To evaluate the safety and efficacy of 2 dose levels of BOTOX® (200 U or 300 U) compared to placebo injected into the detrusor for the treatment of urinary incontinence caused by neurogenic detrusor overactivity in patients who have not been…
ID
Source
Brief title
Condition
- Spinal cord and nerve root disorders
- Respiratory disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety measures are the primary study parameters:
Primary safety measures:
* Forced Vital Capacity (FVC) (percent predicted and absolute value)
* Forced Expiratory Volume (FEV1) (percent predicted and absolute value)
* Oxyhemoglobin Saturation
* Maximum Inspiratory Pressure (MIP)
* Maximum Expiratory Pressure (MEP)
Secondary outcome
Secondary safety measures:
* Serious Medical Events
* Adverse Events
* Physical Examination
* Vital signs
* Hematology and non-fasting chemistry
* Urinalysis
* Bladder and kidney ultrasound
* Post void residual
Secondary efficacy measures:
* Number of episodes of urinary incontinence as recorded in the patient bladder
diary
* Number of episodes voided as recorded in the patient bladder diary
* Urodynamic parameters
Background summary
Recently, studies have been carried out using BOTOX® in the treatment of
patients who suffer from bladder overactivity.
There is evidence for the successful use of BOTOX® in the management of
neurogenic incontinence. It has been shown that botulinum toxin injections of
200 U to 300 U into the detrusor across 20 to 30 injection sites (10 units per
mL per injection site) have been effective in restoring continence and enabling
reduction or cessation of anticholinergic medication in such patients. In one
study enrolling 21 patients, 17 of the 19 patients with follow-up data had
restored continence within 6 weeks. To date, treatment of over 900 neurogenic
overactive bladder patients with BOTOX® at doses ranging from 200 U to 300 U in
20 to 30 injection sites has been reported. Treatment benefit has been
described to last between 6 and 12 months with an acceptable site effect
profile.
Allergan conducted a placebo-controlled phase 2 study to assess the safety and
efficacy of BOTOX® (study AGN 191622-511). Fifty-nine patients were enrolled in
this study and received a single treatment of 200 U BOTOX®, 300 U BOTOX® or
placebo and followed for 24 weeks post-treatment. Treatment effect in both
active groups was observed for the duration of the 24-week study. Urodynamic
parameters, also indicative of efficacy, supported the effectiveness of
BOTOX®. Increased bladder capacity, as determined by maximum cystometric
capacity, was consistently and significantly greater in the BOTOX®-treated
patients through 24 weeks post-treatment. Although statistically significant
superiority to placebo was consistently observed for the 200 U and 300 U doses
throughout the follow-up period, the study was not designed to compare the two
active doses. There were no significant safety observations noted and no
treatment related adverse events were reported in any patients. Therefore, it
was not possible to differentiate between the two doses with respect to
duration of effect. Although the study was not designed to evaluate treatment
duration of effect, study data are consistent with those seen in the literature
of a mean duration of effect for both the 200 U and 300 U doses of at least 6
months.
Based on data from the 191622-511 study and literature reports of BOTOX®
treatment for overactive bladder, Allergan is pursing further clinical
development in both neurogenic and idiopathic clinical patients. A phase 2
dose-response study has been initiated in idiopathic overactive bladder
patients. Two pivotal safety and efficacy studies are planned to support a
neurogenic overactive bladder indication. One phase 3 safety and efficacy
study (191622-515) has been initiated recently and the second, pivotal phase 3
study will be conducted to confirm safety and efficacy in this same patient
population (191622-516).
This phase 3 safety study will evaluate patients with neurogenic detrusor
overactivity who have respiratory impairment due to their underlying neurologic
disease, namely spinal cord injury or multiple sclerosis. Although, there are
no reports of respiratory failure in patients who have received BOTOX® for
overactive bladder or for treatment of detrusor sphincter dyssynergia and
urethral sphincter injections, no acute complications of respiratory depression
were observed, there is a theoretical possibility of systemic spread of BOTOX®.
