- Email: [email protected]
III Dose Ranging Study of Tamsulosin as Treatment for Children With Neuropathic Bladder
Phase IIb/III Dose Ranging Study of Tamsulosin as Treatment for Children With Neuropathic Bladder Yves Homsy,*,† Philip Arnold and Wei Zhang From the Children’s Urology Group, Department of Pediatrics, University of South Florida, Tampa, Florida (YH), and Medical Affairs (PA), and Biometrics and Data Management (WZ), Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut
Purpose: We evaluated the efficacy and safety of tamsulosin hydrochloride in children with increased detrusor leak point pressure associated with neuropathic bladder. Materials and Methods: In a double-blind, randomized, placebo controlled trial patients with detrusor leak point pressure 40 cm H2O or greater were stratified by age (2 to less than 5 years, 5 to less than 10 years, 10 to 16 years) and concomitant anticholinergic use, and were randomized to receive various doses of tamsulosin or placebo. A 2-week titration was followed by a 12-week maintenance treatment period. Primary end point was response, ie detrusor leak point pressure less than 40 cm H2O from 2 evaluations on the same day at week 14. Secondary end points included detrusor leak point pressure change from baseline, hydronephrosis and hydroureter responses, change in catheterization volumes and adverse events. Results: A total of 161 patients received 1 or more treatment doses between January 2008 and February 2009, and 135 were evaluable for the primary end point. A total of 51 patients (37.8%) were detrusor leak point pressure responders, with no statistically significant difference in response rates between each tamsulosin dose and placebo. Adjusting for stratification variables, mean detrusor leak point pressure changes from baseline to week 14 for placebo and low, medium and high dose groups were –11.4, –17.6, – 4.6 and –14.3 cm H2O, respectively. In 141 evaluable patients hydroureter/hydronephrosis improvement rates were 7.1% and 5.7% in left and right kidneys (hydroureter), respectively, and 14.9% and 14.2% in left and right kidneys (hydronephrosis), respectively. No group experienced decreases in median post-void residual volume at week 14. Drug related adverse event incidences were 4.9% (placebo) and 5.8% (tamsulosin). Conclusions: Tamsulosin was well tolerated but not efficacious in this pediatric population with neuropathic bladder.
Abbreviations and Acronyms AE ⫽ adverse event CIC ⫽ clean intermittent catheterization LPP ⫽ leak point pressure Submitted for publication March 15, 2011. Protocol consent and patient information forms were approved by local regulatory authorities in participating countries. * Financial interest and/or other relationship with Boehringer Ingelheim Pharmaceuticals, Inc. † Correspondence: Children’s Urology Group, Department of Pediatrics, University of South Florida, 5507 East Longboat Blvd., Tampa, Florida 33615 (telephone: 813-416-8614; FAX: 813-8184795; e-mail: [email protected]).
Key Words: cholinergic antagonists; hydronephrosis; neurologic manifestations; urinary bladder, neurogenic ALPHA-ADRENERGIC antagonists have been investigated in small studies of children with voiding disorders and neuropathic bladder. In contrast to studies in adults, in which the primary outcome is urethral pressure profiling, the primary outcome for the pediatric population is detrusor leak point pressure. In a nonrandomized trial of 55 children with urinary tract
infection, incontinence and urgency doxazosin decreased post-void residual volume.1 In a nonrandomized study of 17 children with voiding dysfunctions of varied etiology doxazosin improved bladder emptying, and 2 patients with neuropathic bladder demonstrated decreased leak point pressure.2 An open uncontrolled study of 17 children with neuropathic bladder
0022-5347/11/1865-2033/0 THE JOURNAL OF UROLOGY® © 2011 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
Vol. 186, 2033-2039, November 2011 Printed in U.S.A. DOI:10.1016/j.juro.2011.07.021
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RESEARCH, INC.
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EFFICACY OF TAMSULOSIN FOR NEUROPATHIC BLADDER
and increased leak point pressure showed that alfuzosin effectively decreased leak point pressure and increased bladder compliance.3 In adults with neuropathic bladder after spinal cord injury phenoxybenzamine reduced bladder outlet resistance and improved bladder function.4 Tamsulosin hydrochloride, an ␣1A-selective antagonist approved by the United States Food and Drug Administration for the treatment of benign prostatic hyperplasia in adult males, reduces bladder outlet resistance, which improves urine flow rates and bladder symptoms, and decreases postvoid residual volume.5 Tamsulosin demonstrated efficacy and safety in the long-term extension of a double-blind, placebo controlled, randomized clinical trial of 186 adults with neuropathic bladder who received 0.4 or 0.8 mg once daily.6 Investigators did not observe any new or unexpected AEs related to tamsulosin during the study. In this study we evaluated the efficacy and safety of a range of doses of tamsulosin as treatment in children with increased detrusor LPP associated with a neurological deficit (eg spina bifida).
MATERIALS AND METHODS The study population consisted of children 2 to 16 years old who weighed 12.5 to 100 kg and had neuropathic bladder secondary to a known neurological deficit with a detrusor LPP of 40 cm H2O or greater confirmed by 2 measurements from the same day within 3 months before the first on-study visit, as well as those undergoing CIC. Key exclusion criteria were presence of clinically significant vital organ abnormalities unrelated to trial indication; cancer or other clinical condition judged by the investigator to put the patient at risk; history of orthostatic hypotension, fainting or blackouts; laboratory values greater than 2 times the upper limit of normal; severe hydronephrosis (greater than grade III per Society for Fetal Urology classification); febrile urinary tract infection; history of bladder neck surgery, bladder augmentation or permanently exteriorized bladder drainage procedures and any prior surgery under general anesthesia within 30 days before treatment; initiation of therapy for neuropathic bladder during the 4 weeks before screening or anticipated during the study; receipt of botulinum toxin type A injections for urological use within 6 months of randomization; and use of alpha-blockers within 30 days of screening. Stable anticholinergic medications (30 days) before study medication were permitted. No rescue medication was provided. Medications excluded during the trial were ␣-adrenergic agents, parasympathomimetics, cholinergic agonists, cimetidine, ranitidine and warfarin. All patients (or a legally accepted representative) provided written informed consent. This multicenter, double-blind, randomized, placebo controlled, dose ranging trial that involved a 2-week dose titration period and a 12-week maintenance period was conducted at centers in 12 countries (see Appendix). For quality control purposes when sites were asked to perform evaluations that were not part of their normal routine, instructions were provided to minimize variability. The study was also designed to minimize investigator interventions.
