PK/PD, Long-term Safety and Efficacy of Tamsulosin Treatment in Children With Neurogenic Bladder

An Uncontrolled, Open-label, Titration, Long-term Safety (up to 12 Months) and Efficacy Study of Tamsulosin Hydrochloride in Children With Neuropathic Bladder, With a Randomized Pharmacokinetic Sub-study Investigating Low, Medium and High Dose Ranges.

Aims of this study is to characterize the pharmacokinetic/pharmacodynamic profile and evaluate the safety, efficacy and tolerability, of tamsulosin hydrochloride as treatment in children with a neuropathic bladder, over the course of 12 months of active treatment.

Study Overview

• Status: Completed
• Conditions: Bladder, Neurogenic
• Intervention / Treatment: Drug: tamsulosin hydrochloride

• Study Type: Interventional
• Enrollment (Actual): 143
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Gent, Belgium, 9000
• Brazil
  • Santo Andre, Brazil, 09060-650
  • Sao Paulo, Brazil, 05403-000
• Canada
  • Halifax, Canada, B3K 6R8
  • Montreal, Canada, H3H 1P3
  • Montreal, Canada, H3T 1J5
  • Toronto, Canada, M5G 1X8
• Germany
  • Berlin, Germany, 10115
  • Deggendorf, Germany, 94469
  • Essen, Germany, 45122
  • Hamburg, Germany, 22763
  • Mainz, Germany, 55101
• India
  • Ahmedabad, India, 380-006
  • Belgaum, India, 590-010
  • Bengaluru, India, 560-010
  • Hyderabaad, India, 500-029
  • Kochin, India, 682-026
  • Lucknow, India, 226-003
  • Lucknow, India, 226-014
  • Ludhiana, India, 141-001
  • Ludhiana, India, 141-008
  • Manipal, India, 576-104
  • Mumbai, India, 400-008
  • Nadiad, India, 387-001
  • Nagpur, India
  • New Delhi, India, 110-029
  • Pune, India, 411-001
  • Pune, India, 411-053
• Italy
  • Cagliari, Italy, 09134
  • Firenze, Italy, 50139
  • Roma, Italy, 00165
• Korea, Republic of
  • Gwangju, Korea, Republic of, 501-757
  • In Cheon, Korea, Republic of, 400-711
  • Pusan, Korea, Republic of, 602-739
  • Seoul, Korea, Republic of, 138-736
  • Seoul, Korea, Republic of, 110-744
  • Seoul, Korea, Republic of, 120-752
• Mexico
  • Leon, Mexico, 37660
  • Puebla, Mexico, CP 72190
• Philippines
  • Manila, Philippines, 1000
  • Pasig City, Philippines, 1604
  • Quezon City, Philippines, 1104
• Russian Federation
  • Moscow, Russian Federation, 119991
  • St. Petersburg, Russian Federation, 194100
• South Africa
  • Bloemfontein, South Africa, 9300
  • Cape Town, South Africa, 7700
  • Johannesburg, South Africa
  • Pretoria, South Africa, 0028
  • Roodepoort, South Africa
• Spain
  • Barcelona, Spain, 08025
  • Madrid, Spain, 28046
  • Malaga, Spain, 29011
• Ukraine
  • Chernivtsy, Ukraine, 58002
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
  • California
    • Los Angeles, California, United States, 90027
  • Florida
    • Jacksonville, Florida, United States, 32207
    • Tampa, Florida, United States, 33614
  • Illinois
    • Springfield, Illinois, United States, 62702
  • Indiana
    • Indianapolis, Indiana, United States, 46202
  • Louisiana
    • Shreveport, Louisiana, United States, 71106
  • Missouri
    • St Louis, Missouri, United States, 63110
  • New York
    • Buffalo, New York, United States, 14222
    • Lake Success, New York, United States, 11042
    • Tarrytown, New York, United States, 10591
  • North Carolina
    • Winston Salem, North Carolina, United States, 27157
  • Ohio
    • Akron, Ohio, United States, 44308
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
  • Tennessee
    • Nashville, Tennessee, United States, 37232
  • Texas
    • Dallas, Texas, United States, 75235
    • Houston, Texas, United States, 77030
  • Utah
    • Salt Lake City, Utah, United States, 84132
  • Wisconsin
    • Madison, Wisconsin, United States, 53792

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 16 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Neuropathic bladder secondary to known neurological disorder
• Elevated detrusor leak point pressures (LPP) ≥40 cm H2O confirmed by two measurements at baseline