Thus, a potential safety concern arises with BOTOX® if it were to cause
respiratory failure due to paralysis of the diaphragm and other respiratory
muscles. MS and spinal cord injury patients who already have respiratory
compromise would be especially vulnerable to the development of respiratory
failure were this to occur.
Study objective
To evaluate the safety and efficacy of 2 dose levels of BOTOX® (200 U or 300 U)
compared to placebo injected into the detrusor for the treatment of urinary
incontinence caused by neurogenic detrusor overactivity in patients who have
not been adequately managed with anticholinergic therapy and have neurological
respiratory impairment.
Study design
Structure:
Multicenter, double-blind, randomized, placebo-controlled, parallel group study.
Duration:
Patients will complete a 52 week post-treatment follow up period following
Randomization/Day 1. Patients are eligible for up to 2 treatments during the
study with a minimum of 12 weeks between treatments.
Controls:
BOTOX® placebo (saline)
Randomization:
Patients will be centrally randomized and assigned a randomization number prior
to the first treatment, which will be associated with one of the following
treatment sequences:
1) BOTOX® 200 U (treatment 1)/BOTOX® 200 U (treatment 2)
2) BOTOX® 300 U (treatment 1)/BOTOX® 300 U (treatment 2)
3) Placebo (treatment 1)/BOTOX® 200 U (treatment 2)
4) Placebo (treatment 1)/BOTOX® 300 U (treatment 2)
Patients will be randomized to the above treatment sequences in a ratio of
1:1:0.5:0.5, respectively. In order to ensure balance across treatment arms,
patients will be stratified to treatment according to overactive bladder
etiology (multiple sclerosis or spinal cord injury).
Study Design
Dosage/Dose regimen:
Each study treatment will be administered via cystoscopy as 30 injections, each
of 1 mL, evaly distributed into the detrusor (including dome), avoiding the
bladder base and trigone.
Treatment 1:
All eligible patients will receive their first treatment with BOTOX® 200 U or
BOTOX® 300 U or placebo. The first treatment will be administered after
randomization on Randomization/Day 1.
Treatment 2:
All eligbible patients will receiv BOTOX® for their second treatment which may
be administered no sooner than Week 12 if the patient meets re-treatment
criteria. Patients receiving BOTOX® for their first treatment will continue to
be treated with the same dose received in the first treatment. Patients
receiving placebo for the first treatment will receive either BOTOX® 200 U or
300 U for the second treatment, according to the pre-assigned randomization
schedule. In order to allow for appropriate study follow-up, treatment 2 must
occur by Week 40 following Randomization/Day 1.
Intervention
Yes, BOTOX® 200 U, BOTOX® 300 U or placebo will be administered via cystoscopy
as 30 injections, each of 1 mL, evenly distributed into the detrusor (including
dome), avoiding the bladder base and trigone.
Study burden and risks
From the risk benefit assessment it seemed that treatment effect will be
greater than the risks for the patients when participating in the study.
2525 Dupont Drive
92612
Verenigde Staten
2525 Dupont Drive
92612
Verenigde Staten
Listed location countries
Age
Inclusion criteria
7. Patient has urinary incontinence as a result of neurogenic detrusor overactivity for a period of at least 3 months prior to Screening Day -21 due to spinal cord injury or multiple sclerosis, determined by documented patient history. In addition:
* Spinal cord injured patients must have a stable neurological injury between cervical level 5 (C5) and cervical level 8 (C8), inclusively as determined by the neurological definition of SCI; complete or incomplete. The spinal cord injury must have occurred ><= 12 months prior to Screening Day -21
* Multiple sclerosis patients must be clinically stable, in the investigator's opinion, for ><= 3 months prior to Screening and through Randomization/Day 1. Patients must have an Expanded Disability Status Scale score between 7.0 and 8.0, inclusively.