Global vendors were given explicit instructions and hotline availability for electrocardiograms, laboratory evaluations and drug distribution. Finally, a urodynamic standardization was provided as an appendix of the protocol. Protocol consent and patient information forms were approved by the local regulatory authorities in the participating countries. Patients were stratified at enrollment by age (2 to younger than 5 years, 5 to younger than 10 years, 10 to 16 years) and use of concomitant anticholinergic medication. Randomization was performed in a 1:1:1:1 ratio within each stratum by an interactive voice randomization system, with patients assigned to receive placebo or a low (0.001 to 0.002 mg/kg), medium (0.002 to 0.004 mg/kg) or high dose (0.004 to 0.008 mg/kg) of tamsulosin. A precise mg/kg based dosing scheme was not possible due to the modified release formulation characteristics of tamsulosin capsules. All patients randomized to receive tamsulosin received the low dose at week 0, those randomized to receive the medium and high doses received the medium dose at week 1, and those randomized to receive the high dose received the high dose at week 2. To maintain the blinding, study medications were identical in appearance and provided in identical high-density polyethylene bottles. The contents of each placebo capsule had an identical volume to the corresponding capsule of the same dose level of active medication. All efficacy end points were evaluated at baseline and week 14. The primary efficacy end point was response to therapy, defined as detrusor LPP less than 40 cm H2O, as agreed on by the sponsor and the United States Food and Drug Administration, and based on 2 evaluations from the same day. LPP was measured by a standard urodynamic procedure using calibrated electronic equipment (cystometrogram) on which the investigator and clinical staff had been adequately trained. Secondary efficacy end points included absolute and percent change from baseline in LPP, hydroureter, and/or hydronephrosis response based on renal ultrasound performed at screening and at the end of treatment. Changes from baseline in urine catheterization volumes and number of times a patient was wet at catheterization were assessed based on patient catheterization diaries. Post-void residual volume was collected at the urodynamic study and at each evaluation, and was included as a safety end point. LPP was also included as a safety end point. Patients were asked to attempt spontaneous voiding just before insertion of the urodynamic catheter, and the measurement was based on the urine volume obtained after insertion. Safety and tolerability were evaluated based on AEs and discontinuations due to AEs; physical examinations; vital signs; orthostatic tests; laboratory analyses; urinalysis; electrocardiograms, and hormonal, visual and cognitive testing. AEs were coded using the Medical Dictionary for Regulatory Activities, version 11.1. Assuming the response rate with placebo was 0.20, the sample size of 30 patients per group would provide 80% power to detect a difference of 0.433 in response rate in favor of a tamsulosin dose group at an adjusted alpha level of 0.0083 (one third of 0.025) for multiple comparisons (low, medium and high doses vs placebo) using the chi-square test with continuity correction. The nQuery Advisor®, version 6.01 statistical package was used to calculate sample size. Response to treatment was analyzed using multivariate logistic regression with treatment variable and 3 co-
EFFICACY OF TAMSULOSIN FOR NEUROPATHIC BLADDER
variates, namely age group (2 to younger than 5 years, 5 to younger than 10 years, 10 to 16 years), concomitant anticholinergic medications (yes/no) and geographic region (Asia, Europe, North/South America). The primary efficacy analysis was based on all patients who received at least 1 dose of treatment and underwent an on-treatment response assessment. The renal subset included all patients who received at least 1 dose of treatment and underwent at least 1 on-treatment renal ultrasound. The catheterization subset included all patients who received at least 1 dose of treatment, were on a catheterization regimen and underwent at least 1 on-treatment catheterization assessment. Safety was analyzed using all patients who were randomized and received at least 1 dose of treatment.
RESULTS A total of 231 children from 12 countries (see Appendix) were evaluated between January 2008 and February 2009, of whom 162 were enrolled and randomized, and 161 entered treatment and received at least 1 dose of study medication (fig. 1). The 3 largest enrolling countries were India (16 centers, 60 patients [37%]), Korea (6, 18 [11%]) and Mexico (2, 16
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[9.8%]). Mean patient age was 8.2 years. As outlined in table 1, there were only 14 children in the high weight group (50.1 to 100 kg), a subset of whom were randomized to the highest dose. In general, patient demographic and baseline characteristics were similar across treatment groups (table 1). The majority of patients were male, most were of Asian ethnicity and weighed less than 25 kg, and most were receiving anticholinergics. Almost all patients had undergone at least 1 bladder therapy within 8 weeks before the study. The most frequently used bladder therapies were CIC (82 patients, 51%), oxybutynin (26, 16%) and tolterodine (10, 6%). Of 156 patients 21 (13.5%) had presence of hydroureter at baseline for the right kidney and 29 (18.6%) for the left kidney. At baseline hydronephrosis was observed in the right kidney in 40 patients (26%) and the left kidney in 48 (31%). Primary efficacy analysis included 135 patients who completed the study (ie those with baseline and followup data, with noncompleters excluded from analysis). At week 14 a total of 51 patients (of 151)
Figure 1. Flow of patients through trial. One patient randomized to medium dose tamsulosin withdrew consent before receiving study medication. Thus, 161 patients were treated.
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EFFICACY OF TAMSULOSIN FOR NEUROPATHIC BLADDER
Table 1. Patient demographics and baseline characteristics
No. gender/total No. (%): M F Mean ⫾ SD yrs age (range) No. age group/total No. (%): 2–Younger than 5 yrs 5–Younger than 10 yrs 10–16 Yrs No. race/total No. (%): American Indian/Alaska native Asian Black White No. wt/total No. (%): 12.5–Less than 25.1 kg 25.1–Less than 50.1 kg 50.1–100 Kg No. anticholinergic use/total No. (%): No Yes
Placebo
Low Dose Tamsulosin
Medium Dose Tamsulosin
High Dose Tamsulosin
Totals/Overall
25/41 (61) 16/41 (39) 8.4 ⫾ 3.7 (2.0–15.0)
22/40 (55.0) 18/40 (45.0) 8.1 ⫾ 4.2 (2.0–16.0)
25/39 (64.1) 14/39 (35.9) 8.1 ⫾ 3.8 (3.0–15.0)
25/41 (61.0) 16/41 (39.0) 8.2 ⫾ 4.3 (2.0–16.0)
97/161 (60.2) 64/161 (39.8) 8.2 ⫾ 4.0 (2.0–16.0)
7/41 18/41 16/41
(17.1) (43.9) (39.0)
8/40 17/40 15/40
(20.0) (42.5) (37.5)
7/39 17/39 15/39
(17.9) (43.6) (38.5)
8/41 18/41 15/41
(19.5) (43.9) (36.6)
30/161 70/161 61/161
(18.6) (43.5) (37.9)
5/41 23/41 6/41 7/41
(12.2) (56.1) (14.6) (17.1)
3/40 22/40 1/40 14/40
(7.5) (55.0) (2.5) (35.0)
5/39 21/39 2/39 11/39
(12.8) (53.8) (5.1) (28.2)
5/41 23/41 1/41 12/41
(12.2) (56.1) (2.4) (29.3)
18/161 89/161 10/161 44/161
(11.2) (55.3) (6.2) (27.3)
24/41 15/41 2/41
(58.5) (36.6) (4.9)
26/40 9/40 5/40
(65.0) (22.5) (12.5)
22/39 13/39 4/39
(56.4) (33.3) (10.3)
24/41 14/41 3/41
(58.5) (34.1) (7.3)
96/161 51/161 14/161
(59.6) (31.7) (8.7)
25/41 16/41
(61.0) (39.0)
26/40 14/40
(65.0) (35.0)
24/39 15/39
(61.5) (38.5)
23/41 18/41
(56.1) (43.9)
98/161 63/161
(60.9) (39.1)
were LPP responders (37.8%), with no statistically significant difference in response rates between each dose of tamsulosin and placebo, adjusting for age group, anticholinergic use at baseline and geographic region (fig. 2). These findings were robust, as evidenced by similar results obtained in an analysis that treated noncompleters as nonresponders (table 2) and in an analysis that excluded patients with important protocol violations (table 3). No dose-response effect was evident with tamsulosin. Subgroup analyses of response by age group and by use of anticholinergic medications at baseline revealed no influence of these variables on LPP response rates (data not shown). For secondary efficacy end points no significant differences in mean percent or absolute change
from baseline to week 14 in LPP were found between dose groups and placebo after adjusting for stratification variables (table 4). Hydroureter responses were 7.1% (10 of 141 patients) and 5.7% (8) in the left and right kidneys, respectively. Hydronephrosis responses were 14.2% (20 of 141 patients) and 14.9% (21) in the right and left kidneys, respectively. A response in hydroureter or hydronephrosis was defined as an improvement in ultrasound grade from baseline to week 14. No statistically significant differences in hydroureter or hydronephrosis response rates were noted between each tamsulosin dose and placebo. No significant differences in mean change from baseline to week 14 in urine catheterization volumes or number of times a patient was wet at catheterization were found between each tamsulosin dose and placebo after adjusting for stratification variables. Median duration of exposure to study medication was approximately 101 days for each group. Median change from baseline to week 14 in postvoid residual volume was 3.0 ml, –19.0 ml, –1.5 ml and 0 ml for the placebo, and low, medium and Table 2. Response rate by treatment group at week 14, including noncompleters as nonresponders
Placebo Low dose tamsulosin Medium dose tamsulosin High dose tamsulosin Figure 2. Detrusor LPP responders at week 14. Responders were defined as patients with 2 LPP values less than 40 cm H2O at week 14. Analysis was based on evaluable population of 135 patients.
