Hydronephrosis, Neurogenic Bladder
Conditions
Keywords
child, bladder, neuropathic, alpha blockers
Brief summary
Primary objective was to determine efficacy of Alfuzosin in the treatment of children and adolescents 2-16 years of age with newly diagnosed or progressive hydronephrosis due to elevated detrusor Leak Point Pressure \[LPP\] of neuropathic etiology. Secondary objectives were: * To investigate the safety and tolerability of alfuzosin 0.2 mg/kg/day in children and adolescents, * To investigate the number of Urinary Tract Infection (UTI) episodes, * To investigate the pharmacokinetics of Alfuzosin (population kinetics).
Detailed description
The study consisted of 2 phases: * a 12-week efficacy phase then, * a 40-week safety extension phase. All eligible subjects received alfuzosin 0.2 mg/kg/day. The formulation and the frequency was assigned by Interactive Voice Response System (IVRS) according to age group and ability to swallow tablets. Patients who completed the 12-week open-label treatment period were offered to continue in the 40-week open-label safety extension study. The treatment was the same as in the 12-week efficacy phase. All patients had a one-week follow-up period after the last dose intake.
Interventions
DRUGAlfuzosin
Dose: 0.2 mg/kg/day Route: oral
Sponsors
Sanofi
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to 16 Years
Healthy volunteers
No
Inclusion criteria
* Children and adolescents of either gender 2 - 16 years of age with a detrusor Leak Point Pressure (LPP) of 40 cm water or greater and with newly diagnosed or progressive hydronephrosis either Society of Fetal Urology (SFU) grade 1, 2 or 3 due to neuropathic bladder dysfunction.
Exclusion criteria
* Hydronephrosis of non-neuropathic etiology. * Urological surgery in the last 4 months prior to the study. * 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 Participants With a Decrease From Baseline ≥ 1 in the Society of Fetal Urology (SFU) Grade of Hydronephrosis | baseline and 12 weeks (efficacy study phase) | Hydronephrosis was investigated by ultrasound and graded using SFU classification at each time point. 'Complete response' was assessed when bilateral hydronephrosis at baseline and grade decrease from baseline ≥ 1 for both kidneys, or, unilateral hydronephrosis at baseline and grade decrease from baseline ≥ 1 for the affected kidney without worsening of the other kidney. 'Partial response' was assessed when bilateral hydronephrosis at baseline and grade decrease from baseline ≥ 1 for one kidney without worsening of the other kidney. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Symptomatic Urinary Tract Infection (UTI) Episodes | 12 weeks (efficacy study phase) | 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. |
Countries
Bulgaria, Canada, Estonia, India, Malaysia, Poland, Russia, Serbia, Singapore, Slovakia, Taiwan, Turkey (Türkiye)
Participant flow
Recruitment details
This study was conducted at 19 sites in 12 countries. A total of 42 patients were screened between December 2007 and September 2008.
Pre-assignment details
18 of the 42 screened patients were not included in the study. The reasons were the following: * Inclusion/Exclusion criteria not respected (16 patients), * Subject's request (1 patient), * Other (2 patients). Patients could have several reasons for not being included.
Participants by arm
| Arm | Count |
|---|---|
| Alfuzosin Solution - 2-7 Years Alfuzosin solution, daily dose divided in 3 doses given at breakfast, lunch and dinner to children 2-7 years of age. | 12 |
| Alfuzosin Solution - 8-16 Years Alfuzosin solution, daily dose divided in 3 doses given at breakfast, lunch and dinner to children and adolescents 8-16 years of age who were not able to swallow the tablets or preferred to take the solution or had a body weight \< 30 kg. | 6 |
| Alfuzosin Tablet - 8-16 Years Alfuzosin tablet, daily dose divided in 2 doses given at breakfast and dinner to children and adolescents 8-16 years of age who were able to swallow the tablets and had a body weight ≥ 30 kg. | 7 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| 12-week Efficacy Phase | Parent's schedule issue | 1 | 0 | 0 |
| 40-week Safety Extension Phase | Lack of Efficacy | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Alfuzosin Solution - 8-16 Years | Total | Alfuzosin Solution - 2-7 Years | Alfuzosin Tablet - 8-16 Years |
|---|---|---|---|---|
| Age, Continuous | 10.0 years STANDARD_DEVIATION 1.7 | 7.9 years STANDARD_DEVIATION 4 | 4.3 years STANDARD_DEVIATION 1.5 | 11.2 years STANDARD_DEVIATION 2.3 |
| Duration of diagnosis for hydronephrosis | 5.45 years STANDARD_DEVIATION 4.2 | 3.12 years STANDARD_DEVIATION 3.26 | 1.83 years STANDARD_DEVIATION 2.3 | 3.35 years STANDARD_DEVIATION 3.05 |
