Neurogenic Urinary Bladder
Conditions
Keywords
child, bladder, neuropathic, alpha blockers
Brief summary
The primary objective of the study was to evaluate the efficacy of Alfuzosin in comparison to Placebo on the detrusor Leak Point Pressure (LPP) in children and adolescents 2-16 years of age with elevated detrusor LPP of neuropathic etiology and detrusor LPP ≥ 40 cm H2O. Secondary objectives were: * To investigate the safety and tolerability of two doses of Alfuzosin in comparison to Placebo in children and adolescents, * To evaluate the effects of the two doses of Alfuzosin in comparison to Placebo on: * Detrusor compliance, * Urinary tract infection, * To investigate the pharmacokinetics of Alfuzosin (population kinetics), * To evaluate the 12-month long-term safety of Alfuzosin 0.1 mg/kg/day and 0.2 mg/kg/day. The study consisted of 2 periods: * a 12-week double blind treatment period where patients were to receive either Alfuzosin 0.1 mg/kg/day or Alfuzosin 0.2 mg/kg/day or placebo then, * a 40-week open label extension treatment period where patients were to receive either Alfuzosin 0.1 mg/kg/day or Alfuzosin 0.2 mg/kg/day.
Detailed description
Patients who met the study entry criteria were randomized (2:1:2:1) to one of the 4 dosage groups (Alfuzosin 0.1 mg/kg/day, matching placebo 0.1 mg/kg/day, Alfuzosin 0.2 mg/mg/kg, matching placebo 0.2 mg/kg/day). Patients received their treatment using either solution or tablet formulation depending on age as follows: * Solution to children 2-7 years of age or, children and adolescents 8-16 years of age if they were unable to swallow tablets or they preferred to take the solution or if they had a body weight \< 30kg. The daily dose was devided in 3 doses given at at breakfast, lunch and dinner. * Tablet to children and adolescents 8-16 years of age who were able to swallow tablets and had a body weight ≥ 30kg. The daily dose was devided in 2 doses given at at breakfast and dinner. Patients who have completed the 12-week double-blind phase were offered to continue in the 40-week open-label extension study. * Patients receiving Alfuzosin continued with their dosing regimen. * Patients receiving Placebo were switched to Alfuzosin with a dose corresponding to their randomization dose group. All patients had a one-week follow-up period after last dose intake.
Interventions
DRUGAlfuzosin
Form: solution or tablet according to age Route: oral Dose: daily dose adjusted to body weight
DRUGPlacebo
Form: matching solution or matching tablet according to age Route: oral Dose: daily dose adjusted to body weight
Sponsors
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
2 Years to 16 Years
Healthy volunteers
No
Inclusion criteria
* Patient with elevated detrusor Leak Point Pressure (LPP) of neuropathic etiology and Detrusor LPP ≥ 40 cm H2O and \< 100 cm H2O.