Totals/av
No. Pts
No. LPP Responders (%)
OR (95% CI)
p Value
40 39 37 35
12 (30) 16 (41) 9 (24) 14 (40)
1.42 (0.53–3.78) 0.63 (0.22–1.83) 1.62 (0.59–4.43)
0.4831* 0.3972† 0.3456*
151
51 (34)
* Dose group vs placebo. † Cochran-Armitage trend test.
0.7141†
EFFICACY OF TAMSULOSIN FOR NEUROPATHIC BLADDER
Table 3. Response rate by treatment group at week 14, excluding patients with protocol violations
Placebo Low dose tamsulosin Medium dose tamsulosin High dose tamsulosin Totals/av
No. Pts
No. LPP Responders (%)
OR (95% CI)
p Value
30 28 30 27
11 (37) 14 (50) 9 (30) 12 (44)
1.56 (0.51–4.78) 0.63 (0.20–1.99) 1.45 (0.47–4.51)
0.4388* 0.4279* 0.5236*
115
46 (40)
0.9455†
A total of 38 occurrences of important protocol violations were reported for 161 patients. The most common protocol violations consisted of patients with fewer than 2 LPP evaluations performed at the end of treatment (16 occurrences, 42.1%), lack of stable bladder therapy and failure to ingest meal/snack before first dose of study medication or pharmacokinetic sampling (7, 18.4% for both), and informed consent being given late, eg after screening visit or after discontinuation of excluded medications (4, 10.5%). * Dose group vs placebo. † Cochran-Armitage trend test.
high dose groups, respectively. Results demonstrated a high level of variability within each group, since most patients with neuropathic bladder cannot void spontaneously. Of the 161 patients who received at least 1 dose of study treatment the frequency of overall AEs was lower in each of the tamsulosin treatment groups (low dose 32.5% [39 of 120 patients], medium dose 30.0% [24 of 80], high dose 37.5% [15 of 40]) compared to placebo (43.9% [18 of 41]). When analyzed by age group, the highest incidence of AEs was observed in the 2 to less than 5 years group (placebo 57.1%, 4 of 7 patients; tamsulosin doses 65.2%, 15 of 23), and the lowest incidence occurred in the 10 to 16 years group (placebo 31.3%, 5 of 16; tamsulosin doses 44.45, 20 of 25). In all age groups the AE rates were comparable across all active treatment doses. One death occurred during the study, which was considered potentially related to study drug since no postmortem information could be obtained. One additional treatment emergent serious adverse event in a patient randomized to pla-
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cebo (shunt malfunction) occurred. Two other patients experienced serious AEs (moderate abdominal pain, urinary tract infection) before treatment. The patient who experienced abdominal pain did not meet eligibility criteria and, therefore, did not receive study medication. The patient who experienced the urinary tract infection recovered from the event and was later randomized. Two patients (not including the patient who died) were discontinued from the study prematurely due to AEs.
DISCUSSION Incomplete bladder emptying associated with neuropathic bladder resulting from detrusor overactivity and loss of bladder compliance together with external urinary sphincter spasm and/or contracture may result in increased residual urine volume, which increases the risk of urinary tract infections and bladder calculus formation. These complications may result in deterioration of the upper urinary tract.7 Increase of detrusor LPP to greater than 40 cm H2O reduces glomerular filtration rate, and leads to deterioration of ureteral drainage and hydronephrosis,8 which may result in renal insufficiency and necessitate dialysis or renal transplantation. Interventions to decrease LPP minimize the risk of long-term renal damage.8 In pediatric cases of neuropathic bladder therapeutic options include medical management with anticholinergic agents and surgical management with reconstructive procedures, along with antibiotic prophylaxis and CIC.9 In open trials tamsulosin has had observed activity in treating adults and children with voiding dysfunction, and adults with neuropathic bladder.6,10 –12 Our efficacy results revealed no additional benefit from tamsulosin in children with neuropathic bladder. A possible explanation for the lack of effect is the variability in severity of neurological
Table 4. Secondary end points— change from baseline to week 14 Placebo Detrusor LPP: Mean % change Mean change No. hydroureter responders (%):* Lt kidney Rt kidney No. hydronephrosis responders (%):* Lt kidney Rt kidney Mean change urine catheterization vol (ml) Mean change No. times wet at catheterization * Improvement vs baseline.
–19.9 –11.4
Low Dose Tamsulosin p Value Medium Dose Tamsulosin p Value High Dose Tamsulosin p Value –27.4 –17.6
0.4359 0.3097
–1.9 –4.6
0.0658 0.2676
–23.9 –14.3
0.6709 0.6265
1 (2.9) 2 (6.1)
2 (5.9) 1 (2.9)
0.5192 0.5710
4 (12.1) 2 (5.9)
0.1721 0.9950
3 (7.5) 3 (7.5)
0.3849 0.8538
5 (14.7) 7 (21.2) –2.3 0.3
7 (20.6) 3 (8.8) –32.2 –1.7
0.4398 0.1871 0.1373 0.0808
2 (6.1) 2 (5.9) 4.4 0.0
0.2874 0.1038 0.7440 0.8244
7 (17.5) 8 (20.0) 3.3 –0.4
0.7762 0.9235 0.7703 0.5045
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EFFICACY OF TAMSULOSIN FOR NEUROPATHIC BLADDER
impairment in spina bifida. Our patients were not stratified by amount of viable muscle tissue remaining in the bladder and sphincter. Because the degree of bladder and sphincter fibrosis influences outcomes,13 patients with more extensive lesions may have fewer end organ receptors to allow the medication to act. Therefore, in future studies patients should be categorized as those most likely to benefit from tamsulosin based on a more specific evaluation of detrusor and external sphincter function, possibly by assessing the extent of external sphincter denervation and fibrosis. Another possible explanation is that results observed may be reflective of low dose of medication rather than lack of efficacy. Other possible limitations of the current study are 1) the use of 40 cm H2O as a response criterion does not consider the fact that patients may have had a dramatic decrease in LPP without crossing under that threshold to qualify as responders, 2) the required repetitive cystometrography was not the standard of care for some sites and was intrusive, 3) the level of fibrotic disease was not staged at baseline, 4) the 3-month duration of treatment might not have been long enough, 5) the patient population may have been too heterogeneous in that there were
many differing standards of care, and 6) an ␣1Aselective antagonist was used rather than a nonselective alpha antagonist (however, this treatment may have resulted in more side effects). Some support for our findings is provided by results from an uncontrolled study of alfuzosin in children with neuropathic bladder.3 Of 17 children treated marked decreases in LPP to less than 40 cm H2O were observed in 8, reductions to values greater than 40 cm H2O were observed in 5 and no effect on LPP was observed in 4. However, these results should be validated in randomized, controlled, clinical trials. It is possible that children with less advanced lesions would benefit from therapy with tamsulosin. Because our safety results indicated a favorable profile of tamsulosin in children with neuropathic bladder, it has the potential for further study. In conclusion, although tamsulosin was not efficacious for the treatment of this population of children with neuropathic bladder, it was well tolerated at all doses analyzed.
