To evaluate the efficacy and safety of BOTOX® 100 U compared with placebo in patientswith idiopathic OAB with urinary incontinence whose symptoms have not been adequatelymanaged with anticholinergic therapy.
ID
Source
Brief title
Condition
- Bladder and bladder neck disorders (excl calculi)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Efficacy Measure:
There are two co-primary efficacy measures, (except for US FDA analyses-see
Section 10.7):
• Number of episodes of urinary incontinence
• The proportion of patients who have a positive treatment response on the
Treatment
Benefit Scale (score of either 1 or 2, representing *greatly improved* or
*improved*)
The primary time point is at Week 12 following the first treatment.
Secondary outcome
Secondary Efficacy Measures:
• Number of micturition episodes
• Urinary Incontinence-Specific Quality-of-Life Instrument (I-QOL)
• King*s Health Questionnaire (KHQ)
• Number of urgency episodes
Background summary
Botulinum Toxin Type A inhibits vesicle-bound neurotransmitters at the
neuromuscular junction, including acetylcholine (ACh). Injection into the
bladder wall can therefore inhibit the parasympathetic stimulated contraction
of the detrusor muscle. Botulinum toxin has also been suggested to inhibit
other neurotransmitters within the bladder associated with OAB
(Apostolidis, 2006). Randomized controlled trials in idiopathic patients who
have not been adequately managed with anticholinergic therapy have shown that
the treatment is effective, safe and durable (Brubaker, 2008; Sahai, 2007).
These data support the potential utility of BOTOX® for patients with idiopathic
OAB. A phase 2 study in the idiopathic population has been completed.
Phase 2 Data
A total of 313 patients were enrolled into the study. A dose response was
identified in efficacy and urodynamic parameters which was reflected in the
patient perception of benefit. However, a dose response was also observed with
certain safety parameters which were particularly related to the elevation in
PVR urine. The risk/benefit balance was carefully evaluated, with the BOTOX®
dose of 100U being considered the most appropriate for the pivotal phase 3
studies.
Following analysis of the phase 2 data it was determined that a dose of 100 U
BOTOX® provides the appropriate balance between efficacy and safety in the
treatment of patients with idiopathic OAB. This dose will therefore be
evaluated further during this phase 3 study.
Based on this information, we can formulate the following hypothesis:
1. BOTOX® 100 U is more effective than placebo at improving the symptoms of
idiopathic overactive bladder
as measured by the difference between treatment groups in the reduction of
urinary incontinence episodes at Week 12.
2. BOTOX® 100 U is more effective than placebo as assessed by the difference
between treatment groups in the
proportion of patients with a positive treatment response on the Treatment
Benefit Scale at Week 12.
3. BOTOX® 100 U has an acceptable safety profile when injected into the
detrusor of patients with idiopathic
overactive bladder with urinary incontinence whose symptoms have not been
adequately managed with
anticholinergic therapy.
Study objective
To evaluate the efficacy and safety of BOTOX® 100 U compared with placebo in
patients
with idiopathic OAB with urinary incontinence whose symptoms have not been
adequately
managed with anticholinergic therapy.
Study design
This is a phase 3 clinical research study, being conducted with consenting
adults who are
affected by Idiopathic Overactive Bladders (OAB)and urinary incontinence who
have not found
previous benefit from anticholinergic medications. The cause of the problems
associated with
overactive bladders in this study are unknown.
This study asseses the safety and effectiveness of BOTOX® treatment injected
into the bladder
for patients with idiopathic OAB. This study is placebo controlled meaning that
some patients will
receive a dummy drug (placebo) whereas others will receive active drug (BOTOX
100U). Patients
are allocated at random to receive either the placebo or BOTOX® 100 U on a 1:1
basis. This study
is also doubleblind, meaning that neither the patients nor the investigator
knows if they have been
allocated placebo or active drug.
The effect of BOTOX® in improving the condition of OAB is temporary, therefore
re*treatment
will be necessary to regain the benefit. In clinical practice this treatment
would be administered
to patients periodically when required. All patients participating in this
study will receive active
treatment of BOTOX® 100 U if they request a second treatment before their exit
visit.
The study will be conducted internationally with several different centres
taking part in each country.
