Overactive Bladder, Urinary Incontinence
Conditions
Keywords
mirabegron, antimuscarinics, beta 3 agonist, overactive bladder, children
Brief summary
The objective is to evaluate the efficacy and safety of adding mirabegron to an antimuscarinic to treat urinary incontinence in children with Overactive Bladder that are refractory to antimuscarinics.
Detailed description
Overactive bladder (OAB) is a highly prevalent disorder in the pediatric population. This condition comprises many urinary symptoms, such as urgency, increased daytime frequency of micturition, urge incontinence and nocturia. These symptoms are especially troublesome for the pediatric patients and their family since it causes embarrassment and it limits everyday activities and impairs children's development. Furthermore, serious complications are seen if this condition is not treated properly, as urinary tract infection, vesico-ureteral reflux and dysfunctional voiding. Antimuscarinic agents are the current pharmacologic mainstay for OAB. Many side effects are reported with the clinical use of antimuscarinics. Oxybutynin is the most widely antimuscarinic agent used in the pediatric population and is the only molecule approved by Health Canada for children with OAB. However, some patients have a suboptimal response to antimuscarinic and many experience side effects. Children with OAB therefore represent a disease population with a need for an alternative effective, safe and well-tolerated therapy to help manage the overactive detrusor, reducing or preventing incontinence. Mirabegron, a β3-adrenoceptor (β3-AR) agonist approved for the treatment of OAB symptoms in the adult population, is the first of a new class of compounds with a different mechanism of action. The recommended starting dose of mirabegron is 25mg, which can be increased to 50mg, based on individual efficacy and tolerability. Side effects commonly reported with antimuscarinics were not observed more often with mirabegron than with placebo (headache 2.0%, dry mouth 2.0%, constipation 1.6%). Several Phase II and III studies have shown significant improvement in clinical OAB symptoms in adults treated with mirabegron with a favorable tolerability profile. Mirabegron has not been studied yet for pediatric patients and no recommendation with regards to its use has been issued by the manufacturer nor medical regulatory bodies. A prospective open-label study, using an adjusted-dose regimen of mirabegron (25-50mg) added to the existing antimuscanic treatment (dual treatment), including pediatric patients with refractory urinary incontinence due to OAB. This protocol was approved by the investigators' research ethics board. Patients without symptom improvement or with partial response under intensive behavioural protocol and medical therapy (at least 2 different antimuscarinic agents) will be recruited. Pprimary end-point is efficacy toward urinary continence and secondary end-points are tolerability and safety. The patients/parents satisfaction will also be recorded. After 8 to 12 weeks on the new medication, the possibility of up-titration will be assessed. Patients and parents will be questioned on compliance, tolerability and efficacy. If the patient is taking the medication ≥80% of the time, does not have any significant side effects and still has significant OAB symptoms, the investigators will offer a dose increase (Mirabegron 50mg daily). If accepted, the medication will be provided with instructions to report any new side effects. Subjects will complete a 3-day voiding diary prior to each medical visit to assess the efficacy of the treatment and urotherapy. Visits will be done every 3 months.
Interventions
DRUGMirabegron
Patients will keep the antimuscarinic providing some efficacy and that is tolerated and Mirabegron will be added (dual therapy).
Sponsors
CHU de Quebec-Universite Laval
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
5 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Male or female ≥ 5 years old and ≤17 years old * OAB diagnostic according to the International Children Continence Society (ICCS) and less than 65% of the expected mean bladder capacity for age is confirmed (30 + (age in years x 30) mL) on a 3-day voiding diary. * Weight and height are within the normal percentile (3rd to 97th percentile) and weight is ≥ 20 kg (3rd percentile of a 8 y.o. child, boy or girl), according to the CDC growth chart * Ability to swallow pills * Subjects/parents (vs. legal guardian) agree to participate to the following study and sign the informed consent * Subjects/parents (vs. legal guardian) are able to comply with the study requirements and with the medication restrictions. * Female subjects of childbearing potential must have a negative serum or urine pregnancy test at enrollment and must agree to maintain highly effective birth control during the study. Sexually active male subjects agree to use a barrier method of birth control with female partner for the duration of the study and at least one month after ending study treatment. Sexually active male subjects agree to use a condom for the duration of the study and for at least one month after ending study treatment and the female partner to use a reliable form of birth control for the duration of the study and for at least one month after ending study treatment. * Patients without symptom improvement or with partial response under medical therapy (at least 2 different antimuscarinic agents).