ACKNOWLEDGMENTS Dr. Danita Sutton of MedErgy provided writing and editorial assistance.
APPENDIX Investigators and Study Centers Carlos Bezerra, Discipline of Urology-Annex II, Faculdade de Medicina do ABC, Santo Andre and Homero Bruschini, Division of Clinical Urology, Hospital Das Clínicas Da FMUSP, São Paulo, Brazil; Helmut Knispel, Alexian Brothers Ltd., Berlin and Raimund Stein, Urology Clinic, Johannes Gutenberg Universitaet Mainz, Mainz, Germany; Mahesh Desai, Muljibhai Patel Urological Hospital/Kidney Hospital, Gujarat, Apul Goel, King George Medical College/Chhatrapati Shahuji Maharaj Medical University and Rakesh Kapoor, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Uttar Pradesh, Padmaraj Hegde, Kasturba Hospital and Kim Mammen, Christian Medical College and Hospital, Punjab, Georgie Mathew, Department of Urology, Amrita Institute of Medical Sciences and Research Center, Kerala, N. K. Mohanty, V. M. Medical College and Safdurjang Hospital, Delhi, Rajendra B. Nerli, KLES Prabhakar Kore Hospital and S. S. Vasan, Department of Urology, Ankur Medical Center of Excellence, Karnataka, Mallikarjuna Reddy, Department of Urology, Hyderabad Institute of Urology, Andhra Pradesh, Shailesh Shah, Kidneyline Healthcare Pvt. Ltd., Ahmedabad and Sanjay Swain, B. Y. L. Nair Hospital and TN Medical College, and Shirish Yande, Ruby Hall Clinic, Grant Medical Foundation, Maharashtra, India; Mario De Gennaro, Department of Nephrourology, Ospedale Bambino Gesu’, Rome, Giulio Del Popolo, A. O. Universitaria Careggi and U. O. Complessa Neurologia, Firenze and Giuseppe Masnata, Department of Urology and Pediatric Urodynamics, A. O. G. Brotzu, Cagliari, Italy; Hwang Choi, Department of Urology, Seoul National University Hospital, Sang Won Han, Department of Pediatric Urology, Yonsei Severance Hospital and Kun Suk Kim, Department of Urology, Asan Medical Center, Seoul, Taek Lee, Department of Pediatric Urology, Inha University Hospital, Incheon and Sang-Don Lee, Department of Urology, Pusan National University Hospital, Pusan, Korea; Fernando Cuellar Lopez, Pediatric Urology, Hospital Para El Niño Poblano, Puebla CP and Javier Quiroz Guerrero, Department of Urodynamics, Hospital Regional de Alta Especialidad del Bajio, Guanajuato, Mexico; David Bolong, Data Management Unit, Philippine Children’s Medical Center, Quezon City and Dolores Bonzon, Center for Neurosciences, Manila Doctors Hospital, Manila, Philippines; Anna Galustyan, Department of Urology, St. Petersburg Pediatric Medical Academy, St. Petersburg and Sergey N. Zorkin, Russian Academy of Medical Science, State Institute Scientific Center of Children’s Health, Moscow, Russia; Richard Barnes, Division of Pediatric Urology, Red Cross Children’s Hospital, Cape Town, Margaret Fockema, Mayo 9, Mayo Center, Roodepoort and Izak Johannes Van Heerden, Research Unit, Pretoria Urology Hospital, Pretoria, South Africa; Carlos Miguelez Lago, Pediatric Urology, Hospital Materno Infantil–H.Carlos Haya, Malaga, Spain; Andriy Irinchyn, Department of Pediatric Surgery, Bukovinian State Medical University, Chernivtsi, Ukraine; Andy Chang, Urology Division, Children’s Hospital Los Angeles, Los Angeles, California, Israel Franco, Pediatric Urology Associates, New York, New York, Yves Homsy, Comprehensive Research Institute, Tampa, Florida, and Daniel McMahon, Pediatric and Adolescent Urology, Akron Children’s Hospital, Akron, Ohio.
REFERENCES 1. Cain MP, Wu SD, Austin PF et al: Alpha blocker therapy for children with dysfunctional voiding and urinary retention. J Urol 2003; 170: 1514. 2. Austin PF, Homsy YL, Masel JL et al: alphaAdrenergic blockade in children with neuropathic and nonneuropathic voiding dysfunction. J Urol 1999; 162: 1064.
3. Schulte-Baukloh H, Michael T, Miller K et al: Alfuzosin in the treatment of high leak-point pressure in children with neurogenic bladder. BJU Int 2002; 90: 716. 4. Al-Ali M, Salman G, Rasheed A et al: Phenoxybenzamine in the management of neuropathic
bladder following spinal cord injury. Aust N Z J Surg 1999; 69: 660. 5. Narayan P and Tewari A: A second phase III multicenter placebo controlled study of 2 dosages of modified release tamsulosin in patients with symptoms of benign prostatic hyperplasia.
EFFICACY OF TAMSULOSIN FOR NEUROPATHIC BLADDER
United States 93-01 Study Group. J Urol 1998; 160: 1701. 6. Abrams P, Amarenco G, Bakke A et al: Tamsulosin: efficacy and safety in patients with neurogenic lower urinary tract dysfunction due to suprasacral spinal cord injury. J Urol 2003; 170: 1242. 7. Joseph DB: Current approaches to the urologic care of children with spina bifida. Curr Urol Rep 2008; 9: 151.
8. Verpoorten C and Buyse GM: The neurogenic bladder: medical treatment. Pediatr Nephrol 2008; 23: 717. 9. de Jong TP, Chrzan R, Klijn AJ et al: Treatment of the neurogenic bladder in spina bifida. Pediatr Nephrol 2008; 23: 889. 10. Lee KS, Han DH, Lee YS et al: Efficacy and safety of tamsulosin for the treatment of non-neurogenic voiding dysfunction in females: an 8-week prospective study. J Korean Med Sci 2010; 25: 117.
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11. Vanderbrink BA, Gitlin J, Toro S et al: Effect of tamsulosin on systemic blood pressure and nonneurogenic dysfunctional voiding in children. J Urol 2009; 181: 817. 12. Kakizaki H, Ameda K, Kobayashi S et al: Urodynamic effects of alpha1-blocker tamsulosin on voiding dysfunction in patients with neurogenic bladder. Int J Urol 2003; 10: 576. 13. Bauer SB, Labib KB, Dieppa RA et al: Urodynamic evaluation of boy with myelodysplasia and incontinence. Urology 1977; 10: 354.