Each centre will have their own research team. Patients will have to meet
certain requirements to join
this study * these are called the Inclusion and Exclusion Criteria. Patients
will also be informed on entry
to 191622-520 that they may have the opportunity to participate in the long
term followup study 191622-096
after completion of the current study and receive further active treatment.
To enable the investigator and patient to remain blinded to their treatment,
the allocation of study
medication kits will be organised via a central, computerised system. This
system has been used
effectively in many previous studies and is called Interactive Voice Response
System (IVRS)/Interactive
Web Response System (IWRS) * the study site staff are given a choice of using
the telephone to get
the medication information they require or using a computer with internet
access. The patient will not
have to have any dealings with IVRS or IWRS.
Patient Visits and Procedures:
The patient could participate in the study for between 24 and 39 weeks
depending on the number and
timing of study treatments that they qualify for.
The following visits occur:
PreScreening/Washout period
Patients who are currently receiving anticholinergic medications and who have
consented to participate
in the study, will enter a washout period of at least 1 week prior to the start
of the screening period.
Informed consent must be taken before commencing the washout period. Screening
visit takes place
up to 3 weeks prior to randomisation/ day 1 to assess eligibility to enter the
study. If not already taken
at the PreScreening/Washout period informed consent will be taken at the start
of this visit. The patient
will be asked to complete a diary of their bladder function for three
consecutive days in the week before
their Treatment 1 visit. They will also be required to record the volume of
urine voided during a 24 hour
period within these three days. The bladder diary will be competed before all
of the following visits except
in the case of Treatment 2.
Treatment 1 (Randomization/ Day 1):
Eligible patients will be randomized and receive their initial treatment at the
Randomization/Day 1 visit.
Treatment 1 Followup
Visits:
Following the initial treatment, all patients will be evaluated at scheduled
clinic visits at Weeks 2, 6 and 12.
Further followup visits occur at Weeks 18, and 24 (Exit) if qualification for
Treatment 2 is not initiated and/or
Treatment 2 not administered(see below).
Qualification for Treatment 2:
Request for Treatment 2 can be initiated by the patient at the Week 12, 18, or
24 scheduled clinic visits only
(which then turns into a Qualification for Treatment 2 visit). The patient must
meet all qualification criteria before
Treatment 2 can occur (if all are not met, the patient returns to the Treatment
1 followup visit schedule).
Treatment 2:
A patient should be treated within 3 weeks of the Qualification for Treatment 2
visit, provided all
Treatment 2 criteria are met on day of treatment (if all are not met the
patient returns to the
Treatment 1 followup visit schedule).
Treatment 2 Followup
Visits:
After Treatment 2, scheduled followup clinic visits will occur at Weeks 2, 6,
and 12 (Exit) following
the Treatment 2 visit.
Exit Visit:
Patients will participate in the study until completion of 24 weeks post
Randomization/Day 1,
and if a second treatment was received, 12 weeks post treatment followup after
Treatment 2.
The minimum study participation is therefore 24 weeks and the maximum duration
is 39 weeks
(if patient qualified for Treatment 2 at week 24 and received it at Week 27).
Additional unscheduled
visits will occur if a patient has a post treatment PVR urine volume of >= 200mL
(for additional details
see Protocol section 8.3.2.8 Post Void Residual (PVR) Urine Volume).
Intervention
De studiemedicatie wordt in de blaaswand ingespoten door middel van cystoscopie
onder vorm van 20 injecties van elk 0.5 ml. De injecties worden evenredig
verspreid over de detrusor met uitzondering van de trigone en de basis.
The study medication is injected into the bladder wall through cystoscopy
administered as 20 injections of 0.5ml each. The injections will be evenly
distributed into the detrusor, avoiding the trigone and base.
