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Add-on Mirabegron in Pediatric Patients With Refractory Overactive Bladder (Add-on-Mira)

Primary Purpose

Overactive Bladder, Urinary Incontinence

Status
Completed
Phase
Phase 3
Locations
Study Type
Interventional
Intervention
Mirabegron
Sponsored by
CHU de Quebec-Universite Laval
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Overactive Bladder focused on measuring mirabegron, antimuscarinics, beta 3 agonist, overactive bladder, children

Eligibility Criteria

5 Years - 17 Years (Child)All SexesDoes not accept healthy volunteers

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

Sites / Locations

    Arms of the Study

    Arm 1

    Arm Type

    Experimental

    Arm Label

    Add-on Mirabegron

    Arm Description

    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).

    Outcomes

    Primary Outcome Measures

    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).
    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.

    Secondary Outcome Measures

    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.
    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.
    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.

    Full Information

    First Posted
    June 14, 2015
    Last Updated
    March 24, 2018
    Sponsor
    CHU de Quebec-Universite Laval
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    1. Study Identification

    Unique Protocol Identification Number
    NCT02476175
    Brief Title
    Add-on Mirabegron in Pediatric Patients With Refractory Overactive Bladder
    Acronym
    Add-on-Mira
    Official Title
    Add-on Mirabegron in Pediatric Patients With Refractory Overactive Bladder
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    March 2018
    Overall Recruitment Status
    Completed
    Study Start Date
    April 2013 (undefined)
    Primary Completion Date
    April 2016 (Actual)
    Study Completion Date
    June 2016 (Actual)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Principal Investigator
    Name of the Sponsor
    CHU de Quebec-Universite Laval

    4. Oversight

    Data Monitoring Committee
    Yes

    5. Study Description

    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.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Overactive Bladder, Urinary Incontinence
    Keywords
    mirabegron, antimuscarinics, beta 3 agonist, overactive bladder, children

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 3
    Interventional Study Model
    Single Group Assignment
    Masking
    None (Open Label)
    Allocation
    N/A
    Enrollment
    35 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    Add-on Mirabegron
    Arm Type
    Experimental
    Arm Description
    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).
    Intervention Type
    Drug
    Intervention Name(s)
    Mirabegron
    Other Intervention Name(s)
    Myrbetriq
    Intervention Description
    Patients will keep the antimuscarinic providing some efficacy and that is tolerated and Mirabegron will be added (dual therapy).
    Primary Outcome Measure Information:
    Title
    Response to Urinary Incontinence as a Composite Measure of Efficacy of add-on Mirabegron
    Description
    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
    Title
    Number of Participants With Grade 2 or 3 Urgency Episodes as a Measure of Efficacy
    Description
    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
    Secondary Outcome Measure Information:
    Title
    Number of Participants With Cardio Vascular Safety
    Description
    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
    Title
    Number of Participants Showing Improved Quality of Life Using the Patient Perception of Bladder Condition Scale and Voiding Diaries
    Description
    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
    Title
    Number of Participants Without Variation in Heart Rate
    Description
    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

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    5 Years
    Maximum Age & Unit of Time
    17 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    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

    12. IPD Sharing Statement

    Plan to Share IPD
    No

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    Add-on Mirabegron in Pediatric Patients With Refractory Overactive Bladder

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