Purpose: We evaluated the efficacy and safety of tamsulosin hydrochloride in children with increased detrusor leak point pressure associated with neuropathic bladder. Materials and Methods: In a double-blind, randomized, placebo controlled trial patients with detrusor leak point pressure 40 cm H2O or greater were stratified by age (2 to less than 5 years, 5 to less than 10 years, 10 to 16 years) and concomitant anticholinergic use, and were randomized to receive various doses of tamsulosin or placebo. A 2-week titration was followed by a 12-week maintenance treatment period. Primary end point was response, ie detrusor leak point pressure less than 40 cm H2O from 2 evaluations on the same day at week 14. Secondary end points included detrusor leak point pressure change from baseline, hydronephrosis and hydroureter responses, change in catheterization volumes and adverse events. Results: A total of 161 patients received 1 or more treatment doses between January 2008 and February 2009, and 135 were evaluable for the primary end point. A total of 51 patients (37.8%) were detrusor leak point pressure responders, with no statistically significant difference in response rates between each tamsulosin dose and placebo. Adjusting for stratification variables, mean detrusor leak point pressure changes from baseline to week 14 for placebo and low, medium and high dose groups were –11.4, –17.6, – 4.6 and –14.3 cm H2O, respectively. In 141 evaluable patients hydroureter/hydronephrosis improvement rates were 7.1% and 5.7% in left and right kidneys (hydroureter), respectively, and 14.9% and 14.2% in left and right kidneys (hydronephrosis), respectively. No group experienced decreases in median post-void residual volume at week 14. Drug related adverse event incidences were 4.9% (placebo) and 5.8% (tamsulosin). Conclusions: Tamsulosin was well tolerated but not efficacious in this pediatric population with neuropathic bladder.
Abbreviations and Acronyms AE ⫽ adverse event CIC ⫽ clean intermittent catheterization LPP ⫽ leak point pressure Submitted for publication March 15, 2011. Protocol consent and patient information forms were approved by local regulatory authorities in participating countries. * Financial interest and/or other relationship with Boehringer Ingelheim Pharmaceuticals, Inc. † Correspondence: Children’s Urology Group, Department of Pediatrics, University of South Florida, 5507 East Longboat Blvd., Tampa, Florida 33615 (telephone: 813-416-8614; FAX: 813-8184795; e-mail: [email protected]).
Key Words: cholinergic antagonists; hydronephrosis; neurologic manifestations; urinary bladder, neurogenic ALPHA-ADRENERGIC antagonists have been investigated in small studies of children with voiding disorders and neuropathic bladder. In contrast to studies in adults, in which the primary outcome is urethral pressure profiling, the primary outcome for the pediatric population is detrusor leak point pressure. In a nonrandomized trial of 55 children with urinary tract
infection, incontinence and urgency doxazosin decreased post-void residual volume.1 In a nonrandomized study of 17 children with voiding dysfunctions of varied etiology doxazosin improved bladder emptying, and 2 patients with neuropathic bladder demonstrated decreased leak point pressure.2 An open uncontrolled study of 17 children with neuropathic bladder
0022-5347/11/1865-2033/0 THE JOURNAL OF UROLOGY® © 2011 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
Vol. 186, 2033-2039, November 2011 Printed in U.S.A. DOI:10.1016/j.juro.2011.07.021
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RESEARCH, INC.
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EFFICACY OF TAMSULOSIN FOR NEUROPATHIC BLADDER
and increased leak point pressure showed that alfuzosin effectively decreased leak point pressure and increased bladder compliance.3 In adults with neuropathic bladder after spinal cord injury phenoxybenzamine reduced bladder outlet resistance and improved bladder function.4 Tamsulosin hydrochloride, an ␣1A-selective antagonist approved by the United States Food and Drug Administration for the treatment of benign prostatic hyperplasia in adult males, reduces bladder outlet resistance, which improves urine flow rates and bladder symptoms, and decreases postvoid residual volume.5 Tamsulosin demonstrated efficacy and safety in the long-term extension of a double-blind, placebo controlled, randomized clinical trial of 186 adults with neuropathic bladder who received 0.4 or 0.8 mg once daily.6 Investigators did not observe any new or unexpected AEs related to tamsulosin during the study. In this study we evaluated the efficacy and safety of a range of doses of tamsulosin as treatment in children with increased detrusor LPP associated with a neurological deficit (eg spina bifida).
MATERIALS AND METHODS The study population consisted of children 2 to 16 years old who weighed 12.5 to 100 kg and had neuropathic bladder secondary to a known neurological deficit with a detrusor LPP of 40 cm H2O or greater confirmed by 2 measurements from the same day within 3 months before the first on-study visit, as well as those undergoing CIC. Key exclusion criteria were presence of clinically significant vital organ abnormalities unrelated to trial indication; cancer or other clinical condition judged by the investigator to put the patient at risk; history of orthostatic hypotension, fainting or blackouts; laboratory values greater than 2 times the upper limit of normal; severe hydronephrosis (greater than grade III per Society for Fetal Urology classification); febrile urinary tract infection; history of bladder neck surgery, bladder augmentation or permanently exteriorized bladder drainage procedures and any prior surgery under general anesthesia within 30 days before treatment; initiation of therapy for neuropathic bladder during the 4 weeks before screening or anticipated during the study; receipt of botulinum toxin type A injections for urological use within 6 months of randomization; and use of alpha-blockers within 30 days of screening. Stable anticholinergic medications (30 days) before study medication were permitted. No rescue medication was provided. Medications excluded during the trial were ␣-adrenergic agents, parasympathomimetics, cholinergic agonists, cimetidine, ranitidine and warfarin. All patients (or a legally accepted representative) provided written informed consent. This multicenter, double-blind, randomized, placebo controlled, dose ranging trial that involved a 2-week dose titration period and a 12-week maintenance period was conducted at centers in 12 countries (see Appendix). For quality control purposes when sites were asked to perform evaluations that were not part of their normal routine, instructions were provided to minimize variability. The study was also designed to minimize investigator interventions.