Study burden and risks
A. The following side effects have been observed in patients treated with
BOTOX® for the overactive bladder:
In conjunction with the study medication
•Weakness of the bladder muscle, resulting in difficult urination or inability
to urinate (urinary retention) to empty
the bladder for a prolonged time (in most cases less than one month, but may
be longer) after the treatment
•General weakness
In conjunction with the procedure (for example, with the injection, cystoscopy)
•Transient pain
•Transient bleeding at the injection site, resulting in formation of a blood
clot in the bladder tissue
•Blood in the urine
•Difficulty with or pain during urination
•Urinary tract infection
B. The following side effects have not been seen to date with BOTOX®
injections, but may possibly occur in you if you are
treated in this study for your overactive bladder:
In conjunction with the procedure (for example, with the injection, cystoscopy)
•Permanent tissue damage from the repeated injections
•Unintentional perforation of the bladder wall so that BOTOX® enters the
abdominal cavity or adjacent structures
•Abnormal symptoms as a result of overactivity of the nerve supply of the
bladder
•Reaction to the local anaesthetic used, for example, dizziness, nervousness,
spasms, low blood pressure, slow
heart rate or cessation of heart and lung activity (cardio-circulatory arrest)
•Reactions to the anaesthetic (consciousness-lowering sedation), for example,
sleepiness, shallow respiration,
nausea, vomiting, constipation, dry mouth and euphoria
•Injury by the cystoscope, resulting in temporary swelling of the urethra,
injury to the urethra, blockage of the
urinary stream, urinary retention, overextension of the bladder, bleeding or
a bladder infection
C. The side effects and discomforts that are associated with the study
treatment and that you may experience include the
following side effects observed with BOTOX® as treatment for other
disorders (i.e., not overactive bladder):
•Temporary muscle weakness at the injection site
•Slight weakness in other adjacent muscles
•Skin eruption
•Blurred vision
•Allergic reaction
•Itching
•Tingling or pricking sensation
•Reduced sensitivity to contact
•Flu-like symptoms such as muscle pain, chest discomfort, feeling of weakness
or illness, fever, sweating
•Gastrointestinal symptoms such as vomiting, nausea, diarrhea, abdominal pain
and loss of appetite
D.As with any injection of a medication, there may be a possibility of local
pain/ sensitivity, bleeding, blood effusion,
infection and/or swelling. Some people feel lightheaded or faint when they
are injected with a medication.
E. The collection of blood for tests may be associated with pain from the
needle prick, and a blood effusion may form at the
site where the blood was collected. The quantity of blood collected in one
visit during this study is quite small
(approximately 6 teaspoonfuls (30 ml)) and therefore the taking of this
blood is not hazardous to your health.
F. On the basis of the results of experimental study in animals there is a risk
of a miscarriage or malformation of the foetus
(congenital abnormality) if you are pregnant or become pregnant during the
study. The effects of this medication on
pregnancy have not been investigated in humans.
G. Side effects or discomforts that are not known at this time may occur as a
result of the study medication.
H.Patients who perform clean intermittent catheterisation (CIC) can develop a
urinary tract infection, become injured as a
result of the CIC resulting in blood in the urine or experience sensitivity
in the urethra as a result of the repeated
catheterisation.
RARE RISKS OR DISCOMFORT FOR THE PATIENTS
A. Patients with certain muscle-weakening neurologic disorders (such as Lou
Gehrig*s disease or amyotrophic lateral sclerosis (ALS)), myasthenia gravis,
Lambert-Eaton syndrome or motor neuropathy) may be extra sensitive to the
effects of this medication and may develop problems, such as severe
difficulties with swallowing and/or breathing. In rare instances these problems
last for several months, and a feeding tube may be necessary.
B. In rare instances, side effects have been reported as a result of spread
from the injection site, hours to weeks after treatment with medications from
the botulinum toxin class, including BOTOX®. This can cause symptoms in parts
of the body far from the injection site, such as unexpected loss of muscle
strength or muscle weakness, hoarseness or difficulty in speaking, difficulty
in pronouncing words clearly, loss of bladder control, difficulties with
breathing, difficulties with swallowing, double vision, blurred vision and
drooping eyelids. There have been rare reports of death, sometimes associated
with difficulty in swallowing, pneumonia, breathing problems and/or other
important disabilities.
Patients with disorders of the muscular or respiratory systems, such as COPD,
who already had problems with swallowing or breathing, are at greater risk for
these side effects. You are advised to call for medical assistance immediately
if you have difficulties with swallowing, breathing or speaking.