Exclusion criteria
* Urological surgery in the last 4 months prior to the study, * Patients who have urethral dilatation in the last 3 months prior to the baseline urodynamic assessment, * α-blocker therapy in the last 4 weeks prior to the baseline urodynamic assessment, * Detrusor injections of botulinum toxin in the last 6 months, * Urological diseases/conditions other than functional bladder obstruction of neuropathic etiology that can lead to upper urinary tract dilatation (e.g., bladder anomalies, ureterocele), * History of intolerance to α-blocker therapy, * Orthostatic hypotension, * History of risk factors for Torsade de pointes (e.g., family history of Long QT Syndrome). The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Detrusor Leak Point Pressure (LPP) < 40 cm H2O | 12 weeks (double blind treatment period) | Detrusor Leak Point Pressure (LPP) was measured by cystometry. For each measure, 2 or 3 cystometries were carried out depending on the difference between the 2 first LPP values (if the difference ≥ 20 cm H2O, a 3rd cystometry was done). The lowest value was retained. Investigators reading was then consolidated by the review of all cystometry data by 2 external Expert Reviewers, who were blinded for the study treatment. The analysis was performed on consolidated investigators data (i.e. endorsed by the Investigator taking into account reviewers opinion). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change in Detrusor LPP | 12 weeks ((double blind treatment period) | Absolute change = Detrusor LPP at 12 weeks - Detrusor LPP at baseline |
| Relative Change in Detrusor LPP | 12 weeks (double blind treatment period) | Relative change = 100 \* (Detrusor LPP at 12 weeks - Detrusor LPP at baseline) / Detrusor LPP at baseline |
| Detrusor Leak Point Pressure (LPP) | baseline and 12 weeks (double blind treatment period) | Detrusor Leak Point Pressure (LPP) was assessed at baseline and 12 weeks as described for the primary outcome measure. |
| Relative Change in Detrusor Compliance | 12 weeks (double blind treatment period) | Relative change = 100 \* (Detrusor compliance at 12 weeks - Detrusor compliance at baseline) / Detrusor compliance at baseline |
| Number of Participants With Symptomatic Urinary Tract Infection (UTI) Episodes | 12 weeks (double blind treatment period) | When a patient presented with symptoms such as pain, fever or hematuria (discretion of the Investigator), an urinalysis was performed including a dipstick and a quantitative urine culture. A symptomatic UTI was defined as the presence of symptoms and a positive culture with \> 100 000 Colony Forming Units (CFUs) with a single organism. |
| Detrusor Compliance | baseline and 12 weeks (double blind treatment period) | Detrusor compliance is defined as the relationship between change in detrusor volume and change in detrusor pressure. It was calculated by dividing the volume change (ΔV) by the change in detrusor pressure (Δpdet) during that change in detrusor volume at leak point (C= ΔV/Δpdet). |
Countries
Bulgaria, Canada, Estonia, France, Germany, India, Malaysia, Philippines, Poland, Portugal, Russia, Serbia, Singapore, Slovakia, Spain, Taiwan, Turkey (Türkiye), United States
Participant flow
Recruitment details
The study was conducted at 55 sites in 18 countries. A total of 261 patients were screened between September 2007 and November 2008.
Pre-assignment details
172/261 patients were randomized in the 12-week double blind phase. 89/261 patients were not randomized for the following reasons: * Adverse event (1 patient\*), * Inclusion/Exclusion criteria not met (69 patients\*), * Subject's request (11 patients\*), * Other (13 patients\*). '\*' Patients could have several reasons.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Alfuzosin 0.1 mg/kg/day matching placebo or Alfuzosin 0.2 mg/kg/day matching placebo | 57 |
| Alfuzosin 0.1 mg/kg/Day | 57 |
| Alfuzosin 0.2 mg/kg/Day | 58 |
| Total | 172 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| 12-week Double Blind Treatment Period | Adverse Event | 1 | 1 | 2 |
