2.1 Primary Objectives• To identify brain activation evoked by sensation in response to bladder filling in patients with an implanted sacral neurostimulator as a treatment for overactive bladder (OAB), compared to a baseline in OAB patients without…
ID
Source
Brief title
Condition
- Urinary tract signs and symptoms
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
We measure BOLD signal intensity changes in a priori supraspinal regions of
interest (ROI), for example, periaqueductal grey, pons, insula, anterior
cingulate cortex, thalamus, hypothalamus, supplementary motor area and
prefrontal cortex, during fMRI in relation to the specific conditions, that is,
low versus full bladder volume. The subjects register their bladder sensation
during the fMRI scan. This is performed during tthree visits, once at baseline,
once during testing phase of sacral neuromodulation (short-term) and once 3
months after implantation of a sacral neurostimulator (long-term). This will
hopefully provide us with a better understanding of the working mechanism of
sacral neuromodulation, which could lead to better assessment of patients that
might be eligible for treatment with sacral neuromodulation.
Secondary outcome
- The fMRI is made at two timepoints during the treatment: 2-5 days after
implanting the neurostimulator, and 3 months later, comparing the difference
between short-term and long-term activation patterns of the brain during sacral
neuromodulation, and comparing results with healthy participants without OAB.
- A comparison will be made between responders and non-responders, looking at
possible structural differences in brain activation during the pre-implantation
phase, and comparing results with healthy participants without OAB. This could
contribute to the assessment of patients that have an indication for treatment
with sacral neuromodulation.
- The extent of bladder filling and bladder sensations will be compared before
and after implantation of the neurostimulator, correlating it to changes in
brain activation, and comparing results with healthy participants without OAB.
Background summary
Patients that are diagnosed with overactive bladder syndrome (OAB), are
eligible for treatment with sacral neuromodulation after failing other
therapies such as physio- and behavioural therapy, medication or intravesical
botulinum toxin injections. Despite the fact that sacral neuromodulation is an
approved and widely used therapy since the 1990*s, the exact working mechanism
of sacral neuromodulation, and its specific effect on brain activation during
bladder filling and urgency are not clear yet. Because this working mechanism
is still largely unknown, we are unable to understand what causes the success
of a treatment, and predict which patients will respond positively to the
therapy. For this reason, a two-step implantation is performed. This allows us
to test the system first, and see if that particular patient responds well to
the therapy, before implanting the total system.
The effect of sacral neurstimulation on brain activity during bladder filling
has been studied few times, using fMRI or PET CT scans. These studies show that
sacral neurostimulation therapy causes altered brain activation compared to a
state before sacral neurostimulation. However, these results are not
unambiguously, and do not yet present a clear answer to the question. More
studies need to be executed, in order to really understand the working
mechanism of sacral neuromodulation.
This study will explore the influence of sacral neurostimulation on brain
activation during bladder filling, gaining a better understanding of the
working mechanism of this approved and widely used treatment. By using the
ultra-high field 7T fMRI scanner, brain stem nuclei can be studied with
unprecedented detail. Activity patterns within the periaqueductal gray (PAG)
and the relation of the PAG to other brain regions that are associated with
micturition and continence will be studied. Because this is the first time the
brain activity in this population is studied in such detail, this research is
valuable and new in comparison to earlier studies. Moreover, this study will be
an addition to a current study that is performed in our centre, looking at the
difference in brain activity during bladder filling in women with and without
OAB. These two studies can complement each other, and create the opportunity to
gain even more knowledge about the pathology and treatment options in this
patient group.
The ultimate aim is to allow a better patient selection in the future and this
may ideally lead to the ability to perform a one stage procedure in eligible
patients, which will reduce treatment cost, burden and complication risk for
the patients.
Study objective
2.1 Primary Objectives
• To identify brain activation evoked by sensation in response to bladder
filling in patients with an implanted sacral neurostimulator as a treatment for
overactive bladder (OAB), compared to a baseline in OAB patients without
treatment, conducted in another study, through fMRI during associated bladder
sensation measurements.
2.2 Secondary Objectives
• To assess the difference in brain activity during bladder filling after
short-term and long-term treatment with sacral neuromodulation, and comparing
results with healthy participants without OAB.
• To assess the subjects bladder sensations measured by visual analogue scale
(VAS) and 4-points grading scale (see Appendix 2) during natural bladder
filling in fMRI scan, comparing before and after implantation, and comparing
results with healthy participants without OAB.