C. There have also been infrequent reports of heart problems (including
abnormal heart rhythm and heart attack, sometimes fatal) after treatment with
this medication. However, it is not known whether this medication actually
caused the problems; some of these patients already had an elevated risk of
heart disorders. Patients (especially those who are very seriously ill) may
develop such problems even without the use of this medication.
D. A number of cases have been reported of potentially life-threatening
allergic reactions. In some of these cases, the study medication was
administered in combination with another product, so that it was difficult to
determine the cause of the allergic reaction, such as in a case where a patient
died after being injected with the study medication that had been incorrectly
diluted with a local anaesthetic (lidocaine) rather than with the physiologic
salt solution.
E. This medication contains albumin from human blood. Although the blood was
tested thoroughly, there is an extremely small chance that viruses and other
similar infectious materials will be transmitted.
F. Although unusual, patients who receive this medication may develop
antibodies to it (an antibody is part of the body*s natural defence system). As
a result, later treatments with this medication may no longer be effective.
G. On the basis of the results of an experimental study in animals in which the
study medication was injected into the prostate gland, an elevated risk of
developing bladder stones may exist.
H. It is possible that in some patients who suffered from certain
gastrointestinal disorders in which food and excreted materials are not
normally passed from the stomach or the intestine, the use of this study
medication may sometimes make the symptoms of the disorder reappear.
Marlow International - The Parkway
MARLOW Buckinghamshire SL7 1YL
United Kingdom
Marlow International - The Parkway
MARLOW Buckinghamshire SL7 1YL
United Kingdom
Listed location countries
Age
Inclusion criteria
1. Written informed consent has been obtained.
2. Written Authorization for Use and Release of Health and Research Study
Information (US sites only) has been obtained.
3. Written Data Protection Consent (EU sites only) has been obtained.
4. Written documentation has been obtained in accordance with the relevant
country and local privacy requirements, where applicable.
5. Patient is male or female, aged >= 18 years old.
6. Patient weighs >= 40 kg (88 lbs).
7. Patient has symptoms of idiopathic OAB (frequency and urgency) with urinary
incontinence for a period of at least 6 months immediately prior to screening,
determined by documented patient history.
8. Patient experiences >= 3 episodes of urinary urgency incontinence, with no more
than one urgency incontinence-free day, in the 3-day patient bladder diary
completed during the screening period (Screening Day -21 to Randomization/Day
1).
9. Patient experiences urinary frequency, defined as an average of >= 8 micturitions
(toilet voids) per day i.e. a total >= 24 micturitions in the 3-day patient bladder
diary completed during the screening period (Screening Day -21 to Randomization
/Day 1).
10. Patient has not been adequately managed with one or more anticholinergic
agents for treatment of their overactive bladder symptoms, in the opinion of the
investigator.
Not adequately managed is defined as:
• an inadequate response after at least a 4-week period of anticholinergic therapy
on an optimized dose(s), i.e., patient was still incontinent despite anticholinergic
therapy, or
• limiting side effects after at least a 2-week period of anticholinergic therapy on an
optimized dose(s). ;An optimized dose is defined as an approved dose for the indication of OAB.
11. Patient is willing to use clean intermittent catheterization (CIC) to empty the
bladder at any time after study treatment if it is determined to be necessary by
the investigator.
12. Patient has a negative pregnancy test result if female and of childbearing
potential.
13. Patient has a negative urine dipstick reagent strip test at Randomization/Day 1
(for nitrites, blood and leukocyte esterase) and, in the investigator*s opinion,
patient is asymptomatic for UTI on day of treatment.
14. Patient is able to complete study requirements including using the toilet without
assistance, is able to collect volume voided per micturition measurements over
a 24-hour period, complete bladder diaries and questionnaires, and attend all
study visits in the opinion of the investigator.
Exclusion criteria
1. Patient has symptoms of overactive bladder due to any known neurological
reason (eg, spinal cord injury, multiple sclerosis, cerebrovascular accident,
Alzheimer*s disease, Parkinson*s disease, etc).
2. Patient has a predominance of stress incontinence in the opinion of the
investigator, determined by patient history.
3. Patient has received anticholinergics or any other medications or therapies to
treat symptoms of overactive bladder, including nocturia, within 28 days of
Randomization/Day 1.