| 12-week Double Blind Treatment Period | Too many blood draws | 0 | 1 | 0 |
| 40-week Open Label Treatment Period | Adverse Event | 0 | 2 | 1 |
| 40-week Open Label Treatment Period | Lack of Efficacy | 0 | 1 | 0 |
| 40-week Open Label Treatment Period | Other | 0 | 1 | 4 |
| 40-week Open Label Treatment Period | Protocol Violation | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo | Total | Alfuzosin 0.2 mg/kg/Day | Alfuzosin 0.1 mg/kg/Day |
|---|---|---|---|---|
| Age, Continuous | 8.3 years STANDARD_DEVIATION 4.4 | 8.3 years STANDARD_DEVIATION 4 | 8.7 years STANDARD_DEVIATION 3.9 | 7.9 years STANDARD_DEVIATION 3.9 |
| Region of Enrollment Canada | 3 participants | 6 participants | 2 participants | 1 participants |
| Region of Enrollment Estonia | 1 participants | 3 participants | 1 participants | 1 participants |
| Region of Enrollment France | 1 participants | 7 participants | 4 participants | 2 participants |
| Region of Enrollment Germany | 3 participants | 5 participants | 2 participants | 0 participants |
| Region of Enrollment India | 2 participants | 20 participants | 9 participants | 9 participants |
| Region of Enrollment Malaysia | 3 participants | 3 participants | 0 participants | 0 participants |
| Region of Enrollment Poland | 15 participants | 39 participants | 14 participants | 10 participants |
| Region of Enrollment Portugal | 2 participants | 6 participants | 3 participants | 1 participants |
| Region of Enrollment Russian Federation | 8 participants | 19 participants | 4 participants | 7 participants |
| Region of Enrollment Serbia | 4 participants | 17 participants | 7 participants | 6 participants |
| Region of Enrollment Slovakia | 6 participants | 14 participants | 1 participants | 7 participants |
| Region of Enrollment Spain | 2 participants | 7 participants | 2 participants | 3 participants |
| Region of Enrollment Taiwan | 0 participants | 2 participants | 1 participants | 1 participants |
| Region of Enrollment Turkey | 1 participants | 6 participants | 3 participants | 2 participants |
| Region of Enrollment United States | 6 participants | 18 participants | 5 participants | 7 participants |
| Sex: Female, Male Female | 28 Participants | 85 Participants | 30 Participants | 27 Participants |
| Sex: Female, Male Male | 29 Participants | 87 Participants | 28 Participants | 30 Participants |
| Study drug formulation Solution (2-7 years) | 28 participants | 84 participants | 28 participants | 28 participants |
| Study drug formulation Solution (8-16 years) | 8 participants | 27 participants | 9 participants | 10 participants |
| Study drug formulation Tablets (8-16 years) | 21 participants | 61 participants | 21 participants | 19 participants |
| Urinary Tract Infection (UTI) history in the last 3 months No UTI episode | 48 participants | 138 participants | 40 participants | 50 participants |
| Urinary Tract Infection (UTI) history in the last 3 months One UTI episode | 8 participants | 29 participants | 16 participants | 5 participants |
| Urinary Tract Infection (UTI) history in the last 3 months Two UTI episodes | 1 participants | 5 participants | 2 participants | 2 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 37 / 83 | 43 / 86 |
| serious Total, serious adverse events | 10 / 83 | 7 / 86 |
Outcome results
Primary
Number of Patients With Detrusor Leak Point Pressure (LPP) < 40 cm H2O
Detrusor Leak Point Pressure (LPP) was measured by cystometry. For each measure, 2 or 3 cystometries were carried out depending on the difference between the 2 first LPP values (if the difference ≥ 20 cm H2O, a 3rd cystometry was done). The lowest value was retained. Investigators reading was then consolidated by the review of all cystometry data by 2 external Expert Reviewers, who were blinded for the study treatment. The analysis was performed on consolidated investigators data (i.e. endorsed by the Investigator taking into account reviewers opinion).