• To assess the correlation between bladder filling and subject*s bladder
sensations, comparing before and after implantation, and comparing results with
healthy participants without OAB.
• To assess symptom severity, symptom bother and quality of life using:
ICIQ-OAB, ICIQ-OABqol and a 3-day micturition bladder diary as background
information to determine the difference before and after implantation, and
comparing results with healthy participants without OAB.
• To assess the anxiety and depression status of study subjects through HADS
questionnaire, comparing before and after implantation, and comparing results
with healthy participants without OAB.
• To assess the severity and bother of sexual complaints, associated with OAB
by using ICIQ-FLUTSsex, comparing before and after implantation, and comparing
results with healthy participants without OAB.
Study design
All OAB patients will receive sacral neuromodulation as an intended treatment
for their OAB symptoms. The study aims to identify brain regions involved in
the sensation of bladder filling that are influenced by sacral neuromodulation,
using conventional urodynamic assessment in combination with bladder sensation
assessment.
The study will be conducted according to open, uncontrolled, pretest-posttest
group design.
Patients will be recruited via the urological outpatient clinic of the MUMC+
and Erasmus MC. They receive information about the study from a urologist or
the nurse who provides neuromodulation care and who registers the patients for
the procedure. A member of the research team will then contact the candidate to
further explain the study or resolve any doubts, and give the candidate at
least one week of consideration time. Afther this, the researcher contacts the
candidate again, giving the candidate the opportunity to ask additional
questions. If the patient agrees to participate, a screening visit will be set
at the University/Urology Department with the researcher. At the start of this
visit, the participant is able to ask any questions, and if they agree to
participate, the informed consent will be signed. No study related procedures
will take place before this step. After this screening appointment, the study
will start, if the patient can be included. The subjects will receive maximally
4 extra visits compared to the regular treatment (1 screening visit, 2 or 3
separate scan sessions).
Healthy participants will be recruited through flyers and advertisements. The
research team will also provide study information to interested participants
via phone and e-mail after which they will also receive at least one week
consideration time before a screening visit is planned.
As is standard treatment, the implantation of the sacral neuromodulation system
will be performed in two steps. This 2 step procedure including a 2 weeks test
stimulation is necessary as it is not known yet which patients will have a
beneficial response to therapy, and which will not. A beneficial respons is
defined as more than 50% improvement on one of the urinary complaints (urgency,
frequency, voided volume and urinary loss), measured by a 3 day voiding diary
filled out before and during testphase. During the first surgical procedure,
the lead is implanted in foramen S3 (or in some cases S4), and is connected to
an external testing device. When the patient has a beneficial respons to the
therapy, during a second surgery, the lead will be connected to an internal
pulse generator (IPG). This IPG is implanted in the gluteus maximus. In case
the patient has little or no effect of the therapy, the testing system will be
explanted during the second surgery.
The study participants will consist out of two groups defined as: Healthy
individuals without OAB and not undergoing any treatments, and OAB subjects
with or without detrusor overactivity (DO), that are eligible for treatment
with sacral neuromodulation.
All healthy volunteers will complete the same procedures and assessments in the
same order.
All patients that have a beneficial respons to sacral neuromodulation therapy
will undergo a total of two 7 Tesla fMRI scans and pariticpants in Maastricht
will also complete a long-term follow up at 3T MRI scan at Scannexus in
Maastricht, during all these scanning sessions their bladder is filled via
natural diuresis and the subjects perform a task regarding their subjective
bladder filling (IUSS and VAS score). For the patients that do not have a
beneficial respons to the therapy, only two scans will be executed in the MUMC+
as well (baseline and during testing phase), and they will exit the study after
explantation of the testing system for sacral neurmodulation.
Course of the study:
After the start of the study, an SR-BD (sensation related bladder diary) and
questionnaires are completed (regular care), after which a baseline fMRI scan
is performed (study - all study participants). Then the test phase of sacral
neuromodulation is implanted in the operating room (regular care). 2-5 days
after this the 2nd fMRI scan is performed (study - OAB group). The patient then
completes an SR-BD and the questionnaires during the testing phase (regular
care), and based on the results, receives an explantation of the testing system
or an implantation of the IPG (regular care). The patient then completes an
SR-BD and questionnaires again 3 months after implantation (study - MUMC+
only), and the last fMRI scan is performed (study - MUMC+ only).