Exclusion criteria
* Subject has a diagnostic of dysfunctional voiding * Post-voiding residue \> 20 cc * Polyuria (\> 75 ml/kg/b.w./24 hours) * Nephrogenic of central diabetes insipidus * Constipation at screening (if the patient is treated and the treatment is successful, the patient will be eligible to the study) * Urinary tract infection at visit 2-3-4. If UTI is present at the screening visit, the UTI must be treated and the success of the treatment must be documented with a negative urinalysis at visit 2. * QTc interval greater than 460 ms, or any increase of 30 ms on follow-up EKG (mean of 6 separate EKG-3 from visit week-2 and 3 from visit week 0). If a patient meets those criteria in the first month (initial dose), he will be excluded from the study. If the QTc change is noted after the up-titration, the dose will be decreased and EKG will be repeated within 1 week to ensure normalization of QTc. * Clinically significant unstable medical condition or disorder * Subject is pregnant or intends to become pregnant * Serum creatinin more than or equal to 2 times the upper limit of normal * Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) more than or equal to 2 times ULN, or bilirubin more than or equal to 1.5 times ULN. * Known hypersensitivity to mirabegron or any contraindication to the use of the molecule, in accordance to the product monography (to the exception of pediatric age). * Subject is taking medication that interact with mirabegron and this medication can't be discontinued (see appendix 1 of excluded drugs) * Known urological pathology other than OAB that could explain urinary symptoms (as bladder stone…) * Non-treated or non-controlled arterial hypertension
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Response to Urinary Incontinence as a Composite Measure of Efficacy of add-on Mirabegron | up to 52 weeks | Results were based on the International Children's Continence Sociéty classification. Parents or patients supervised by their parents rated symptom relief on a questionnaire as complete cure (definied as dryness) or partial response (reduction of 50% to 99% in incontinence episodes). |
| Number of Participants With Grade 2 or 3 Urgency Episodes as a Measure of Efficacy | up to 52 weeks | On voiding diary, participants described their urgency according to the Canadian Urological Association voiding diary, range 0 to 3 at study entry and at study end. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Cardio Vascular Safety | Participants will be followed for the duration of the study, up to 52 weeks | Cardiovascular safety: mean difference in blood pressure (Variation in blood pressure: systolic ±20 mmHg, diastolic ±15 mmHg), blood pressure was taken at each visit and at the study end. |
| Number of Participants Showing Improved Quality of Life Using the Patient Perception of Bladder Condition Scale and Voiding Diaries | Participants will be followed for the duration of the study, up to 52 weeks | Effectiveness will also be assessed using the Patient Perception of Bladder Condition (PPBC) scale on a 6-point scale ranging from 1 to 6 ( 1 is the best score and 6 is the worst score), at study initiation, every visit and at the study end. Results will be documented based on subjective relief of symptoms and objective voiding diaries. Participants perception of bladder condition score at initiation of treatment was:4 and at last follow up score was: 2. |
| Number of Participants Without Variation in Heart Rate | Participants will be followed for the duration of the study, up to 52 weeks | Cardiovascular safety: mean difference in heart rate (with variation in heart rate increase of more than 20%). Heart rate was taken at initiation of study drug, at each visit and at the study end. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Add-on Mirabegron Experimental: Add-on Mirabegron Patients without symptom improvement or with partial response under intensive behavioural protocol and medical therapy (at least 2 different antimuscarinic agents) will be recruited. They will keep the antimuscarinic and Mirabegron will be added (dual therapy).
