with a lower level of evidence (level 3, grade B/C) [7].

Since 1985, propiverine is labelled for treatment of children with nonneurogenic detrusor overactivity, incontinence, urgency, and/or small bladder volume from age 5 yr and neurogenic detrusor overactivity from age 1 yr in Germany, Czech Republic, and Slovakia used as tablets with 5 mg propiverine in a recommended daily dose of 0.8 mg/kg body weight (BW).

Earlier studies [5], [8], and [9] already demonstrated efficacy and safety of propiverine, but did not fulfill all strict criteria from the current guidelines or standards of good clinical practice (GCP).

The trial presented here was designed according to the recommendations of the German authorities and the current international treatment guidelines provided by the ICI in 2002 [10] and was performed between June 2004 and December 2006.

2. Materials and methods

The study was conducted by 38 investigators from six European countries.

Pretreated children had to undergo a 4-wk wash-out phase before attending to the trial. The four clinical trial visits are demonstrated in the flowchart (Table 1). At visit 1 a check of in- and exclusion criteria (Table 2), urologic baseline diagnostics and uroflowmetry was performed. Enrolled children and their parents received detailed lifestyle advice (urotherapy) according to the International Children's Continence Society (ICCS) with explanation of normal body and lower urinary tract (LUT) function, voiding position, timed voiding, drinking habits, quality of beverages, and prevention of constipation for the 3-wk run-in period. A specially designed children's diary with small paintings and space for symbols after each voiding was handed out to improve the compliance of children and to keep them busy with their own voiding behaviour.

In between visit 1 and visit 2 uroflowmetry was centrally approved regarding maximum voided volume and exclusion of other underlying diseases; for example, dysfunctional voiding and mechanical obstruction (a statistical evaluation of these parameters was not intended). At visit 2 all in- and exclusion criteria had been rechecked and uroflow was performed again if necessary. An informed consent was obtained from parents and children. Only patients without other underlying LUT symptoms and who still fulfilled the requested criteria received study medication for a period of 8 wk (57.5 ± 5.6 d).

Randomization was performed within fixed blocks (ratio 1:1) by an independent unit, assigning the random numbers in increasing order per centre. Depending on body weight children were treated twice daily with propiverine (coated tablets 5 mg) or corresponding placebo:

• –BW 17.0 to 27.9 kg: 20 mg propiverine/d (dosing schedule 2-0-2)

• –BW 28.0 to 45.0 kg: 30 mg propiverine/d (dosing schedule 3-0-3).

Due to the lack of an adequate statistical database for estimating required sample size in children, an interim analysis with adaptive design [11] was planned following the recruitment of 60 patients. Thereafter propiverine was already superior to placebo (p = 0.0043 < 0.0102) but the national regulatory authority recommended a continuation of the trial. Sample size for an additional second part of trial was estimated with 104 patients. For confirmatory analysis of the primary efficacy variable one-sided tests were carried out at a significance level of α = 0.025 and ß = 0.2.

Efficacy parameters were assessed by questioning about voiding behaviour and incontinence episodes over the last 7 d and with a 3-d bladder diary (fluid intake, voided volume, voiding frequency, incontinence episodes) on the weekend before visit 2 and visit 4. Families were reminded to conduct both bladder diaries under comparable drinking habits.

As primary efficacy parameter the change in voiding frequency between baseline and end of treatment was chosen. Therefore patients were classified as responder to therapy if voiding frequency decreased by at least 1.5 voidings. Secondary efficacy variables included voided volume, incontinence episodes per day as well as within 7d and weekly maximum voided volume. For the last parameter, parents were introduced to a micturition volume protocol recording the amount of urine of one single voiding per week when the child was having strong desire. This protocol is suitable to monitor variances in bladder capacity over time. A subjective evaluation of benefit from therapy and final tolerability was assessed at visit 4 by children, parents, and investigators.

Safety assessment included continuous recording of character, intensity, and frequency of all adverse events. Vital signs (blood pressure, pulse rate, urinalysis, and electrocardiogram) were analysed. Although propiverine has a proven cardiac safety in adults, additional information in children should be obtained. In agreement with ethics committees, electrocardiogram (ECG) was performed facultative because not all investigators were able to perform a high-quality ECG at the study site.

All randomized patients receiving one or more doses of trial medication were included into the intent-to-treat population (ITT). Demographic data and baseline characteristics were analysed for safety, ITT, and per protocol (PP) population, stratified by gender. Sensitivity analyses of the efficacy variables were planned and conducted stratified by gender and dose group according to body weight using the ITT population. The age-dependent analyses have been included afterwards. For subjective evaluation of efficacy and tolerability by parents, patients, and investigator, Cochran-Mantel-Haenszel tests were used. Efficacy parameters have been presented with mean and standard deviation. For all ANCOVA models, two-sided 95% confidence intervals (CI) were calculated for the treatment difference “propiverine–placebo.”

