E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Urinary Incontinence Due to Neurogenic Detrusor Overactivity |
|
E.1.1.1 | Medical condition in easily understood language |
Urinary Incontinence Due to Neurogenic Detrusor Overactivity |
|
E.1.1.2 | Therapeutic area | Not possible to specify |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10046543 |
E.1.2 | Term | Urinary incontinence |
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 |
The objective of this study is to evaluate the safety and efficacy of BOTOX for the treatment of urinary incontinence due to Neurogenic Detrusor Overactivity (NDO) in patients 8 to 17 years of age who have not been adequately managed with anticholinergic therapy. |
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E.2.2 | Secondary objectives of the trial |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. written informed consent has been obtained from the legally
authorized representative and written minor assent has been obtained,
in accordance with local laws and institutional review board
(IRB)/independent ethics committee (IEC) requirements.
2. written documentation has been obtained in accordance with the
relevant country and local privacy requirements, where applicable (eg,
Written Authorization for Use and Release of Health and Research Study
Information (US sites) and written Data Protection consent (European
sites).
3. male or female, aged ≥ 5 years to ≤ 17 years of age at the time of
informed consent.
4. patient has NDO based on either:
- presence of an IDC during the urodynamic assessment performed in
the screening period or on day 1 (prior to randomization), or
- documented presence of an IDC from an historical urodynamic
assessment within 12 months of screening
5. patient has NDO due to either:
- spinal dysraphism, which includes spina bifida(eg, myelomeningocele, meningocele), and all forms of tethered cord or
- acquired NDO from a spinal cord injury, with the injury having occurred
at least 6 months prior to screening, or
- acquired NDO due to transverse myelitis with diagnosis at least 18
monthsprior to screening
6. neurological lesion/injury must be at thoracic level T1 or below
7. patient must be regularly using CIC to empty the bladder (CIC can be
performed by either the patient or the parent/caregiver):
- the CIC schedule must be at least 3 times per day
-CIC must have been initiated at least 3 months prior to screening
8. patient has a total of ≥ 4 daytime urinary incontinence episodes over
the 2-day bladder diary completed during the screening period, despite
regular CIC(daytime is defined as time between waking up to start the
day and going to bed to sleep for the night).
NOTE: If the patient has had a Mitrofanoff procedure, urinary leakage
must be via the
urethra.
9. patient has not been adequately managed with 1 or more
anticholinergic agents for the treatment of NDO in the opinion of the
investigator. This includes patients who are still incontinent despite
anticholinergic therapy, experiencing intolerable side effects, or are
unwilling to continue to take the medication for any reason:
- if continuing to take anticholinergics, patients should be willing to
maintain a stable dose throughout the study (this does not include
intravesical anticholinergics, which are not permitted). The stable dose,
as determined by the investigator, should have been established prior to
the start of screening.
- if not continuing to take anticholinergics, patients should stop their use
for at least 7 days prior to the start of the screening bladder diary and
screening urodynamics
10. negative urine pregnancy test for females who are postmenarche.
11. patient is able to complete study requirements including completion
of bladder diaries and HRQOL questionnaires (these can also be
completed by the parent/caregiver), and is likely to attend study visits
in the opinion of the investigator |
|
E.4 | Principal exclusion criteria |
• patient has an uncontrolled systemic disease, previous or current
diagnosis of malignancy.
• patient has had surgery of the spinal cord within 6 months of
screening.
• patient has a history or evidence of any pelvic or urological
abnormalities, except NDO, including:
o bladder neck surgery resulting in an open bladder neck, or
reconstructive surgery of the lower urinary tract (eg, urinary diversion,
urostomy), except for the Mitrofanoff procedure, which is permitted.
o anatomical evidence of bladder outlet obstruction, urethral or urethral
valve obstruction/stricture at screening
o surgery of the urinary tract including minimally invasive surgery (eg,
bulking agents,
sling), within 6 months of screening (except those listed above which are exclusionary for any time period).
o circumcision within 1 month of screening
• patient has cerebral palsy
• patient has uncontrolled epilepsy, defined as:
o more than 1 generalized seizure per month within 3 months prior to
screening, or history of prolonged seizures or repetitive seizure activity
requiring administration of a rescue benzodiazepine (oral, rectal, etc)
more than once a month, seizures lasting more than 10 minutes, status
epilepticus, or epilepsy with autonomic involvement within 9 months
prior to screening.
• patient has history of dysphagia, aspiration pneumonia, or significant
lung disease (eg, bronchiectasis)
• patient has predominance of stress incontinence, in the opinion of the
investigator
• patient currently uses or plans to use a baclofen pump
• patient currently uses or plans to use an implantable or
nonimplantable electrostimulation/neuromodulation device for
treatment of NDO. (If a nonimplantable device is used, it must be
discontinued at least 7 days prior to the first screening procedure; if a
device is implanted, it must be inactive for at least 4 weeks prior to the
first screening procedure; neither should be used during the study).
• patient uses an indwelling catheter rather than CIC for treatment of
NDO (NOTE:
an indwelling catheter can be used if needed overnight, as long as it is
not used during the diary collection
periods)
• patient has had previous or current botulinum toxin therapy of any
serotype for any urological condition, or treatment with botulinum toxin
of any serotype within 3 months of randomization/day 1 for any other
condition or use
• patient has been treated with intravesical capsaicin or resiniferatoxin
within 12 months of screening
• patient has been treated with an intravesical anticholinergic within 4
weeks of screening
• patient has received any other medications or therapies, other than
anticholinergics, to treat the symptoms
of NDO within 7 days of the start of the screening period procedures and
during the study
• patient has a known allergy or sensitivity to components of any
botulinum toxin preparation (including the
study medication preparation), anesthetics, or antibiotics to be used
during the study
• postmenarche female patients who are pregnant, nursing, or planning
to become pregnant during the study
(postmenarche female patients must also either be sexually abstinent or
use another acceptable form of
contraception – see Section 4.5.1.1)
• patient has a condition or is in a situation which in the investigator's
opinion may put the patient at significant risk, may confound the study results, or may interfere significantly with the patient's participation in
the study. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy measure is the number of daytime urinary incontinence episodes as recorded in the 2-day bladder diary during the week preceding each study visit. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary timepoint is week 6 after treatment. |
|
E.5.2 | Secondary end point(s) |
There are several urodynamic secondary efficacy measures; a central reviewer will determine the final value.
• MCC (mL)
-the MCC will also be presented as a proportion of the expected bladder capacity (EBC), where EBC is calculated as: (30 + [age in years × 30]) for patients who have volumes below the adult volume of 500 mL (age is at the time of the assessment) (Nevéus et al, 2006)
• presence or absence of an IDC
• if an IDC is present, maximum detrusor pressure during the first IDC (PdetMax1stIDC) (cm H2O)
• maximum detrusor pressure during the storage phase (PdetMax) (cm H2O)
• if a leak occurs, detrusor leak point pressure (DLPP) (cm H2O)
• urine volume at first morning catheterization (mL)
• presence or absence of night time urinary incontinence
In addition, the following duration of effect measures are considered secondary efficacy measures:
• time to patient request and time to patient qualification for retreatment |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
The secondary timepoint is 6 weeks. |
|
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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
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 | No |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
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
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 17 |
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 |
Austria |
Belgium |
Canada |
Czech Republic |
France |
Germany |
Italy |
Poland |
Turkey |
United States |
|
E.8.7 | Trial has a data monitoring committee | No |
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
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | 29 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 29 |