| Grade of hydronephrosis Left kidney | 1.5 grade | 2 grade | 2 grade | 2 grade |
| Grade of hydronephrosis Right kidney | 2 grade | 1 grade | 1 grade | 1 grade |
| Region of Enrollment India | 1 participants | 3 participants | 2 participants | 0 participants |
| Region of Enrollment Malaysia | 0 participants | 1 participants | 0 participants | 1 participants |
| Region of Enrollment Poland | 2 participants | 8 participants | 4 participants | 2 participants |
| Region of Enrollment Russian Federation | 2 participants | 7 participants | 3 participants | 2 participants |
| Region of Enrollment Singapore | 0 participants | 1 participants | 1 participants | 0 participants |
| Region of Enrollment Slovakia | 0 participants | 2 participants | 1 participants | 1 participants |
| Region of Enrollment Taiwan | 1 participants | 2 participants | 0 participants | 1 participants |
| Region of Enrollment Turkey | 0 participants | 1 participants | 1 participants | 0 participants |
| Sex: Female, Male Female | 4 Participants | 16 Participants | 7 Participants | 5 Participants |
| Sex: Female, Male Male | 2 Participants | 9 Participants | 5 Participants | 2 Participants |
| Type of hydronephrosis Bilateral hydronephrosis (both kidneys affected) | 4 participants | 20 participants | 11 participants | 5 participants |
| Type of hydronephrosis Unilateral hydronephrosis (one kidney affected) | 2 participants | 5 participants | 1 participants | 2 participants |
| Urinary Tract Infection (UTI) history within the last 3 months No UTI episode | 4 participants | 19 participants | 9 participants | 6 participants |
| Urinary Tract Infection (UTI) history within the last 3 months One UTI episode | 2 participants | 5 participants | 2 participants | 1 participants |
| Urinary Tract Infection (UTI) history within the last 3 months Two UTI episodes | 0 participants | 1 participants | 1 participants | 0 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 9 / 12 | 5 / 6 | 5 / 7 |
| serious Total, serious adverse events | 2 / 12 | 2 / 6 | 0 / 7 |
Outcome results
Primary
Number of Participants With a Decrease From Baseline ≥ 1 in the Society of Fetal Urology (SFU) Grade of Hydronephrosis
Hydronephrosis was investigated by ultrasound and graded using SFU classification at each time point. 'Complete response' was assessed when bilateral hydronephrosis at baseline and grade decrease from baseline ≥ 1 for both kidneys, or, unilateral hydronephrosis at baseline and grade decrease from baseline ≥ 1 for the affected kidney without worsening of the other kidney. 'Partial response' was assessed when bilateral hydronephrosis at baseline and grade decrease from baseline ≥ 1 for one kidney without worsening of the other kidney.
Time frame: baseline and 12 weeks (efficacy study phase)
Population: The analysis was on the intent-to-treat (ITT) population (i.e. all included patients who received at least one dose of Alfuzosin) excluding the patients who didn't have baseline SFU grade. Patients without post-baseline SFU grade before Week 12 were included as non-responders.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Alfuzosin Solution - 2-7 Years | Number of Participants With a Decrease From Baseline ≥ 1 in the Society of Fetal Urology (SFU) Grade of Hydronephrosis | Complete response | 2 participants |
| Alfuzosin Solution - 2-7 Years | Number of Participants With a Decrease From Baseline ≥ 1 in the Society of Fetal Urology (SFU) Grade of Hydronephrosis | - Unilateral hydronephrosis | 1 participants |
| Alfuzosin Solution - 2-7 Years | Number of Participants With a Decrease From Baseline ≥ 1 in the Society of Fetal Urology (SFU) Grade of Hydronephrosis | - Bilateral hydronephrosis | 1 participants |
| Alfuzosin Solution - 2-7 Years | Number of Participants With a Decrease From Baseline ≥ 1 in the Society of Fetal Urology (SFU) Grade of Hydronephrosis | Partial response | 3 participants |
| Alfuzosin Solution - 8-16 Years | Number of Participants With a Decrease From Baseline ≥ 1 in the Society of Fetal Urology (SFU) Grade of Hydronephrosis | Complete response | 5 participants |
| Alfuzosin Solution - 8-16 Years | Number of Participants With a Decrease From Baseline ≥ 1 in the Society of Fetal Urology (SFU) Grade of Hydronephrosis | Partial response | 0 participants |
| Alfuzosin Solution - 8-16 Years | Number of Participants With a Decrease From Baseline ≥ 1 in the Society of Fetal Urology (SFU) Grade of Hydronephrosis | - Unilateral hydronephrosis | 2 participants |