Exclusion Criteria:

• Clinically significant abnormalities as determined by the investigator
• A history of relevant orthostatic hypotension, fainting spells or blackouts

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1. Low dose group	Drug: tamsulosin hydrochloride; oral
Experimental: 2. Medium dose group	Drug: tamsulosin hydrochloride; oral
Experimental: 3. High dose group	Drug: tamsulosin hydrochloride; oral

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of LPP Responders for Group D-Denovo and Group D-527.51 Rollover	Group D-Denovo: Leak point pressure (LPP) Response at(response defined as a subject who achieves an LPP pressure <40 cm H2O) at the end of treatment based on two confirmatory values. Group D-527.51 Rollover: Leak point pressure (LPP) Response at (response defined as a subject who achieves an LPP pressure <40 cm H2O) last value of the treatment based on two confirmatory values. The last value on treatment included any final value prior to discontinuation of treatment, regardless of the length of treatment. Detrusor leak point pressure (LPP) recorded in cm H2O which was obtained using a standard urodynamic technique, a cystometrogram. Descriptive statistics were used to assess this endpoint. This Outcome Measure was only pre-specified for Group D-Denovo and Group D-527.51 Rollover subjects, so results of these two groups are provided.	Group D-Denovo: Week 52. Group D-527.51 Rollover: Week 1, Week 2, Week 3 and Week 4 prior to dose administration and Week9 (optional), Week 13 (additional), Week 26 (optional) and Week 52 after drug administration.
Number of LPP Responders at Each Visit Over Time (Classified by Last Value on Treatment) for Group D-527.51 Rollover.	Number of Leak point pressure (LPP) Responders at each visit (week) over time (classified by last value on treatment). Due to the early termination of the study, most of the LPP assessments were conducted within Weeks 1-9 of treatment. Summary of LPP response rates provided over time.The subjects are classified according to the treatment they were receiving at the last value on treatment. Therefore, no assumptions can be made regarding what dose they were receiving at a particular time point. LD: Low Dose, MD: Medium Dose and HD: High Dose This Outcome Measure was only pre-specified for Group D-527.51 Rollover subjects, so results of this group is provided.	Week 1 (Visit 3) , Week 2 (Visit 4) , Week 3 (Visit 5) and Week 4 (Visit 6) prior to dose administration and Week 9 (Visit 7) (optional), Week 13 (Visit 8) (additional), Week 26 (Visit 9) (optional) and Week 52 (Visit 11) after drug administration.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Early Responders Who Maintained Their LPP Below 40 cm H2O During the Study for Group D-Denovo and Group D-527.51 Rollover	Early responders who maintained their detrusor leak point pressure (LPP) below 40 cm H2O during the study. Timeframe for Group D-Denovo: Low dose: Week 1, 3 & 4 prior to dose and Week 2, 9 & 26 (optional), 13(additional) & 52 post dose. Medium dose: Week 1, 2 & 4 prior to dose and Week 3, 9(optional), 13(additional), 26 (optional) & 52 post dose. High dose: Week 1, 2 & 3 prior to dose administration and Week 4, 9(optional), 13(additional), 26 (optional) & 52 post dose. Group D-527.51 Rollover: Week 1, 2,3 & 4 prior to dose and Week 9 &26 (optional),13 (additional) & 52 post dose. This Outcome Measure was only pre-specified for Group D-Denovo and Group D-527.51 Rollover subjects, However this endpoint was not analysed for Group D-527.51 Rollover as very limited data were collected due to early termination of the study & no alternative endpoint was defined in the Group D-527.51 rollover, so only the results for Group D-Denovo is provided.	Week 1 to Week 52 (Time frame for all weeks are described study wise in the Description).
Change From Baseline in LPP for Group D-527.51 Rollover	Median change from baseline in detrusor leak point pressure (LPP) by treatment group (subjects are classified according to the treatment they were taking at end of treatment) and week. Baseline assessments were obtained from trial 527.51 for Group D-527.51 Rollover. The results from Week 1 were reported because there were very few subjects who reported data at subsequent visits due to the termination of the trial. This Outcome Measure was only pre-specified for Group D-527.51 Rollover subjects, so results of this group is provided.	Baseline and week 1