Time frame: 12 weeks (double blind treatment period)
Population: The Intent-to-treat (ITT) population was used for the analysis. All randomized patients were included in the analysis in the treatment group to which they were allocated as per randomization.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Patients With Detrusor Leak Point Pressure (LPP) < 40 cm H2O | < 40 cmH2O (Success) | 23 participants |
| Placebo | Number of Patients With Detrusor Leak Point Pressure (LPP) < 40 cm H2O | ≥ 40 cmH2O or missing (Failure) | 34 participants |
| Alfuzosin 0.1 mg/kg/Day | Number of Patients With Detrusor Leak Point Pressure (LPP) < 40 cm H2O | < 40 cmH2O (Success) | 23 participants |
| Alfuzosin 0.1 mg/kg/Day | Number of Patients With Detrusor Leak Point Pressure (LPP) < 40 cm H2O | ≥ 40 cmH2O or missing (Failure) | 34 participants |
| Alfuzosin 0.2 mg/kg/Day | Number of Patients With Detrusor Leak Point Pressure (LPP) < 40 cm H2O | < 40 cmH2O (Success) | 28 participants |
| Alfuzosin 0.2 mg/kg/Day | Number of Patients With Detrusor Leak Point Pressure (LPP) < 40 cm H2O | ≥ 40 cmH2O or missing (Failure) | 30 participants |
p-value: 1Fisher Exact
p-value: 0.91Fisher Exact
Secondary
Absolute Change in Detrusor LPP
Absolute change = Detrusor LPP at 12 weeks - Detrusor LPP at baseline
Time frame: 12 weeks ((double blind treatment period)
Population: The analysis was performed on the same population as previously (i.e. ITT population excluding the patients who didn't have baseline and/or post-baseline value).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Absolute Change in Detrusor LPP | -5.4 cmH2O | Standard Error 2.8 |
| Alfuzosin 0.1 mg/kg/Day | Absolute Change in Detrusor LPP | -11.7 cmH2O | Standard Error 2.8 |
| Alfuzosin 0.2 mg/kg/Day | Absolute Change in Detrusor LPP | -12.5 cmH2O | Standard Error 2.8 |
Comparison: Change in detrusor LPP was analyzed using a three-way analysis of covariance (ANCOVA) including 3 variables as fixed effects:~* treatment group (alfuzosin 0.1 mg/kg/day, alfuzosin 0.2 mg/kg/day or placebo),~* age/formulation group (2-7 years of age on solution, 8-16 years of age on solution or 8-16 years of age on tablets),~* anticholinergic/antimuscarinic use (yes or no),~and using centered baseline detrusor LPP as covariate.p-value: 0.10495% CI: [-13.72, 1.29]ANCOVA
p-value: 0.10495% CI: [-14.51, 0.39]ANCOVA
Secondary
Detrusor Compliance
Detrusor compliance is defined as the relationship between change in detrusor volume and change in detrusor pressure. It was calculated by dividing the volume change (ΔV) by the change in detrusor pressure (Δpdet) during that change in detrusor volume at leak point (C= ΔV/Δpdet).
Time frame: baseline and 12 weeks (double blind treatment period)
Population: The analysis was performed on the intent-to-treat (ITT) population excluding the patients who didn't have baseline and/or post baseline detrusor compliance values. Patients were included in the treatment group to which they were allocated as per randomization.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Detrusor Compliance | Baseline | 3.4 mL/cmH20 | Standard Deviation 2.8 |
| Placebo | Detrusor Compliance | 12 weeks | 4.8 mL/cmH20 | Standard Deviation 5 |
| Alfuzosin 0.1 mg/kg/Day | Detrusor Compliance | Baseline | 3.4 mL/cmH20 | Standard Deviation 2.8 |
| Alfuzosin 0.1 mg/kg/Day | Detrusor Compliance | 12 weeks | 5.3 mL/cmH20 | Standard Deviation 4.9 |
| Alfuzosin 0.2 mg/kg/Day | Detrusor Compliance | Baseline | 3.3 mL/cmH20 | Standard Deviation 2.5 |
| Alfuzosin 0.2 mg/kg/Day | Detrusor Compliance | 12 weeks | 5.8 mL/cmH20 | Standard Deviation 5.9 |
Secondary
Detrusor Leak Point Pressure (LPP)
Detrusor Leak Point Pressure (LPP) was assessed at baseline and 12 weeks as described for the primary outcome measure.