9. Patient has a Forced Vital Capacity (FVC) between 50% and 80% of predicted value on two separate testing days during Screening (Day -21 to Day -1). Note: The difference between the largest FVC observed on each testing day must not exceed 20%. There should be at least 7 days between the two screening PFTs and the second PFT must occur withing 0-5 days prior to Randomization/Day 1 Visit.
10. Patient has detrusor overactivity (defined as a phasic rise in bladder pressure during the filling phase as determined by urodynamics) demonstrated during the Screening period (Day -21 to Day -1) or Randomization/Day -1.
12. Patient has not been adequately managed with one or more anticholinergics for their urinary incontinence, in the opinion of the investigator. "Not adequately managed' is defined as an inadequate response to, or intolerable side effects while taking an optimized dose for at least one month.
15. Both multiple sclerosis (MS) and spinal cord injury (SCI) patients must be willing to use intermittent catherization (IC) to empty the bladder and maintain an established catheterization frequency throughout the study. Caregiver may perform IC for patient, if patient is unable to do this. (Indwelling catheters are not permitted).
16. Patient experiences ><= 4 episodes of urinary incontinence (leakage) over 3 days determined by completion of a bladder diary during the Screening period.
Exclusion criteria
1. Patient has had previous or current botulinum toxin therapy of any serotype for any urological condition or treatment within 3 months of Randomization/Day 1 for any other condition.
3. Patient has history or evidence of any significant pelvic or urological abnormality, including, but not limited to, the following:
* elevated serum creatinin > 2 times the upper limit of normal (reference range)
* history of or current hematuria, 1) if the hematuria is determined to be due to a pathologic condition or 2) is uninvestigated
* interstitial cystitis in the opinion of the investigator
* bladder stones within 6 months of Screening Day -21
* surgery or bladder disease other than detrusor overactivity that may impact bladder function with the exception of surgeries for bladder stones (>6 months) and stress incontinence, uterine prolapse, rectocele, or cystocele (> 1 year from Screening Day -21)
6. Patient has discontinued anticholinergic medication for the treatment of overactive bladder <21 days prior to Randomization/Day1.
7. Patient has an untreated or symptomatic (e.g. fever, recent change in neurological status) urinary tract infection (UTI) on Randomization/Day 1.
10. Patient has an acute respiratory tract infection. Patient may qualify for re-screening upon clinical resolution and stabilization (one month, or longer based on the investigator's opinion, has elapsed after clinical resolution without recurrent symptoms).
11. Patient has a clinically significant abnormal chest X-ray (CXR) finding. Patient may qualify for re-screening upon resolution, or the CXR finding is no longer considered clinically significant.
12. Patient has clinically significant intrinsic lung disease (e.g. sarcoidosis, pulmonary fibrosis, bronchiectasis).
13. Asthmatics whose disease is not stable (i.e., have had exacerbation(s) of asthma within 3 months prior to Screening Day -21) Note: Stable, preventative respiratory medications/therapy are permitted
14. Patient has a history of, or acute exacerbation of COPD within 3 months prior to Screening Day -21.
15. Patient has a pulmonary embolus (PE) within 6 months of screening Day -21, or a history of recurrent pulmonary emboli (i.e., a diagnosis of PE on more than one occasion per lifetime)
16. Patient has aspiration pneumonia, aspiration pneumonitis or acute respiratory failure wihin 12 months prior to Screening Day -21.
17. Patient requires supplemental oxygen and/or ventilatory support.
18. Patient has evidence of carbon dioxide (CO2) retention as indicated by a serum bicarbonate level greater than the upper limit of the normal (reference range) at Screening Day -21.
19. Patient has used any antiplatelet or anticoagulant therapy or is using medications with anticoagulative effects within 3 days prior to treatment. Some medications may need to be withheld for > 3 days per clinical judgement of the investigator (refer to Section 8.2.2 Prohibited Medications/Treatments for details).
21. Patient is currently using, or plans to use, an implanted or non-implantable electrostimulation/neuromodulation device for treatment of overactive bladder.
22. Patient is currently being treated with an intrathecal baclofen pump.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2006-006299-39-NL |
| CCMO | NL17079.029.07 |