Global vendors were given explicit instructions and hotline availability for electrocardiograms, laboratory evaluations and drug distribution. Finally, a urodynamic standardization was provided as an appendix of the protocol. Protocol consent and patient information forms were approved by the local regulatory authorities in the participating countries. Patients were stratified at enrollment by age (2 to younger than 5 years, 5 to younger than 10 years, 10 to 16 years) and use of concomitant anticholinergic medication. Randomization was performed in a 1:1:1:1 ratio within each stratum by an interactive voice randomization system, with patients assigned to receive placebo or a low (0.001 to 0.002 mg/kg), medium (0.002 to 0.004 mg/kg) or high dose (0.004 to 0.008 mg/kg) of tamsulosin. A precise mg/kg based dosing scheme was not possible due to the modified release formulation characteristics of tamsulosin capsules. All patients randomized to receive tamsulosin received the low dose at week 0, those randomized to receive the medium and high doses received the medium dose at week 1, and those randomized to receive the high dose received the high dose at week 2. To maintain the blinding, study medications were identical in appearance and provided in identical high-density polyethylene bottles. The contents of each placebo capsule had an identical volume to the corresponding capsule of the same dose level of active medication. All efficacy end points were evaluated at baseline and week 14. The primary efficacy end point was response to therapy, defined as detrusor LPP less than 40 cm H2O, as agreed on by the sponsor and the United States Food and Drug Administration, and based on 2 evaluations from the same day. LPP was measured by a standard urodynamic procedure using calibrated electronic equipment (cystometrogram) on which the investigator and clinical staff had been adequately trained. Secondary efficacy end points included absolute and percent change from baseline in LPP, hydroureter, and/or hydronephrosis response based on renal ultrasound performed at screening and at the end of treatment. Changes from baseline in urine catheterization volumes and number of times a patient was wet at catheterization were assessed based on patient catheterization diaries. Post-void residual volume was collected at the urodynamic study and at each evaluation, and was included as a safety end point. LPP was also included as a safety end point. Patients were asked to attempt spontaneous voiding just before insertion of the urodynamic catheter, and the measurement was based on the urine volume obtained after insertion. Safety and tolerability were evaluated based on AEs and discontinuations due to AEs; physical examinations; vital signs; orthostatic tests; laboratory analyses; urinalysis; electrocardiograms, and hormonal, visual and cognitive testing. AEs were coded using the Medical Dictionary for Regulatory Activities, version 11.1. Assuming the response rate with placebo was 0.20, the sample size of 30 patients per group would provide 80% power to detect a difference of 0.433 in response rate in favor of a tamsulosin dose group at an adjusted alpha level of 0.0083 (one third of 0.025) for multiple comparisons (low, medium and high doses vs placebo) using the chi-square test with continuity correction. The nQuery Advisor®, version 6.01 statistical package was used to calculate sample size. Response to treatment was analyzed using multivariate logistic regression with treatment variable and 3 co-
EFFICACY OF TAMSULOSIN FOR NEUROPATHIC BLADDER
variates, namely age group (2 to younger than 5 years, 5 to younger than 10 years, 10 to 16 years), concomitant anticholinergic medications (yes/no) and geographic region (Asia, Europe, North/South America). The primary efficacy analysis was based on all patients who received at least 1 dose of treatment and underwent an on-treatment response assessment. The renal subset included all patients who received at least 1 dose of treatment and underwent at least 1 on-treatment renal ultrasound. The catheterization subset included all patients who received at least 1 dose of treatment, were on a catheterization regimen and underwent at least 1 on-treatment catheterization assessment. Safety was analyzed using all patients who were randomized and received at least 1 dose of treatment.
RESULTS A total of 231 children from 12 countries (see Appendix) were evaluated between January 2008 and February 2009, of whom 162 were enrolled and randomized, and 161 entered treatment and received at least 1 dose of study medication (fig. 1). The 3 largest enrolling countries were India (16 centers, 60 patients [37%]), Korea (6, 18 [11%]) and Mexico (2, 16
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[9.8%]). Mean patient age was 8.2 years. As outlined in table 1, there were only 14 children in the high weight group (50.1 to 100 kg), a subset of whom were randomized to the highest dose. In general, patient demographic and baseline characteristics were similar across treatment groups (table 1). The majority of patients were male, most were of Asian ethnicity and weighed less than 25 kg, and most were receiving anticholinergics. Almost all patients had undergone at least 1 bladder therapy within 8 weeks before the study. The most frequently used bladder therapies were CIC (82 patients, 51%), oxybutynin (26, 16%) and tolterodine (10, 6%). Of 156 patients 21 (13.5%) had presence of hydroureter at baseline for the right kidney and 29 (18.6%) for the left kidney. At baseline hydronephrosis was observed in the right kidney in 40 patients (26%) and the left kidney in 48 (31%). Primary efficacy analysis included 135 patients who completed the study (ie those with baseline and followup data, with noncompleters excluded from analysis). At week 14 a total of 51 patients (of 151)
Figure 1. Flow of patients through trial. One patient randomized to medium dose tamsulosin withdrew consent before receiving study medication. Thus, 161 patients were treated.
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EFFICACY OF TAMSULOSIN FOR NEUROPATHIC BLADDER
Table 1. Patient demographics and baseline characteristics
No. gender/total No. (%): M F Mean ⫾ SD yrs age (range) No. age group/total No. (%): 2–Younger than 5 yrs 5–Younger than 10 yrs 10–16 Yrs No. race/total No. (%): American Indian/Alaska native Asian Black White No. wt/total No. (%): 12.5–Less than 25.1 kg 25.1–Less than 50.1 kg 50.1–100 Kg No. anticholinergic use/total No. (%): No Yes
Placebo
Low Dose Tamsulosin
Medium Dose Tamsulosin
High Dose Tamsulosin
Totals/Overall
25/41 (61) 16/41 (39) 8.4 ⫾ 3.7 (2.0–15.0)
22/40 (55.0) 18/40 (45.0) 8.1 ⫾ 4.2 (2.0–16.0)
25/39 (64.1) 14/39 (35.9) 8.1 ⫾ 3.8 (3.0–15.0)
25/41 (61.0) 16/41 (39.0) 8.2 ⫾ 4.3 (2.0–16.0)
97/161 (60.2) 64/161 (39.8) 8.2 ⫾ 4.0 (2.0–16.0)
7/41 18/41 16/41
(17.1) (43.9) (39.0)
8/40 17/40 15/40
(20.0) (42.5) (37.5)
7/39 17/39 15/39
(17.9) (43.6) (38.5)
8/41 18/41 15/41
(19.5) (43.9) (36.6)
30/161 70/161 61/161
(18.6) (43.5) (37.9)
5/41 23/41 6/41 7/41
(12.2) (56.1) (14.6) (17.1)
3/40 22/40 1/40 14/40
(7.5) (55.0) (2.5) (35.0)
5/39 21/39 2/39 11/39
(12.8) (53.8) (5.1) (28.2)
5/41 23/41 1/41 12/41
(12.2) (56.1) (2.4) (29.3)
18/161 89/161 10/161 44/161
(11.2) (55.3) (6.2) (27.3)
24/41 15/41 2/41
(58.5) (36.6) (4.9)
26/40 9/40 5/40
(65.0) (22.5) (12.5)
22/39 13/39 4/39
(56.4) (33.3) (10.3)
24/41 14/41 3/41
(58.5) (34.1) (7.3)
96/161 51/161 14/161
(59.6) (31.7) (8.7)
25/41 16/41
(61.0) (39.0)
26/40 14/40
(65.0) (35.0)
24/39 15/39
(61.5) (38.5)
23/41 18/41
(56.1) (43.9)
98/161 63/161
(60.9) (39.1)
were LPP responders (37.8%), with no statistically significant difference in response rates between each dose of tamsulosin and placebo, adjusting for age group, anticholinergic use at baseline and geographic region (fig. 2). These findings were robust, as evidenced by similar results obtained in an analysis that treated noncompleters as nonresponders (table 2) and in an analysis that excluded patients with important protocol violations (table 3). No dose-response effect was evident with tamsulosin. Subgroup analyses of response by age group and by use of anticholinergic medications at baseline revealed no influence of these variables on LPP response rates (data not shown). For secondary efficacy end points no significant differences in mean percent or absolute change
from baseline to week 14 in LPP were found between dose groups and placebo after adjusting for stratification variables (table 4). Hydroureter responses were 7.1% (10 of 141 patients) and 5.7% (8) in the left and right kidneys, respectively. Hydronephrosis responses were 14.2% (20 of 141 patients) and 14.9% (21) in the right and left kidneys, respectively. A response in hydroureter or hydronephrosis was defined as an improvement in ultrasound grade from baseline to week 14. No statistically significant differences in hydroureter or hydronephrosis response rates were noted between each tamsulosin dose and placebo. No significant differences in mean change from baseline to week 14 in urine catheterization volumes or number of times a patient was wet at catheterization were found between each tamsulosin dose and placebo after adjusting for stratification variables. Median duration of exposure to study medication was approximately 101 days for each group. Median change from baseline to week 14 in postvoid residual volume was 3.0 ml, –19.0 ml, –1.5 ml and 0 ml for the placebo, and low, medium and Table 2. Response rate by treatment group at week 14, including noncompleters as nonresponders
Placebo Low dose tamsulosin Medium dose tamsulosin High dose tamsulosin Figure 2. Detrusor LPP responders at week 14. Responders were defined as patients with 2 LPP values less than 40 cm H2O at week 14. Analysis was based on evaluable population of 135 patients.