Mirabegron: Patients will keep the antimuscarinic providing some efficacy and that is tolerated and Mirabegron will be added (dual therapy). | 35 |
| Total | 35 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 2 |
Baseline characteristics
| Characteristic | Add-on Mirabegron | — |
|---|---|---|
| Age, Categorical <=18 years | 35 Participants | — |
| Age, Categorical >=65 years | 0 Participants | — |
| Age, Categorical Between 18 and 65 years | 0 Participants | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Region of Enrollment Canada | 35 Participants | — |
| Sex: Female, Male Female | 7 Participants | — |
| Sex: Female, Male Male | 28 Participants | — |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 5 / 35 |
| serious Total, serious adverse events | 0 / 35 |
Outcome results
Primary
Number of Participants With Grade 2 or 3 Urgency Episodes as a Measure of Efficacy
On voiding diary, participants described their urgency according to the Canadian Urological Association voiding diary, range 0 to 3 at study entry and at study end.
Time frame: up to 52 weeks
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Add-on Mirabegron | Number of Participants With Grade 2 or 3 Urgency Episodes as a Measure of Efficacy | Participants with urgency 2-3 at entry | 32 Participants |
| Add-on Mirabegron | Number of Participants With Grade 2 or 3 Urgency Episodes as a Measure of Efficacy | Participants without urgency2-3 at week 52studyend | 19 Participants |
Primary
Response to Urinary Incontinence as a Composite Measure of Efficacy of add-on Mirabegron
Results were based on the International Children's Continence Sociéty classification. Parents or patients supervised by their parents rated symptom relief on a questionnaire as complete cure (definied as dryness) or partial response (reduction of 50% to 99% in incontinence episodes).
Time frame: up to 52 weeks
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Add-on Mirabegron | Response to Urinary Incontinence as a Composite Measure of Efficacy of add-on Mirabegron | Complete response:100%improvement of incontinence | 12 Participants |
| Add-on Mirabegron | Response to Urinary Incontinence as a Composite Measure of Efficacy of add-on Mirabegron | Partial response: 50 to 99 % reduction | 23 Participants |
Secondary
Number of Participants Showing Improved Quality of Life Using the Patient Perception of Bladder Condition Scale and Voiding Diaries
Effectiveness will also be assessed using the Patient Perception of Bladder Condition (PPBC) scale on a 6-point scale ranging from 1 to 6 ( 1 is the best score and 6 is the worst score), at study initiation, every visit and at the study end. Results will be documented based on subjective relief of symptoms and objective voiding diaries. Participants perception of bladder condition score at initiation of treatment was:4 and at last follow up score was: 2.
Time frame: Participants will be followed for the duration of the study, up to 52 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Add-on Mirabegron | Number of Participants Showing Improved Quality of Life Using the Patient Perception of Bladder Condition Scale and Voiding Diaries | 35 Participants |
Secondary
Number of Participants With Cardio Vascular Safety
Cardiovascular safety: mean difference in blood pressure (Variation in blood pressure: systolic ±20 mmHg, diastolic ±15 mmHg), blood pressure was taken at each visit and at the study end.
Time frame: Participants will be followed for the duration of the study, up to 52 weeks
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Add-on Mirabegron | Number of Participants With Cardio Vascular Safety | No variation:systolic ±20 mmHg in blood pressure | 35 Participants |
| Add-on Mirabegron | Number of Participants With Cardio Vascular Safety | No variation:Diastolic ±15 mmHg in blood pressure | 35 Participants |
Secondary
Number of Participants Without Variation in Heart Rate
Cardiovascular safety: mean difference in heart rate (with variation in heart rate increase of more than 20%). Heart rate was taken at initiation of study drug, at each visit and at the study end.
Time frame: Participants will be followed for the duration of the study, up to 52 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Add-on Mirabegron | Number of Participants Without Variation in Heart Rate | 35 Participants |