After the last fMRI session, or after removing the test phase in case of
insufficient effect, all data is collected and participation in the study is
complete.
Study burden and risks
Most of the assessments performed during the study (physical examination, diary
and questionnaires) are all part of the standard care for patients that are
eligible for neuromodulation and they do not pose additional risk to patients.
The pregnancy test is an extra test during this study, but does not pose an
additional risk to the patients either. How to fill in these questionnaires and
the diary will be explained to the patients carefully. We will focus on the
fact that they have to complete the diary after every micturition, to keep the
results as accurate as possible. The possible physical burden of the fMRI scan
is explained in the next paragraph. A urodynamic investigation is part of the
regular work-up for neuromodulation. The procedure will be explained carefully
and the possible risks as well.
For the individual subjects there will be no additional personal benefit, but
it will be explained that they are helping in improving the understanding of
and possible future treatment for OAB. The time invested is explained in the
participants* information letter. The fMRI is a new concept for most of the
participants and is explained further below.
fMRI
1.5T and 3T MRI scanners are widely used in clinical environments. A static
magnetic field of up to 14T or more does not harm biological tissue, but the
radiofrequency and MR gradient applied can influence the human body via heating
(specific absorption rate (SAR)) or peripheral stimulation. Therefore, limits
of the radiofrequency (RF) and magnetic resonance (MR) gradient are encoded in
the MRI scanner. Certified users will always stay below these limits making
scanning harmless. When scanning the subjects in this study, it is assured that
the MRI field specifications that are stated in the product brochures of the
sacrale neuromodulation system are not exceeded. Other metallic objects however
cannot be inserted into the scanner area of the MRI scanner. Therefore,
subjects with not-adequately fixed metallic prostheses, non MRI safe
pacemakers, metal clips on blood vessels, metal parts in the eye, an
intrauterine device (except for Mirena, a hormonal IUD), metal braces and other
metal objects will be excluded from the study. Prior to scanning all subjects
will fill out a form to screen for these metallic objects. Although 7T MRI is
harmless if contra-indications are taken heed of and if operated by certified
users, a small amount of people (5%) may experience vertigo or nausea while
entering the scanner. However, slowing the subject*s entry and exit time into
the magnetic field will minimize these symptoms. Also, a smaller amount of
people may experience a metallic taste in their mouth during the scan.
The sacral neuromodulation system in this particular version has not been used
during a 7 Tesla fMRI scan before. To predict the effect when patients with
this device are placed in the fMRI scan, a safety analysis has been performed.
This analysis shows no significant side effects to be expected during the
study.
There is no intended direct clinical benefit for the subjects participating to
this study.
P. Debyelaan 25
Maastricht 6229 HX
NL
P. Debyelaan 25
Maastricht 6229 HX
NL
Listed location countries
Age
Inclusion criteria
In order to be eligible to participate in this study, a subject must meet all
of the following criteria:
1. Female subjects above 18 years of age.
2. Has provided written informed consent prior to any study related procedures.
3. Indication for treatment with sacral neuromodulation (for patient group)
4. History of signs and symptoms of OAB including urinary frequency, urgency or
urge incontinence for greater than or equal to 3 months. (for patient group)
5. The subjects must have (for patient group):
a. At least 1 episode of urgency with or without incontinence in the last 3-day
micturition diary.
b. Frequency of micturition greater than or equal to 8 per 24 hours period
during the 3-day micturition diary period
6. At the screening visit, when patient is on medicinal treatment for OAB they
should be willing to undergo a washout period for 3 weeks. (for patient group)
Exclusion criteria
1. Stress urinary incontinence more profound than urge urinary incontinence,
urethral sphincter incompetence and neurogenic detrusor overactivity.
2. Current urinary tract infection (confirmed by positive urine analysis).
3. Bladder outlet obstruction (not including detrusor-overactivity), for
example bladder/vesico-uterine prolapse (> grade II) or chronic obstruction.
4. History of urinary tract surgery less than or equal to 6 months prior to
screening.
5. Intermittent catheterization or permanent catheter.
6. History of pelvic area radiotherapy treatment.
7. Has a history of treatment of OAB with botulinum toxin within less than 12
months prior to screening.
8. Patients with any metal implants in the body (except dental implants) that
would prevent the patients to undergo fMRI scan, excluding MRI safe nerve
stimulators.
Design
Recruitment
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 |
|---|---|
| CCMO | NL80374.068.22 |