Terminology within this publication was adapted to the current report from the Standardization Committee of the ICCS from 2006 [12].

3. Results

3.1. Demographics

Of 303 enrolled children (194 male, 109 female) at the first visit 171 children (107 male, 64 female; safety population) were finally randomized and medically treated (Fig. 1). The remaining 132 children (43.6%) were excluded after the run-in period of urotherapy because of diagnostic findings such as inappropriate uroflowmetry, maximum voided volume showing expected bladder capacity according to age, voiding frequency below 8 micturitions per day, missing incontinence episodes within 7 d, postvoid residual urine (PVR) > 10 ml, and other issues such as withdrawal of informed consent or compliance problems.

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Fig. 1 Flow diagram of the clinical trial.

The ITT population consisted of 164 patients (104 male, 60 female). Seven children had been withdrawn after randomization because of side-effects (two propiverine, one placebo), insufficient efficacy or absence for further evaluation (both placebo) and other reasons (one propiverine, one placebo).

Mean age of the children was 7.0 yr; the mean body mass index (BMI) was 16.31 kg/m². The propiverine and placebo group were comparable regarding demographic and clinical characteristics (Table 3).

Table 3 Baseline demographic and clinical data (ITT population)^*

Characteristics	Propiverine (n = 84)		Placebo (n = 80)		p-value**
Distribution of gender
Male	n = 49	(58.3%)	n = 55	(68.8%)	0.353
Female	n = 35	(41.7%)	n = 25	(31.3%)
Age [yr]	7.0	(1.6)	7.0	(1.4)	1.0
Height [cm]	127.1	(10.2)	127.0	(11.4)	0.953
Weight [kg]	26.8	(6.7)	26.2	(5.4)	0.530
BMI [kg/m2]	16.4	(2.4)	16.1	(1.8)	0.368
Voiding frequency per day	8.9	(2.2)	9.1	(2.5)	0.587
Voided volume [ml]	102.9	(36.3)	100.3	(33.8)	0.636
Incontinence episodes per day	0.8	(0.8)	1.1	(1.0)	0.035
Incontinence episodes within last 7 days	5.4	(8.3)	5.4	(5.9)	1.0
Enuretic episodes within last 7 nights	3.1	(3.4)	3.3	(3.0)	0.988

^* If not otherwise stated mean (standard deviation) was provided.

^** Significance is given if p < 0.05.

3.2. Efficacy

Overall 171 children (safety population) were randomized and treated body-weight adjusted either with propiverine (n = 87) or with placebo (n = 84). Table 3 summarizes the demographic data for the ITT population. All determined efficacy parameters from the bladder diary are listed in Table 4 for the ITT population (164 children). Significant superiority of propiverine over placebo after 8 wk of medical treatment was achieved in the overall population. Separate evaluation of study endpoints for gender demonstrated significant benefit from propiverine for all but one efficacy parameters (p = 0.0608 for incontinence episodes per day in females). Separate analysis of the two body-weight-adjusted dose groups could not show significance for voiding frequency in children receiving doses higher than 0.9 mg/kg BW (Table 4).

Table 4 Results for change of efficacy parameters between baseline and end of treatment for the overall population and stratified with respect to gender and dose (ITT population)^*

Results	Propiverine (n = 84)		Placebo (n = 80)		p-value
Voiding frequency per day	−2.0	(2.3)	−1.2	(2.2)	0.0007**
Male	−2.2	(2.5)	−1.1	(1.9)	0.0146
Female	−1.7	(1.8)	−1.4	(2.8)	0.0384
<0.9 mg/kg BW†	−2.1	(2.2)	−0.9	(1.9)	0.0008
>0.9 mg/kg BW‡	−1.9	(2.4)	−1.4	(2.4)	0.1674
Voided volume [ml]	31.4	(29.3)	5.1	(25.1)	<0.0001
Male	32.5	(30.3)	4.8	(21.8)	<0.0001
Female	29.8	(28.3)	5.6	(31.4)	0.0014
<0.9 mg/kg BW†	28.4	(30.8)	5.1	(19.6)	0.0001
>0.9 mg/kg BW‡	33.9	(28.2)	5.0	(28.2)	<0.0001
Incontinence episodes per day	−0.5	(0.7)	−0.2	(0.9)	0.0005
Male	−0.5	(0.7)	−0.3	(1.1)	0.0038
Female	−0.4	(0.6)	−0.2	(0.7)	0.0608
<0.9 mg/kg BW†	−0.5	(0.8)	−0.2	(0.7)	0.0442
>0.9 mg/kg BW‡	−0.4	(0.6)	−0.3	(1.2)	0.0046

^* If not otherwise stated mean (standard deviation) was provided.