Totals/av
No. Pts
No. LPP Responders (%)
OR (95% CI)
p Value
40 39 37 35
12 (30) 16 (41) 9 (24) 14 (40)
1.42 (0.53–3.78) 0.63 (0.22–1.83) 1.62 (0.59–4.43)
0.4831* 0.3972† 0.3456*
151
51 (34)
* Dose group vs placebo. † Cochran-Armitage trend test.
0.7141†
EFFICACY OF TAMSULOSIN FOR NEUROPATHIC BLADDER
Table 3. Response rate by treatment group at week 14, excluding patients with protocol violations
Placebo Low dose tamsulosin Medium dose tamsulosin High dose tamsulosin Totals/av
No. Pts
No. LPP Responders (%)
OR (95% CI)
p Value
30 28 30 27
11 (37) 14 (50) 9 (30) 12 (44)
1.56 (0.51–4.78) 0.63 (0.20–1.99) 1.45 (0.47–4.51)
0.4388* 0.4279* 0.5236*
115
46 (40)
0.9455†
A total of 38 occurrences of important protocol violations were reported for 161 patients. The most common protocol violations consisted of patients with fewer than 2 LPP evaluations performed at the end of treatment (16 occurrences, 42.1%), lack of stable bladder therapy and failure to ingest meal/snack before first dose of study medication or pharmacokinetic sampling (7, 18.4% for both), and informed consent being given late, eg after screening visit or after discontinuation of excluded medications (4, 10.5%). * Dose group vs placebo. † Cochran-Armitage trend test.
high dose groups, respectively. Results demonstrated a high level of variability within each group, since most patients with neuropathic bladder cannot void spontaneously. Of the 161 patients who received at least 1 dose of study treatment the frequency of overall AEs was lower in each of the tamsulosin treatment groups (low dose 32.5% [39 of 120 patients], medium dose 30.0% [24 of 80], high dose 37.5% [15 of 40]) compared to placebo (43.9% [18 of 41]). When analyzed by age group, the highest incidence of AEs was observed in the 2 to less than 5 years group (placebo 57.1%, 4 of 7 patients; tamsulosin doses 65.2%, 15 of 23), and the lowest incidence occurred in the 10 to 16 years group (placebo 31.3%, 5 of 16; tamsulosin doses 44.45, 20 of 25). In all age groups the AE rates were comparable across all active treatment doses. One death occurred during the study, which was considered potentially related to study drug since no postmortem information could be obtained. One additional treatment emergent serious adverse event in a patient randomized to pla-
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cebo (shunt malfunction) occurred. Two other patients experienced serious AEs (moderate abdominal pain, urinary tract infection) before treatment. The patient who experienced abdominal pain did not meet eligibility criteria and, therefore, did not receive study medication. The patient who experienced the urinary tract infection recovered from the event and was later randomized. Two patients (not including the patient who died) were discontinued from the study prematurely due to AEs.
DISCUSSION Incomplete bladder emptying associated with neuropathic bladder resulting from detrusor overactivity and loss of bladder compliance together with external urinary sphincter spasm and/or contracture may result in increased residual urine volume, which increases the risk of urinary tract infections and bladder calculus formation. These complications may result in deterioration of the upper urinary tract.7 Increase of detrusor LPP to greater than 40 cm H2O reduces glomerular filtration rate, and leads to deterioration of ureteral drainage and hydronephrosis,8 which may result in renal insufficiency and necessitate dialysis or renal transplantation. Interventions to decrease LPP minimize the risk of long-term renal damage.8 In pediatric cases of neuropathic bladder therapeutic options include medical management with anticholinergic agents and surgical management with reconstructive procedures, along with antibiotic prophylaxis and CIC.9 In open trials tamsulosin has had observed activity in treating adults and children with voiding dysfunction, and adults with neuropathic bladder.6,10 –12 Our efficacy results revealed no additional benefit from tamsulosin in children with neuropathic bladder. A possible explanation for the lack of effect is the variability in severity of neurological
Table 4. Secondary end points— change from baseline to week 14 Placebo Detrusor LPP: Mean % change Mean change No. hydroureter responders (%):* Lt kidney Rt kidney No. hydronephrosis responders (%):* Lt kidney Rt kidney Mean change urine catheterization vol (ml) Mean change No. times wet at catheterization * Improvement vs baseline.
–19.9 –11.4
Low Dose Tamsulosin p Value Medium Dose Tamsulosin p Value High Dose Tamsulosin p Value –27.4 –17.6
0.4359 0.3097
–1.9 –4.6
0.0658 0.2676
–23.9 –14.3
0.6709 0.6265
1 (2.9) 2 (6.1)
2 (5.9) 1 (2.9)
0.5192 0.5710
4 (12.1) 2 (5.9)
0.1721 0.9950
3 (7.5) 3 (7.5)
0.3849 0.8538
5 (14.7) 7 (21.2) –2.3 0.3
7 (20.6) 3 (8.8) –32.2 –1.7
0.4398 0.1871 0.1373 0.0808
2 (6.1) 2 (5.9) 4.4 0.0
0.2874 0.1038 0.7440 0.8244
7 (17.5) 8 (20.0) 3.3 –0.4
0.7762 0.9235 0.7703 0.5045
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EFFICACY OF TAMSULOSIN FOR NEUROPATHIC BLADDER
impairment in spina bifida. Our patients were not stratified by amount of viable muscle tissue remaining in the bladder and sphincter. Because the degree of bladder and sphincter fibrosis influences outcomes,13 patients with more extensive lesions may have fewer end organ receptors to allow the medication to act. Therefore, in future studies patients should be categorized as those most likely to benefit from tamsulosin based on a more specific evaluation of detrusor and external sphincter function, possibly by assessing the extent of external sphincter denervation and fibrosis. Another possible explanation is that results observed may be reflective of low dose of medication rather than lack of efficacy. Other possible limitations of the current study are 1) the use of 40 cm H2O as a response criterion does not consider the fact that patients may have had a dramatic decrease in LPP without crossing under that threshold to qualify as responders, 2) the required repetitive cystometrography was not the standard of care for some sites and was intrusive, 3) the level of fibrotic disease was not staged at baseline, 4) the 3-month duration of treatment might not have been long enough, 5) the patient population may have been too heterogeneous in that there were
many differing standards of care, and 6) an ␣1Aselective antagonist was used rather than a nonselective alpha antagonist (however, this treatment may have resulted in more side effects). Some support for our findings is provided by results from an uncontrolled study of alfuzosin in children with neuropathic bladder.3 Of 17 children treated marked decreases in LPP to less than 40 cm H2O were observed in 8, reductions to values greater than 40 cm H2O were observed in 5 and no effect on LPP was observed in 4. However, these results should be validated in randomized, controlled, clinical trials. It is possible that children with less advanced lesions would benefit from therapy with tamsulosin. Because our safety results indicated a favorable profile of tamsulosin in children with neuropathic bladder, it has the potential for further study. In conclusion, although tamsulosin was not efficacious for the treatment of this population of children with neuropathic bladder, it was well tolerated at all doses analyzed.