Time frame: baseline and 12 weeks (double blind treatment period)
Population: The analysis was performed on the Intent-to-treat (ITT) population excluding the patients who didn't have baseline and/or post-baseline LPP values. Patients were included in the treatment group to which they were allocated as per randomization.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Detrusor Leak Point Pressure (LPP) | Baseline | 54.2 cmH2O | Standard Deviation 12.6 |
| Placebo | Detrusor Leak Point Pressure (LPP) | 12 Weeks | 48.2 cmH2O | Standard Deviation 23.4 |
| Alfuzosin 0.1 mg/kg/Day | Detrusor Leak Point Pressure (LPP) | Baseline | 53.3 cmH2O | Standard Deviation 13.4 |
| Alfuzosin 0.1 mg/kg/Day | Detrusor Leak Point Pressure (LPP) | 12 Weeks | 41.6 cmH2O | Standard Deviation 18.2 |
| Alfuzosin 0.2 mg/kg/Day | Detrusor Leak Point Pressure (LPP) | Baseline | 50.9 cmH2O | Standard Deviation 10 |
| Alfuzosin 0.2 mg/kg/Day | Detrusor Leak Point Pressure (LPP) | 12 Weeks | 39.4 cmH2O | Standard Deviation 19.5 |
Secondary
Number of Participants With Symptomatic Urinary Tract Infection (UTI) Episodes
When a patient presented with symptoms such as pain, fever or hematuria (discretion of the Investigator), an urinalysis was performed including a dipstick and a quantitative urine culture. A symptomatic UTI was defined as the presence of symptoms and a positive culture with \> 100 000 Colony Forming Units (CFUs) with a single organism.
Time frame: 12 weeks (double blind treatment period)
Population: The analysis was performed on the intent-to-treat (ITT) population. All randomized patients were included in the analysis in the treatment group to which they were allocated as per randomization.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants With Symptomatic Urinary Tract Infection (UTI) Episodes | One symptomatic UTI | 5 participants |
| Placebo | Number of Participants With Symptomatic Urinary Tract Infection (UTI) Episodes | No symptomatic UTI | 50 participants |
| Placebo | Number of Participants With Symptomatic Urinary Tract Infection (UTI) Episodes | Two symptomatic UTI | 2 participants |
| Alfuzosin 0.1 mg/kg/Day | Number of Participants With Symptomatic Urinary Tract Infection (UTI) Episodes | One symptomatic UTI | 3 participants |
| Alfuzosin 0.1 mg/kg/Day | Number of Participants With Symptomatic Urinary Tract Infection (UTI) Episodes | No symptomatic UTI | 53 participants |
| Alfuzosin 0.1 mg/kg/Day | Number of Participants With Symptomatic Urinary Tract Infection (UTI) Episodes | Two symptomatic UTI | 1 participants |
| Alfuzosin 0.2 mg/kg/Day | Number of Participants With Symptomatic Urinary Tract Infection (UTI) Episodes | No symptomatic UTI | 51 participants |
| Alfuzosin 0.2 mg/kg/Day | Number of Participants With Symptomatic Urinary Tract Infection (UTI) Episodes | Two symptomatic UTI | 1 participants |
| Alfuzosin 0.2 mg/kg/Day | Number of Participants With Symptomatic Urinary Tract Infection (UTI) Episodes | One symptomatic UTI | 6 participants |
Secondary
Number of Participants With Symptomatic Urinary Tract Infection (UTI) Episodes
Symptomatic UTI episodes were assessed similar to the previous outcome measure but for a longer follow-up period.