^** The primary parameter was evaluated confirmatory with one-sided p-value; all other parameters were evaluated exploratory with the two-sided p-value. Significance is given if p < 0.05.

^† Dose <0.9 mg/kg body weight (n = 38 propiverine, n = 32 placebo).

^‡ Dose >0.9 mg/kg body weight (n = 46 propiverine, n = 48 placebo).

The primary efficacy parameter—voiding frequency per day—was reduced about 20% from baseline (−2.0 episodes) with propiverine compared to 11% (−1.2 episodes) with placebo (p = 0.0007). A decrease of at least 1.5 voidings per day (defined as “response to therapy” per protocol) was achieved in 64.3% (n = 54) of patients with propiverine and 40.0% (n = 32) with placebo (p = 0.0018). Incontinence episodes per day were decreased by −0.5 episodes with propiverine compared to placebo with −0.2 episodes (p = 0.0005). The mean voided volume significantly increased at 31.4 ml on average for propiverine compared to only 5.1 ml for placebo (p = 0.0001). Separating these results into age groups of <7, 7–8 and >8 years, the group that benefits best were children older than 8 yr compared to baseline whereas no benefit of the placebo group in all age groups was found (Fig. 2).

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Fig. 2 Mean changes of voided volume per single voiding from baseline to end of treatment (EoT) according to three different age groups.

Based on case history, incontinence episodes within 7 d were decreased by −2.8 episodes with propiverine versus −1.2 episodes in the placebo group (p = 0.0002). Enuretic episodes decreased by −0.72 episodes with propiverine compared to −0.41 episodes with placebo (p = 0.2123).

Efficacy could also been shown in the micturition volume protocol performed once weekly starting after 1 wk of treatment. The median of voided volume increased 36 ml in children treated with propiverine, whereas in placebo only 10 ml could be stated (Fig. 3).

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Fig. 3 Results from the weekly micturition volume protocol with change of volume of a single voiding from week 1 to week 8 of treatment period.

Subjective final evaluation of efficacy was comparable between investigator, child, and parents. Investigators judged response rate on treatment with propiverine in 64.3% as “very good” and “good” compared to only 32.6% on placebo.

4. Discussion

This trial should prove efficacy and tolerability of propiverine for children suffering from urinary incontinence and OAB and could demonstrate significant superiority over placebo in all analysed efficacy parameters.

One interpretation of the results is the adapted trial design, which differed in some aspects from previous studies in children; for example, urotherapy prior to medication, children's diary, and micturition volume protocol [3], [5], and [13]. Urotherapy improved symptoms in a number of patients, avoiding the necessity of medical treatment, and helped to identify the remaining patient target group who might benefit from antimuscarinic treatment. This strategy also minimized placebo effects in patients allocated to pharmacologic treatment. The data published by Allen [14] showed comparable results, reflecting that urotherapy significantly improved overactive bladder symptoms in 45% of children.

Because urotherapy was not in the primary focus of the trial and only one bladder diary was kept in between the first visit and randomization to treatment arms (visit 2) but not prior to start of urotherapy, a separate evaluation of the clinical effect of 3 wk of urotherapy could not be derived from the analyzed data.

Ayan et al [15] presented data from 72 children with nonneurogenic voiding dysfunction and urgency symptoms who were randomly allocated to three treatment groups (tolterodine or placebo together with behavioural modification and behavioural modification alone). Judging the decrease in a new, hitherto not established, dysfunctional voiding score system (DVSS) as a parameter for clinical outcome, an increase in efficacy if antimuscarinics were combined with behavioural modification was found.

Another publication supporting these experiences included holding manoeuvres to oxybutynin treatment and could show superior effects compared to antimuscarinic therapy alone [16].

In real life children might suffer from additional symptoms such as behavioural problems or other underlying symptoms of the LUT and would probably benefit best from combination treatment, for example, propiverine with biofeedback or desmopressin [13]; however, this was out of scope of this study.