4. Patient uses CIC or indwelling catheter to manage their urinary incontinence.
5. Patient has been treated with any intravesical pharmacologic agent (eg,
capsaicin, resiniferatoxin) within 12 months of Randomization/Day 1.
6. Patient has had previous or current botulinum toxin therapy of any serotype for
any urological condition.
7. Patient has had previous or current botulinum toxin therapy of any serotype for
any non-urological condition within 12 weeks of Randomization/Day 1.
8. Patient has been immunized for any botulinum toxin serotype.
9. Patient has history or evidence of any pelvic or urological abnormalities, bladder
surgery or disease, other than *overactive bladder*, that may affect bladder
function including but not limited to:
• Bladder stones and/or bladder stone surgery at the time of screening or within
6 months prior to screening
• Surgery (including minimally invasive surgery) within 1 year of screening for:
stress incontinence, uterine prolapse, rectocele, or cystocele.
• Current or planned use of an implanted electrostimulation/neuromodulation
device for treatment of urinary incontinence (if a device is still implanted, it must
be inactive 4 weeks prior to Randomization/Day 1 and for the duration of the
study); use of other non-implantable electrostimulatory devices is also
exclusionary.
10. Patient has a history of interstitial cystitis/painful bladder syndrome, in the
opinion of the investigator.
11. Patient has an active genital infection, other than genital warts, either
concurrently or within 4 weeks prior to screening.
12. Patient has a history or current diagnosis of bladder cancer or other urothelial
malignancy, and/or has uninvestigated suspicious urine cytology results.
Suspicious urine cytology abnormalities require that urothelial malignancy is
ruled out to the satisfaction of the investigator according to local site practice.
13. Patient is male with previous or current diagnosis of prostate cancer or a
prostatespecific antigen (PSA) level of > 10 ng/L at screening. Patients with a
PSA level of >= 4 ng/L but <= 10 ng/L must have prostate cancer ruled out to the
satisfaction of the investigator according to local site practice.
14. Patient has evidence of urethral and/or bladder outlet obstruction, in the
opinion of the investigator at screening or Randomization/Day 1.
15. Patient has a PVR urine volume of > 100 mL at screening. The PVR measurement
can be repeated once; the patient is to be excluded if the repeated measure is
above 100 mL.
16. Patient has had urinary retention or an elevated PVR urine volume that has
been treated with an intervention (such as catheterization) within 6 months of
screening.
Note: voiding difficulties as a result of surgical procedures that resolved within
24 hours are not exclusionary.
17. Patient has a 24-hour total volume of urine voided > 3000 mL, collected over 24
consecutive hours during the 3-day bladder diary collection period prior to
Randomization/Day 1.
18. Patient has a history of 2 or more urinary tract infections within 6 months of
screening.
19. Patient has a serum creatinine level > 2 times the upper limit of normal at
screening.
20. Patient has current or previous uninvestigated hematuria. Patient with
investigated hematuria may enter the study if urological/renal pathology has
been ruled out to the satisfaction of the investigator.
21. Patient has hemophilia, or other clotting factor deficiencies, or disorders that
cause bleeding diathesis.
22. Patient cannot withhold any antiplatelet, anticoagulant therapy or medications
with anticoagulant effects for 3 days prior to Randomization/Day 1. Note: some
medications may need to be withheld for > 3 days, per clinical judgment of the
investigator. Please refer to Section 8.2.1 Permissible Medications/Treatments
for additional details.
23. Patient has a known allergy or sensitivity to any components of the study
medication, anesthetics or antibiotics to be used during the study.
24. Patient has any medical condition that may put them at increased risk with
exposure to BOTOX® including diagnosed myasthenia gravis, Eaton-Lambert
syndrome, or amyotrophic lateral sclerosis.
25. Females who are pregnant, nursing or planning a pregnancy during the study or
females of childbearing potential who are unable or unwilling to use a reliable
form of contraception during the study (see section 8.2.3).
26. Patient is currently participating in or has previously participated in another
therapeutic study within 30 days of screening (or longer if local requirements
specify).
27. Patient has any condition or situation which, in the investigator*s opinion, puts
the patient at significant risk, could confound the study results, or may interfere
significantly with the patient*s participation in the study.
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 | EUCTR2009-013088-20-NL |
| CCMO | NL28921.078.09 |