Percent Change From Baseline in LPP for Group D-527.51 Rollover	Percent change from baseline in actual detrusor leak point pressure (LPP) by treatment group (subjects are classified according to the treatment they were taking at end of treatment) and Week. Baseline assessments were obtained from trial 527.51 for Group D-527.51 Rollover. The results from Week 1 were reported because there were very few subjects who reported data at subsequent visits due to the termination of the trial. This Outcome Measure was only pre-specified for Group D-527.51 Rollover subjects, so results of this group is provided.	Baseline and Week 1
Response Defined as Stabilization or Improvement of Hydroureter Measured by Renal Ultrasound Compared to Baseline for Group D-Denovo and Group D-527.51 Rollover	Response defined as stabilization or improvement of hydroureter measured by renal ultrasound compared to baseline by treatment group (subjects are classified according to the treatment they were taking at Week 52 or end of treatment) at week 52 for Group D-Denovo and (subjects are classified according to the treatment they were taking at the end of treatment) at last value on treatment for Group D-527.51 Rollover. Baseline assessments were obtained from trial 527.51 for Group D-527.51 Rollover. The overall treatment duration was not sufficient to reach any meaningful conclusions regarding improvement or stabilization of hydroureter in the Group D-527.51 Rollover. Hydroureter response is defined as improvement or stabilization based upon the presence or absence of hydroureter at end of treatment compared to baseline. This Outcome Measure was only pre-specified for Group D-Denovo and Group D-527.51 Rollover subjects, so results of these two groups are provided.	Group D-Denovo: Baseline and Week 52. Group D-527.51 Rollover: Baseline, Week 26 and Week 52.
Response Defined as Stabilization or Improvement of Hydronephrosis Measured by Renal Ultrasound Compared to Baseline for Group D-Denovo and Group D-527.51 Rollover	Response defined as stabilization or improvement of hydronephrosis measured by renal ultrasound compared to baseline by treatment group (subjects are classified according to the treatment they were taking at Week 52 or end of treatment) at week 52 for Group D-Denovo and (subjects are classified according to the treatment they were taking at the end of treatment) at last value on treatment for Group D-527.51 Rollover. Baseline assessments were obtained from trial 527.51 for Group D-527.51 Rollover. The overall treatment duration was not sufficient to reach any meaningful conclusions regarding improvement or stabilization of hydronephrosis in the Group D-527.51 Rollover. Hydronephrosis response is defined as an improvement or stabilization based upon ultrasound grading at the end of the study. The lower or same grade at end of treatment compared to baseline is considered an improvement or stabilization.	Group D-Denovo: Baseline and Week 52. Group D-527.51 Rollover: Baseline, Week 26 and Week 52.
LPP Response at Any Time During the Trial for Group D-Denovo and Group D-527.51 Rollover	Response rates of LPP responders (2 LPP values < 40 cm H2O) at any time during the trial by treatment group. Timeframe for Group D-Denovo: Low dose: Week 1, 3 & 4 prior to dose and Week 2, 9 & 26 (optional), 13(additional) & 52 post dose. Medium dose: Week 1, 2 & 4 prior to dose and Week 3, 9(optional), 13(additional), 26 (optional) & 52 post dose. High dose: Week 1, 2 & 3 prior to dose administration and Week 4, 9(optional), 13(additional), 26 (optional) & 52 post dose. Group D-527.51 Rollover: Week 1, 2, 3 & 4 prior to dose and Week 9 &26 (optional),13 (additional) & 52 post dose. This Outcome Measure was only pre-specified for Group D-Denovo and Group D-527.51 Rollover subjects, so results of these two groups are provided.	Week 1 to Week 52 (described study wise in the Description).
Number of Participants With Clinically Relevant Abnormalities for Physical Examination, Vital Signs/Orthostatic Testing, Electrocardiogram (ECG), Laboratory Values,Urinalysis,Occurence of Adverse Events & Cognitive Testing for Group D-527.51 Rollover	Number of participants with Clinically Relevant Abnormalities for Physical Examination, Vital Signs/Orthostatic testing, Electrocardiogram (ECG), Laboratory Values, Urinalysis, Occurence of Adverse events and Cognitive Testing. Relevant findings or worsening of baseline conditions were reported as adverse events. Below mentioned result are the number of subjects who had the clinical relevant abnormalities for the preferred term 'Hepatic enzyme increased'. This Outcome Measure was only pre-specified for Group D-527.51 Rollover subjects, so results of this group is provided.	From first drug administration until 28 days after last study drug administration, upto 395 days
