| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Neurogenic Detrusor Overactivity (NDO). |
|
| E.1.1.1 | Medical condition in easily understood language |
| Bladder overactivity caused by a neurological condition such as spina bifida, known medically as neurogenic detrusor overactivity. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Symptoms and general pathology [C23] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10029279 |
| E.1.2 | Term | Neurogenic bladder |
| E.1.2 | System Organ Class | 10038359 - Renal and urinary disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To determine the safety and efficacy of fesoterodine 4 mg and 8 mg following once daily treatment for 12 weeks in pediatric NDO subjects with weight >25 kg.
To determine the safety and efficacy of fesoterodine 2 mg and 4 mg following once daily treatment for 12 weeks in pediatric NDO subjects with weight ≤ 25 kg. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are to:
• evaluate the safety and efficacy of fesoterodine versus oxybutynin in pediatric NDO subjects with weight >25 kg
• evaluate the safety of fesoterodine 4 mg and 8 mg once daily treatment for up to 24 weeks in pediatric NDO subjects with weight >25 kg
• evaluate the safety of fesoterodine 2 mg and 4 mg once daily treatment for up to 24 weeks in pediatric NDO subjects with weight ≤25 kg.
• determine the steady-state population pharmacokinetics of 5-HMT following fesoterodine 4 mg and 8 mg once daily treatment in pediatric NDO subjects with weight >25 kg.
• determine the steady-state population pharmacokinetics of 5-HMT following treatment with two doses of fesoterodine 2 mg and 4 mg once daily in pediatric NDO subjects. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study:
1. Male or female subjects aged 6 to 17 years 11 months (age at time of first dose); that is subjects who have passed their sixth birthday but not reached their eighteenth birthday.
2. Subjects with stable neurological disease and clinically- or urodynamically-demonstrated NDO, confirmed urodynamically at Visit 2, by detrusor overactivity or decreased bladder compliance, with decreased maximum cystometric bladder capacity.
NOTE: Subjects with hypocontractile bladder, detrusor underactivity, or a 'flaccid' bladder should not be included.
3. Evidence of a personally signed and dated informed consent document indicating that the subject or a legally acceptable representative (or representatives, as per local regulatory and legal requirements) has been informed of all pertinent aspects of the study. In addition, an assent from the subject will be obtained when appropriate, and when the potential subject is capable of providing assent.
4. Female subjects who are of child-bearing potential (defined as ≥9 years old or have experienced menarche, whichever is earlier) must not be intending to become pregnant, currently pregnant, or lactating. The following conditions apply:
a. Subjects of childbearing potential must have a confirmed negative pregnancy test prior to randomization.
b. Subjects of child-bearing potential must agree to use effective contraception during the period of the trial and for at least 28 days after completion of treatment. Effective contraception includes abstinence.
c. Sexually active male subjects must agree to use effective contraception during the period of the trial and for at least 28 days after completion of treatment.
5. Swallowing:
a. Subjects >25 kg must already have the ability to swallow tablets whole, without chewing or crushing. The first dose of medication will be given in clinic under observation, and any subject not able to swallow tablets will be excluded from the
study.
b. Subjects ≤25 kg can either swallow the capsules whole or sprinkle on food.
6. Subjects, and their Caregivers/parents who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures. |
|
| E.4 | Principal exclusion criteria |
Subjects presenting with any of the following will not be included in the study:
(In France, see Appendix 5 of the protocol)
1. Any condition known to affect drug absorption (eg, gastrectomy).
2. History of surgical procedures that could confound study results or increase the risk to subjects, including but not limited to: sphincterotomy, artificial sphincter, implantable stent, bladder augmentation procedures, urinary diversion procedures. Continent diversion procedures eg, Mitrofanoff are permitted.
3. A history of indwelling urinary catheter within 4 weeks of participation in this study. Intermittent catheterization is permitted.
4. Any comorbid condition that, in the opinion of the investigator, would confound study results or increase the risk to subjects eg, current history of bladder calculus.
5. A history of autonomic dysreflexia eg, increased blood pressure with bladder filling or other stimuli.
6. Subjects with clinically relevant out-of-range values for hematology or serum chemistry as confirmed by blood tests performed at Visit 1, and which require the subject’s exclusion in the opinion of the investigator.
7. A 12-lead ECG at screening with clinically significant abnormality.
8. Unwilling or unable to comply with the Lifestyle guidelines described in this protocol.
9. Subjects required to take or expected to initiate concomitant medications that can interact with the pharmacokinetics and/or pharmacodynamics of fesoterodine or oxybutynin, such as:
• Potent CYP3A4 inhibitors within 3 weeks prior to Visit 2 (baseline), or the expectation to start such a treatment during the trial. • Medications capable of inducing CYP3A4 enzyme metabolism. • Drugs for the treatment of overactive bladder (eg, darifenacin, oxybutynin (including intravesical), propiverine, tolterodine, fesoterodine, solifenacin and trospium). • Treatment with botulinum toxin A within 9 months prior to Visit 2 (baseline). • Drugs with antispasmodic, parasympathetic, or cholinergic effects. Stable use of desmopressin for enuresis is allowed if established for at least 3 months.