Clinical experience over two decades verified the body-weight-adjusted dose regimen of propiverine. At the same time as this trial, a dose-escalating pharmacokinetic study with body-weight-adjusted doses of 5, 10, or 15 mg propiverine twice daily in children aged 5 to 10 yr was initiated suggesting a therapeutic dose of 10 to 15 mg twice daily for this patient population [17]. The results also explain the decision as to why 48 children (55.2%) had a propiverine dose increasing the recommended 0.8 mg/kg BW per day, which has to be taken into consideration when judging the incidence of antimuscarinic side-effects.

Voiding frequency deriving from bladder diary as primary efficacy parameter seemed to be more significant in children than incontinence episodes per day, which may not occur due to coping strategies such as restricted fluid intake. According to the recommendations of ICCS [12] for bladder diary and experiences with other clinical trials in children, urgency was not included because younger children are often unable to indicate different bladder sensations, and strong desire to void is probably the only sensation they can express.

An important treatment goal in children suffering from OAB and incontinence is an observable increase of bladder volume. In several publications [18], and [19] a correlation between incontinence and a decreased expected bladder capacity related to age could be demonstrated in children. Only a combination of adequate fluid intake and provable increase in bladder volume leads to a reliable, effective decrease in voiding frequency and incontinence episodes.

The bladder volume in propiverine-treated children increased approximately 6-fold higher (+31 ml) than in placebo-treated children (+5 ml), which underlines older data indicating that bladder volume is an effective prognostic parameter [13]. Additionally, the home-conducted micturition volume protocol demonstrated a continuous increase of volume over time (Fig. 3).

Under propiverine, mild to moderate side-effects occurred in 95% of patients, which was comparable to placebo-treated patients (94%). The total number of side-effects in both treatment groups was comparable (propiverine 23% and placebo 20%), whereas infections of the respiratory tract were most commonly reported. The safety results support previous clinical experiences with children where dry mouth or visual disturbances occur less frequently compared to adults when treated with propiverine [13], [20], and [21].

5. Conclusion

For the first time a confirmatory clinical trial could demonstrate superior efficacy of an antimuscarinic (propiverine) in children suffering from OAB and urinary incontinence. The results will support the importance of propiverine for further evaluation of treatment options in these children, resulting in recommendation by ICI. The fact that urotherapy minimized placebo effects by identifying the relevant patient target group who benefits from medical treatment might be relevant for adults as well.
Author contributions: Daniela Marschall-Kehrel had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Marschall-Kehrel.

Acquisition of data: Feustel.

Analysis and interpretation of data: Marschall-Kehrel; Feustel.

Drafting of the manuscript: Marschall-Kehrel; Feustel.

Critical revision of the manuscript for important intellectual content: Persson de Geeter, Stehr, Radmayr, Sillen, Strugala.

Statistical analysis: CRO PAREXEL under supervision of APOGEPHA Arzneimittel GmbH Dresden, Germany.

Obtaining funding: None.

Administrative, technical, or material support: None.

Supervision: Marschall-Kehrel.

Other (specify): None.

Financial disclosures: I certify 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 filed, received, or pending), are the following: Daniela Marschall-Kehrel is a company consultant for Allergan, Bayer, Ferring, Lilly and Pfizer; receives a research grant from Ferring; and has additionally a company speaker honorarium at APOGEPHA Arzneimittel GmbH. Cornelia Feustel and Gerhard Strugala are employees of APOGEPHA Arzneimittel GmbH.

Funding/Support and role of the sponsor: This study was sponsored by APOGEPHA Arzneimittel GmbH Dresden, Germany.

Acknowledgement statement: The authors acknowledge the additional investigators and study sites not mentioned in the list of authors (arranged alphabetically within the participating countries):

Citibor Marek, Jihlava, Mita Rosenberg, Plzen, Lubomir Skalka, Českà Lípa, Jaroslav Všetička, Jablonec nad Nisou; Czech Republic.

Hermann van Ahlen, Osnabrück, Peter Alken, Mannheim, Hans-Joachim Forth, Emmendingen, Elke Heßdörfer, Berlin, Thomas Kapellen, Leipzig, Uwe Matschke, Neubrandenburg, Ludwig Patzer, Halle, Peter Raue, Leipzig, Kassel, Arndt Richter, Dresden, Heike Rosswog, Berlin, Andreas Schildknecht, Potsdam, Jörg Seibold, Stuttgart, Gabriele Simson, Lauenburg, München, Olaf Umbreit, Naumburg, Manfred P. Wirth, Dresden, Simone Wygoda, Leipzig; Germany.

Dušan Martinčok, Košiče, Vladimir Polák, Bratislava, Slovakia.

Ioana Alina Anca, Bucharest, Sebastian Ionescu, Bucharest, Eva Kiss, Targu-Mures, Andrei Valentin Manu-Marin, Bucharest; Romania.