Time frame: 52 weeks (double blind treatment period + open label extension treatment period)
Population: The analysis was performed on the exposed population (i.e. all patients who received at least one dose of Alfuzosin regardless of the amount of treatment received). It included 3 + 3 patients treated during the 1st treatment period only, 26 + 28 patients treated during the 2nd treatment period only and 54 + 55 patients treated during both periods.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants With Symptomatic Urinary Tract Infection (UTI) Episodes | One symptomatic UTI | 12 participants |
| Placebo | Number of Participants With Symptomatic Urinary Tract Infection (UTI) Episodes | Three symptomatic UTI | 1 participants |
| Placebo | Number of Participants With Symptomatic Urinary Tract Infection (UTI) Episodes | Two symptomatic UTI | 3 participants |
| Placebo | Number of Participants With Symptomatic Urinary Tract Infection (UTI) Episodes | Four symptomatic UTI | 1 participants |
| Placebo | Number of Participants With Symptomatic Urinary Tract Infection (UTI) Episodes | No symptomatic UTI | 66 participants |
| Alfuzosin 0.1 mg/kg/Day | Number of Participants With Symptomatic Urinary Tract Infection (UTI) Episodes | Four symptomatic UTI | 2 participants |
| Alfuzosin 0.1 mg/kg/Day | Number of Participants With Symptomatic Urinary Tract Infection (UTI) Episodes | No symptomatic UTI | 70 participants |
| Alfuzosin 0.1 mg/kg/Day | Number of Participants With Symptomatic Urinary Tract Infection (UTI) Episodes | One symptomatic UTI | 13 participants |
| Alfuzosin 0.1 mg/kg/Day | Number of Participants With Symptomatic Urinary Tract Infection (UTI) Episodes | Two symptomatic UTI | 0 participants |
| Alfuzosin 0.1 mg/kg/Day | Number of Participants With Symptomatic Urinary Tract Infection (UTI) Episodes | Three symptomatic UTI | 1 participants |
Secondary
Relative Change in Detrusor Compliance
Relative change = 100 \* (Detrusor compliance at 12 weeks - Detrusor compliance at baseline) / Detrusor compliance at baseline
Time frame: 12 weeks (double blind treatment period)
Population: The analysis was performed on the same population as previously (i.e. ITT population excluding the patients who didn't have baseline and/or post-baseline value).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Relative Change in Detrusor Compliance | 113.6 percentage of mL/cmH2O | Standard Error 35.26 |
| Alfuzosin 0.1 mg/kg/Day | Relative Change in Detrusor Compliance | 126.6 percentage of mL/cmH2O | Standard Error 35.76 |
| Alfuzosin 0.2 mg/kg/Day | Relative Change in Detrusor Compliance | 98.6 percentage of mL/cmH2O | Standard Error 35.24 |
Comparison: Change in detrusor compliance was analyzed using a three-way analysis of covariance (ANCOVA) including 3 variables as fixed effects:~* treatment group (alfuzosin 0.1 mg/kg/day, alfuzosin 0.2 mg/kg/day or placebo),~* age/formulation group (2-7 years of age on solution, 8-16 years of age on solution or 8-16 years of age on tablets),~* anticholinergic/antimuscarinic use (yes or no),~and using centered baseline detrusor compliance as covariate.p-value: 0.7889ANCOVA
p-value: 0.7889ANCOVA
Secondary
Relative Change in Detrusor LPP
Relative change = 100 \* (Detrusor LPP at 12 weeks - Detrusor LPP at baseline) / Detrusor LPP at baseline
Time frame: 12 weeks (double blind treatment period)
Population: The analysis was performed on the same population as previously (i.e. ITT population excluding the patients who didn't have baseline and/or post-baseline value).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Relative Change in Detrusor LPP | -9.2 percentage of cmH2O | Standard Error 5.53 |
| Alfuzosin 0.1 mg/kg/Day | Relative Change in Detrusor LPP | -20.6 percentage of cmH2O | Standard Error 5.56 |
| Alfuzosin 0.2 mg/kg/Day | Relative Change in Detrusor LPP | -23.5 percentage of cmH2O | Standard Error 5.51 |
Comparison: Change in detrusor LPP was analyzed using a three-way analysis of covariance (ANCOVA) including 3 variables as fixed effects:~* treatment group (alfuzosin 0.1 mg/kg/day, alfuzosin 0.2 mg/kg/day or placebo),~* age/formulation group (2-7 years of age on solution, 8-16 years of age on solution or 8-16 years of age on tablets),~* anticholinergic/antimuscarinic use (yes or no),~and using centered baseline detrusor LPP as covariate.p-value: 0.133895% CI: [-26.27, 3.53]ANCOVA
p-value: 0.115295% CI: [-29.1, 0.47]ANCOVA