Number of Participants With Clinically Relevant Abnormalities for Physical Examination, Vital Signs/Orthostatic Testing, Electrocardiogram (ECG), Laboratory Values, Urinalysis, Occurence of Adverse Events and Cognitive Testing for Group D-Denovo	Number of participants with Clinically Relevant Abnormalities for Physical Examination, Vital Signs/Orthostatic testing, Electrocardiogram (ECG), Laboratory Values, Urinalysis, Occurence of Adverse events and Cognitive Testing. Relevant findings or worsening of baseline conditions were reported as adverse events. Subjects who experienced orthostatic hypotension during orthostatic testing were reported as adverse events. This Outcome Measure was only pre-specified for Group D-Denovo, so results of this group is provided.	From first drug administration until 28 days after last study drug administration, upto 450 days
Vision Testing for Group D-Denovo	Number of subjects with a change from baseline in visual acuity by treatment group (subjects are classified according to the treatment they were taking at Week 52 or end of treatment). They were analysed based on the below mentioned category in both the Eyes: 1) No Change 2) Decrease in visual acuity 3) Increase in visual acuity 4) Missing. Missing includes subjects with no baseline exam and subjects with exam scores missing. This Outcome Measure was only pre-specified for Group D-Denovo subjects, so results of this group is provided.	Baseline, Week 26 and Week 52.
Vision Testing for Group D-527.51 Rollover	Number of subjects with a change from baseline in visual acuity by treatment group (subjects are classified according to the treatment they were taking at end of treatment). They were analysed based on the below mentioned category in both the Eyes: 1) No Change 2) Decrease in visual acuity 3) Increase in visual acuity 4) Missing. Missing includes subjects with no baseline exam and subjects with exam scores missing. This Outcome Measure was only pre-specified for Group D-527.51 Rollover subjects, so results of this group is provided.	Baseline and Week 52
Cmax,1	Maximum measured concentration of the analyte in plasma following the first dose, Cmax,1. This Outcome Measure was only pre-specified for PK Study- single dose group subjects, so results of this group is provided.	-0.25h prior to dose and 2h, 4h, 6h and 8h after the drug administration.
Tmax, 1	Time from dosing to maximum measured concentration of the analyte in plasma after administration of the first dose, tmax, 1. This Outcome Measure was only pre-specified for PK Study- single dose group subjects, so results of this group is provided.	-0.25h prior to dose and 2h, 4h, 6h and 8h after the drug administration.
Cmax, 1 ,DW ,Norm	Dose- and weight-normalized Cmax,1 (Cmax,1,DW,norm). Weight normalization of Cmax,1 was performed by dividing the respective quantities by the reciprocal of body weight in kg. This Outcome Measure was only pre-specified for PK Study- single dose group subjects, so results of this group is provided.	-0.25h prior to dose and 2h, 4h, 6h and 8h after the drug administration.
Cpre,ss	Pre-dose concentration of the analyte in plasma at steady state immediately before administration of the next dose, Cpre,ss. This Outcome Measure was only pre-specified for PK Study- steady state group subjects, so results of this group is provided.	-0.25h prior to dose and 2h, 4h, 6h, 8h, 10h, 24h and 33h after the drug administration.
Cmax,ss	Maximum measured concentration of the analyte in plasma at steady state over a uniform dosing interval τ, Cmax,ss. This Outcome Measure was only pre-specified for PK Study- steady state group subjects, so results of this group is provided.	-0.25h prior to dose and 2h, 4h, 6h, 8h, 10h, 24h and 33h after the drug administration.
Cmax,ss, DW, Norm	Dose- and weight-normalized for Cmax,ss, Cmax,ss, DW, norm. Weight normalization of Cmax,ss was performed by dividing the respective quantities by the reciprocal of body weight in kg. This Outcome Measure was only pre-specified for PK Study- steady state group subjects, so results of this group is provided.	-0.25h prior to dose and 2h, 4h, 6h, 8h, 10h, 24h and 33h after the drug administration.
Cmin,ss	Minimum measured concentration of the analyte in plasma at steady state over a uniform dosing interval τ, Cmin,ss. This Outcome Measure was only pre-specified for PK Study- steady state group subjects, so results of this group is provided.	-0.25h prior to dose and 2h, 4h, 6h, 8h, 10h, 24h and 33h after the drug administration.
