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

Study Overview
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Brief Summary
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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.

Official Title
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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.

Conditions
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Bladder, Neurogenic

Intervention / Treatment
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* Drug: tamsulosin hydrochloride


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1. Low dose group<br> | Drug: tamsulosin hydrochloride<br>* oral<br>|
| Experimental: 2. Medium dose group<br> | Drug: tamsulosin hydrochloride<br>* oral<br>|
| Experimental: 3. High dose group<br> | Drug: tamsulosin hydrochloride<br>* oral<br>|

What is the study measuring?
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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 |
| --- | --- | --- |
| 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. | 
| 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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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tamsulosin, pediatric, neurogenic bladder