ACKNOWLEDGMENTS Dr. Danita Sutton of MedErgy provided writing and editorial assistance.
APPENDIX Investigators and Study Centers Carlos Bezerra, Discipline of Urology-Annex II, Faculdade de Medicina do ABC, Santo Andre and Homero Bruschini, Division of Clinical Urology, Hospital Das Clínicas Da FMUSP, São Paulo, Brazil; Helmut Knispel, Alexian Brothers Ltd., Berlin and Raimund Stein, Urology Clinic, Johannes Gutenberg Universitaet Mainz, Mainz, Germany; Mahesh Desai, Muljibhai Patel Urological Hospital/Kidney Hospital, Gujarat, Apul Goel, King George Medical College/Chhatrapati Shahuji Maharaj Medical University and Rakesh Kapoor, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Uttar Pradesh, Padmaraj Hegde, Kasturba Hospital and Kim Mammen, Christian Medical College and Hospital, Punjab, Georgie Mathew, Department of Urology, Amrita Institute of Medical Sciences and Research Center, Kerala, N. K. Mohanty, V. M. Medical College and Safdurjang Hospital, Delhi, Rajendra B. Nerli, KLES Prabhakar Kore Hospital and S. S. Vasan, Department of Urology, Ankur Medical Center of Excellence, Karnataka, Mallikarjuna Reddy, Department of Urology, Hyderabad Institute of Urology, Andhra Pradesh, Shailesh Shah, Kidneyline Healthcare Pvt. Ltd., Ahmedabad and Sanjay Swain, B. Y. L. Nair Hospital and TN Medical College, and Shirish Yande, Ruby Hall Clinic, Grant Medical Foundation, Maharashtra, India; Mario De Gennaro, Department of Nephrourology, Ospedale Bambino Gesu’, Rome, Giulio Del Popolo, A. O. Universitaria Careggi and U. O. Complessa Neurologia, Firenze and Giuseppe Masnata, Department of Urology and Pediatric Urodynamics, A. O. G. Brotzu, Cagliari, Italy; Hwang Choi, Department of Urology, Seoul National University Hospital, Sang Won Han, Department of Pediatric Urology, Yonsei Severance Hospital and Kun Suk Kim, Department of Urology, Asan Medical Center, Seoul, Taek Lee, Department of Pediatric Urology, Inha University Hospital, Incheon and Sang-Don Lee, Department of Urology, Pusan National University Hospital, Pusan, Korea; Fernando Cuellar Lopez, Pediatric Urology, Hospital Para El Niño Poblano, Puebla CP and Javier Quiroz Guerrero, Department of Urodynamics, Hospital Regional de Alta Especialidad del Bajio, Guanajuato, Mexico; David Bolong, Data Management Unit, Philippine Children’s Medical Center, Quezon City and Dolores Bonzon, Center for Neurosciences, Manila Doctors Hospital, Manila, Philippines; Anna Galustyan, Department of Urology, St. Petersburg Pediatric Medical Academy, St. Petersburg and Sergey N. Zorkin, Russian Academy of Medical Science, State Institute Scientific Center of Children’s Health, Moscow, Russia; Richard Barnes, Division of Pediatric Urology, Red Cross Children’s Hospital, Cape Town, Margaret Fockema, Mayo 9, Mayo Center, Roodepoort and Izak Johannes Van Heerden, Research Unit, Pretoria Urology Hospital, Pretoria, South Africa; Carlos Miguelez Lago, Pediatric Urology, Hospital Materno Infantil–H.Carlos Haya, Malaga, Spain; Andriy Irinchyn, Department of Pediatric Surgery, Bukovinian State Medical University, Chernivtsi, Ukraine; Andy Chang, Urology Division, Children’s Hospital Los Angeles, Los Angeles, California, Israel Franco, Pediatric Urology Associates, New York, New York, Yves Homsy, Comprehensive Research Institute, Tampa, Florida, and Daniel McMahon, Pediatric and Adolescent Urology, Akron Children’s Hospital, Akron, Ohio.
REFERENCES 1. Cain MP, Wu SD, Austin PF et al: Alpha blocker therapy for children with dysfunctional voiding and urinary retention. J Urol 2003; 170: 1514. 2. Austin PF, Homsy YL, Masel JL et al: alphaAdrenergic blockade in children with neuropathic and nonneuropathic voiding dysfunction. J Urol 1999; 162: 1064.
3. Schulte-Baukloh H, Michael T, Miller K et al: Alfuzosin in the treatment of high leak-point pressure in children with neurogenic bladder. BJU Int 2002; 90: 716. 4. Al-Ali M, Salman G, Rasheed A et al: Phenoxybenzamine in the management of neuropathic
bladder following spinal cord injury. Aust N Z J Surg 1999; 69: 660. 5. Narayan P and Tewari A: A second phase III multicenter placebo controlled study of 2 dosages of modified release tamsulosin in patients with symptoms of benign prostatic hyperplasia.
EFFICACY OF TAMSULOSIN FOR NEUROPATHIC BLADDER
United States 93-01 Study Group. J Urol 1998; 160: 1701. 6. Abrams P, Amarenco G, Bakke A et al: Tamsulosin: efficacy and safety in patients with neurogenic lower urinary tract dysfunction due to suprasacral spinal cord injury. J Urol 2003; 170: 1242. 7. Joseph DB: Current approaches to the urologic care of children with spina bifida. Curr Urol Rep 2008; 9: 151.
8. Verpoorten C and Buyse GM: The neurogenic bladder: medical treatment. Pediatr Nephrol 2008; 23: 717. 9. de Jong TP, Chrzan R, Klijn AJ et al: Treatment of the neurogenic bladder in spina bifida. Pediatr Nephrol 2008; 23: 889. 10. Lee KS, Han DH, Lee YS et al: Efficacy and safety of tamsulosin for the treatment of non-neurogenic voiding dysfunction in females: an 8-week prospective study. J Korean Med Sci 2010; 25: 117.
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11. Vanderbrink BA, Gitlin J, Toro S et al: Effect of tamsulosin on systemic blood pressure and nonneurogenic dysfunctional voiding in children. J Urol 2009; 181: 817. 12. Kakizaki H, Ameda K, Kobayashi S et al: Urodynamic effects of alpha1-blocker tamsulosin on voiding dysfunction in patients with neurogenic bladder. Int J Urol 2003; 10: 576. 13. Bauer SB, Labib KB, Dieppa RA et al: Urodynamic evaluation of boy with myelodysplasia and incontinence. Urology 1977; 10: 354.