Previous treatment with these medications does not exclude subjects. However, prohibited concomitant medications must have a minimum washout appropriate to the drug so any clinical effect is at a minimum prior to beginning the bladder diary, and baseline urodynamic evaluations.
10. Intermittent or unstable use of diuretics or alpha blockers, tricyclic antidepressants or any other treatment that may confound the results of the study, within 2 weeks or an appropriate washout period (whichever is longer) prior to starting the bladder diary or during the course of the study. Stable usage/dosage is allowed if established for at least 3 months.
11. Electrostimulation therapy or bladder retraining if started within 30 days of Visit 1 or are expected to start such therapy during the study period. Subjects who are on an established regimen may remain on this for the duration of the study.
12. Subjects with a clinically significant urinary tract infection (UTI) at screening.
Urine microscopy, culture and sensitivity testing will be performed in the event of:
• presence of symptoms (eg, fever, flank pain), or • positive leucocytes and/or nitrites on urinalysis, or • if subject has a documented history of vesicoureteral reflux (VUR).
A clinically significant UTI is defined as:
• positive urine culture with a uropathogen and the presence of symptoms, or • pyuria (defined as >50 white blood cells (WBC)/hpf)and the presence of symptoms, or • positive urine culture with a uropathogen with or without symptoms in a subject with a documented history of VUR.
Subjects who are found to have an active UTI during screening may continue screening activities on resolution of symptoms or treatment of the UTI to the satisfaction of the treating physician.
13. Subjects not requiring intermittent catheterization who have a post-void residual volume greater than 20 ml as determined by transabdominal ultrasound (eg, bladder scan) immediately after urination. If at screening, the PVR is found to be greater than 20 ml the subject will be asked to void again. Repeat PVR assessment should be made as soon as possible, and no more than 5 minutes, after the second void. Subjects found to have a persistently elevated PVR >20 ml at this visit will be excluded from the study.
14. Subjects with any history of malignancy.
For the remaining exclusion criteria please refer to the Protocol.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Maximum cystometric bladder capacity defined as maximal tolerable cystometric capacity or until voiding/leaking begins or at 40 cm H2O. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Maximum cystometric bladder capacity (urodynamics) - Visits 2 & 5 |
|
| E.5.2 | Secondary end point(s) |
Efficacy Endpoints
• Detrusor pressure at maximum bladder capacity.
• Presence of involuntary detrusor contractions (IDC).
• Bladder volume at first IDC.
• Bladder compliance.
• Mean number of micturitions and/or catheterizations/24 hrs.
• Mean number of incontinence episodes/24 hrs.
• Mean urgency episodes/24 hrs if applicable (only for sensate subjects).
• Mean volume voided per micturition or mean volume per catheterization.
Safety Endpoints
• Adverse events, including monitoring of targeted events including, but not limited to:
• Anticholinergic effects such as dry mouth, dry eyes and constipation.
• CNS effects such as behavioral changes (eg, aggression), decreased cognitive function, headache, seizures, somnolence.
• Visual effects such as accommodation disorder, blurred vision, and amblyopia.
• Visual acuity and accommodation tests.
• Cognitive function by the Child Behavior CheckList and Grooved Pegboard Test.
• Vital Signs, including heart rate in the context of age-appropriate norms.
• Urinary Tract Infection, as evidenced by urinalysis, urine microscopy, culture and sensitivity.
• Clinical Laboratory Evaluations in the context of age-appropriate norms, with particular reference to liver function tests and renal chemistry.
• Post-void residual volume (PVR) in subjects not performing CIC, or with >1 urinary tract infection (UTI) during the study.
Pharmacokinetic Endpoints
• Model-based pharmacokinetic parameter estimates for absorption rate constant (Ka), apparent oral clearance (CL/F) and volumes of distribution (Vd) to predict the area under the curve (AUC), maximum concentration (Cmax), time to reach Cmax (Tmax) and half-life of 5-HMT. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Urodynamic endpoints at Visits 2 & 5
ediary endpoints = Visits 2 & 5
PinQ endpoint = Visits 2 & 5
Vital Signs, including heart rate.= Visits 1, 2, 3, 5 & 7
Adverse events = Visits 2, 3 , 4, 5, 6, 7 & 8 (Also, weeks 1, 2 & 3 for oxybutynin subjects)
Clinical Laboratory Evaluations =Visits 1, 2, 3, 5, & 7
Post-void residual volume (PVR) in subjects not performing CIC, or with >1 urinary tract
infection (UTI) during the study= Visits 1, 2 ,3, 5 & 7
Pharmacokinetic Endpoints = Visit 5 ( 3 samples) |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 46 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Belgium |
| Brazil |
| Chile |
| Czech Republic |
| Estonia |
| Finland |
| France |
| Greece |
| India |
| Italy |
| Japan |
| Korea, Republic of |
| Mexico |
| Netherlands |
| Poland |
| Romania |
| Russian Federation |
| Slovakia |
| South Africa |
| Spain |
| Sweden |
| Switzerland |
| Taiwan |
| Turkey |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| LSLV or the date upon which Pfizer receives notification by the External Data Monitoring Committee to terminate the study - as per protocol |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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