Extension Study of Fesoterodine for Overactive Bladder Syndrome in Children. (FOXY2015)

Efficacy and Tolerability of Fesoterodine for Overactive Bladder Syndrome in Children: an Extension Study.

The purpose of this study is to evaluate the long term tolerability of Fesoterodine and its efficacy for overactive bladder syndrome in children.

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. In the last years, Fesoterodine, a new antimuscarinic, has been developed for the treatment of OAB. Studies show significant improvement of clinical symptoms in adults with OAB and fewer side effects. The outcomes for the pediatric population remain unknown due to lack of studies. Antimuscarinic agents are the mainstay of the current treatment of OAB. 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. Fesoterodine is a new antimuscarinic drug available as a prolonged release (PR) tablet formulation, and is approved in Europe, Canada and the USA at doses of 4 mg and 8 mg once daily for the treatment of OAB in adults; it is not approved for use in the pediatric population. This study is the extension of our ongoing protocol. Before randomization, subjects will undergo 2 weeks of urotherapy. At the end of these 2 weeks, the inclusion and exclusion criteria will be reassessed and the subjects admissible for the initial study will be randomized for a 8 week-treatment period during which the urotherapy will be continued. Eligible subjects will be randomized to 8 weeks of single-blind treatment with Fesoterodine 4 mg Po Die or Oxybutynin XL 10 mg Po Die. At the end of the 8 week-treatment period, subjects will stop their current therapy for one week. At week 9, both cohorts will do a cross over. The cohort on Fesoterodine will be on Oxybutynin XL and vice versa. After 4 weeks on any given medication, the possibility of up-titration will be assessed. On a telephone interview with the research nurse, 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 (Fesoterodine 8mg or Oxybutynin XL 20mg daily). If accepted, the medication will be provided with instructions to report any new side effects. Oxybutynin XL (Ditropan XL) is the extended release and once a day formulation of Oxybutynin (actual gold standard for OAB in children). By using this formulation with children who can swallow pills, the control group has the same once a day regimen as Fesoterodine (Toviaz), thus avoiding this possible bias. The bid or tid immediate release formulation is known to create more side effects and decreases the compliance (sometime hard to administer the afternoon dose to children at school). Subjects will complete a 3-day voiding diary prior to each medical visit to assess the efficacy of the single-blind treatment and urotherapy. Visits will be done on week -2, 0, 8 and 17 (+/- 5 days). After both cycles on OAB medication, patients will be asked to report which medication they preferred (least side effects, best efficacy). If they tolerated well Fesoterodine, they will be offered to enter FOXY2015, the 12-month extension study on Fesoterodine. If they prefer to continue on Ditropan XL, it will be prescribed to the patient and will be followed in regular clinic. Subjects will have completed a 3-day voiding diary prior to that medical visit to assess the efficacy of the single-blind treatment and urotherapy. During FOXY2014, four visits were done on week -2, 0, 8 and 17. If they provide informed consent, it will become Visit-5 in FOXY2015. The patient will also start the extension study at the highest well-tolerated dose of fesoterodine while on FOXY2014. If he was using 4mg daily, he will still have the opportunity to increase the dosage to 8mg daily (based on efficacy and tolerability assessed by the research nurse phone call after 4 weeks of treatment or at visit 6).

Side effects: the number of patients presenting side effects of grade 1, 2 and 3 (mild, moderate, severe). Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment will be aggregated to arrive at one reported value. Between study arms, for cardiovascular safety: mean difference in blood pressure, mean difference in heart rate, mean difference in QTcB. Vital signs (blood pressure and heart rate), Increase of more than 20% of heart rate at rest Variation in blood pressure: systolic ±20 mmHg, diastolic ±15 mmHg Or symptoms suggesting it, without reaching those variations. o Parameters to be measure at each visit, to be obtained before and 1 hour after taking the medication. Blood tests profile comparing number of subjects with significant changes: Blood work (including hepatic and renal workups, electrolytes, Hb-Ht).

Number of Participants with Improved Overactive Bladder Symptoms as a Measure of Efficacy of Fesoterodine

Improved symptoms: Change from baseline to final voiding diary in mean volume per micturition (first micturition of the day excluded).

Mean number of daytime incontinence per 24 h. Mean number of nighttime incontinence per 24 h. Mean number of micturition per 24 h. Results will be documented based on subjective relief of symptoms and objective voiding diaries following the ICCS classification.

• Effectiveness will also be assessed using the Patient Perception of Bladder Condition (PPBC) scale on a 6-point scale ranging from 1 to 6, at study initiation and every visit.

Inclusion Criteria: Male or female ≥ 5 years old and ≤14 years old, and that completed the initial randomized study (Foxy2014). 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. 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 Oxybutynin or Fesoterodine or any contraindication to the use of those 2 molecules, in accordance to the product monography (to the exception of pediatric age). Subject is taking medication that interact with Fesoterodine 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