| Alfuzosin Solution - 8-16 Years | Number of Participants With a Decrease From Baseline ≥ 1 in the Society of Fetal Urology (SFU) Grade of Hydronephrosis | - Bilateral hydronephrosis | 3 participants |
| Alfuzosin Tablet - 8-16 Years | Number of Participants With a Decrease From Baseline ≥ 1 in the Society of Fetal Urology (SFU) Grade of Hydronephrosis | Partial response | 3 participants |
| Alfuzosin Tablet - 8-16 Years | Number of Participants With a Decrease From Baseline ≥ 1 in the Society of Fetal Urology (SFU) Grade of Hydronephrosis | - Unilateral hydronephrosis | 2 participants |
| Alfuzosin Tablet - 8-16 Years | Number of Participants With a Decrease From Baseline ≥ 1 in the Society of Fetal Urology (SFU) Grade of Hydronephrosis | - Bilateral hydronephrosis | 1 participants |
| Alfuzosin Tablet - 8-16 Years | Number of Participants With a Decrease From Baseline ≥ 1 in the Society of Fetal Urology (SFU) Grade of Hydronephrosis | Complete response | 3 participants |
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 (efficacy study phase)
Population: The analysis was performed on the ITT population (i.e. all included patients who received at least one dose of Alfuzosin).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Alfuzosin Solution - 2-7 Years | Number of Participants With Symptomatic Urinary Tract Infection (UTI) Episodes | One symptomatic UTI | 0 participants |
| Alfuzosin Solution - 2-7 Years | Number of Participants With Symptomatic Urinary Tract Infection (UTI) Episodes | No symptomatic UTI | 11 participants |
| Alfuzosin Solution - 2-7 Years | Number of Participants With Symptomatic Urinary Tract Infection (UTI) Episodes | Two symptomatic UTI | 1 participants |
| Alfuzosin Solution - 8-16 Years | Number of Participants With Symptomatic Urinary Tract Infection (UTI) Episodes | One symptomatic UTI | 1 participants |
| Alfuzosin Solution - 8-16 Years | Number of Participants With Symptomatic Urinary Tract Infection (UTI) Episodes | No symptomatic UTI | 5 participants |
| Alfuzosin Solution - 8-16 Years | Number of Participants With Symptomatic Urinary Tract Infection (UTI) Episodes | Two symptomatic UTI | 0 participants |
| Alfuzosin Tablet - 8-16 Years | Number of Participants With Symptomatic Urinary Tract Infection (UTI) Episodes | No symptomatic UTI | 7 participants |
| Alfuzosin Tablet - 8-16 Years | Number of Participants With Symptomatic Urinary Tract Infection (UTI) Episodes | Two symptomatic UTI | 0 participants |
| Alfuzosin Tablet - 8-16 Years | Number of Participants With Symptomatic Urinary Tract Infection (UTI) Episodes | One symptomatic UTI | 0 participants |
Secondary
Number of Participants With Symptomatic Urinary Tract Infection (UTI) Episodes
Time frame: 52 weeks (efficacy and extension study phases)
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).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Alfuzosin Solution - 2-7 Years | Number of Participants With Symptomatic Urinary Tract Infection (UTI) Episodes | No symptomatic UTI | 8 participants |
| Alfuzosin Solution - 2-7 Years | Number of Participants With Symptomatic Urinary Tract Infection (UTI) Episodes | One symptomatic UTI | 2 participants |
| Alfuzosin Solution - 2-7 Years | Number of Participants With Symptomatic Urinary Tract Infection (UTI) Episodes | Two symptomatic UTI | 2 participants |
| Alfuzosin Solution - 2-7 Years | Number of Participants With Symptomatic Urinary Tract Infection (UTI) Episodes | Three symptomatic UTI | 0 participants |
| Alfuzosin Solution - 8-16 Years | Number of Participants With Symptomatic Urinary Tract Infection (UTI) Episodes | Three symptomatic UTI | 1 participants |
| Alfuzosin Solution - 8-16 Years | Number of Participants With Symptomatic Urinary Tract Infection (UTI) Episodes | No symptomatic UTI | 5 participants |
| Alfuzosin Solution - 8-16 Years | Number of Participants With Symptomatic Urinary Tract Infection (UTI) Episodes | Two symptomatic UTI | 0 participants |
| Alfuzosin Solution - 8-16 Years | Number of Participants With Symptomatic Urinary Tract Infection (UTI) Episodes | One symptomatic UTI | 0 participants |
| Alfuzosin Tablet - 8-16 Years | Number of Participants With Symptomatic Urinary Tract Infection (UTI) Episodes | Three symptomatic UTI | 0 participants |
| Alfuzosin Tablet - 8-16 Years | Number of Participants With Symptomatic Urinary Tract Infection (UTI) Episodes | One symptomatic UTI | 2 participants |
| Alfuzosin Tablet - 8-16 Years | Number of Participants With Symptomatic Urinary Tract Infection (UTI) Episodes | Two symptomatic UTI | 0 participants |
| Alfuzosin Tablet - 8-16 Years | Number of Participants With Symptomatic Urinary Tract Infection (UTI) Episodes | No symptomatic UTI | 5 participants |