Tmax,ss	Time from last dosing to maximum concentration of the analyte in plasma at steady state over a uniform dosing interval τ, tmax,ss. This Outcome Measure was only pre-specified for PK Study- steady state group subjects, so results of this group is provided.	-0.25h prior to dose and 2h, 4h, 6h, 8h, 10h, 24h and 33h after the drug administration.
AUCτ,ss	Area under the concentration-time curve of the analyte in plasma at steady state over a uniform dosing interval τ , AUCτ,ss. This Outcome Measure was only pre-specified for PK Study- steady state group subjects, so results of this group is provided.	-0.25h prior to dose and 2h, 4h, 6h, 8h, 10h, 24h and 33h after the drug administration.
AUCτ ,ss ,DW ,Norm	Dose- and weight-normalized of AUCτ ,ss ( AUCτ ,ss ,DW ,norm). Weight normalization of AUCτ,ss was performed by dividing the respective quantities by the reciprocal of body weight in kg. This Outcome Measure was only pre-specified for PK Study- steady state group subjects, so results of this group is provided.	-0.25h prior to dose and 2h, 4h, 6h, 8h, 10h, 24h and 33h after the drug administration.
λz,ss	Terminal rate constant of the analyte in plasma at steady state, λz,ss. This Outcome Measure was only pre-specified for PK Study- steady state group subjects, so results of this group is provided.	-0.25h prior to dose and 2h, 4h, 6h, 8h, 10h, 24h and 33h after the drug administration.
t1/2,ss	Terminal half-life of the analyte in plasma at steady state, t1/2,ss. This Outcome Measure was only pre-specified for PK Study- steady state group subjects, so results of this group is provided.	-0.25h prior to dose and 2h, 4h, 6h, 8h, 10h, 24h and 33h after the drug administration.
MRTpo,ss	Mean residence time of the analyte in the body at steady state after oral administration,MRTpo,ss. This Outcome Measure was only pre-specified for PK Study- steady state group subjects, so results of this group is provided.	-0.25h prior to dose and 2h, 4h, 6h, 8h, 10h, 24h and 33h after the drug administration.
CL/F,ss,W,Norm	Weight-normalized CL/F,ss (apparent clearance of the analyte in the plasma at steady state after extravascular multiple dose administration), CL/F,ss,W,norm. Weight-normalized CL/F,ss was calculated by dividing the respective quantities by body weight in kg. This Outcome Measure was only pre-specified for PK Study- steady state group subjects, so results of this group is provided.	-0.25h prior to dose and 2h, 4h, 6h, 8h, 10h, 24h and 33h after the drug administration.
Vz/F,ss,W,Norm	Weight-normalized Vz/F,ss (apparent volume of distribution during the terminal phase λz at steady state following extravascular administration), Vz/F,ss,W,norm. Weight-normalized VzF,ss was calculated by dividing the respective quantities by body weight in kg. This Outcome Measure was only pre-specified for PK Study- steady state group subjects, so results of this group is provided.	-0.25h prior to dose and 2h, 4h, 6h, 8h, 10h, 24h and 33h after the drug administration.
RA,Cmax	The accumulation ratio was calculated from the patients who were randomised to the low dose group and for whom both parameters at first dose and steady state dose were available. Accumulation ratios of tamsulosin HCl in plasma at steady state after multiple dose administration over a uniform dosing interval τ, expressed as ratio of Cmax at steady state and after single dose. The accumulation ratio RA,Cmax was calculated as: Cmax,ss/Cmax,1. This Outcome Measure was only pre-specified for PK Study- steady state group subjects, so results from this group is provided.	-0.25h prior to dose and 2h, 4h, 6h, 8h, 10h, 24h and 33h after the drug administration.

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: April 1, 2006
• Primary Completion (Actual): June 1, 2009
• Study Completion (Actual): June 1, 2009

Study Registration Dates

• First Submitted: June 19, 2006
• First Submitted That Met QC Criteria: June 19, 2006
• First Posted (Estimate): June 21, 2006

Study Record Updates

• Last Update Posted (Estimate): February 17, 2016
• Last Update Submitted That Met QC Criteria: January 20, 2016
• Last Verified: January 1, 2016

More Information

Terms related to this study

• Keywords: pediatric; tamsulosin; neurogenic bladder
• Additional Relevant MeSH Terms: Nervous System Diseases; Urologic Diseases; Urinary Bladder Diseases; Neurologic Manifestations; Urinary Bladder, Neurogenic; Physiological Effects of Drugs; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Urological Agents; Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Tamsulosin
• Other Study ID Numbers: 527.66