Integrated Overactive Bladder Clinical Trial in clinical practice III

In the Netherlands many persons suffer from Overactive Bladder Syndrome (OABs)
or shortly Overactive Bladder (OAB). After stress urinary incontience with a
prevalence of 49%, is it the most prevalent lower urinary tract complaint
(17%). OAB might, especially in case of complaints of urgency urinary
incontinence (UUI), limit profoundly the patient 's quality of life. According
to recent data more than 5% of all women might have UUI, while half of these
women really suffer because of it. This means that in the Netherlands more than
300000 women have UUI. When also those with mixed urinary incontinence will be
taken into account, there are more than 1 miljon. The ICS defines OAB as a
disfunction of the bladder during the filling/storing phase when during an
(ambulatory) urodynamic investigation involuntary contractions of the bladder
can be demonstrated while the patient tries to surpress these. Patients have
strong compelling urgency to void, visit frequently the toilet (frequency),
feel the urency need to go to the toilet during the night (nocturia) (symptoms
of urgency and frequency, without urinary incontinence are called 'OAB dry')
and have, based on urgency, involuntary loss of urine (urgency, frequency with
urinary incontinence are called 'OAB wet'). These symptoms migth occur
seperately or in combination. An OAB patient produces often small volumes of
urine (< 150 ml.), pointing at a smaller functional capacity of the bladder.
Often this might lead to extensive loss of urine, up to a complete loss of
urine out of the bladder. This has a dramatic impact on the emotional and moral
feelings of those affected by this. Especially young women OAB has a hugh
impact. The most important effect of UI in man is 'the feeling of being out of
controle' while in women in general 'the feeling of the need to take
precautions' might be the most important factor related to the subjective
experience of the impact of the loss of urine (Teunissen 2005).

Costs for incontinence absortion materials (IAM) are about ¤ 300 per person per
year (CvZ: GIPeilingen 2007). In case there is no adequate intervention the
need to use IAM is permanent. While costs of IAM return every year, despite the
fact that effective treatment might be expensive, treatment might be efficient
for the long term. Costs for society are even much higher because of indirect
costs related to absence of work and environnement such as collection and
destroying IAM. For 2006 total annual Dutch economical costs for only
incontinence absortion materials were calculated to be > ¤ 163 miljons (CvZ:
GIPeilingen 2007).

Rationale for botulinum toxin injections and sacral neuromodulation
In case patients develop intractable symptoms, until not too long time ago, the
only remaining option was major reconstructive surgery such as bladder
augmentation with the aim of increasing the capacity of the bladder. In
addition to the risk of a major surgical procedure, complications such as
metabolic disorders and chronic retention are common and these procedures do
not guarantee continence. Consequently, this is generally considered an option
of last resort that is appropriate only for a very small minority of patients
(Chartier-Kastler 2007).Therefore, for the vast majority of patients with OAB
and UUI who do not benefit from anticholinergic therapy, pelvic physiotherapy
or PTNS, acceptable effective treatment options after failed conservative
therapy are needed.

Nowadays, implantable neuromodulation systems, such as sacral neuromodulation
or Sacral Nerve Stimulation (SNS) are available.
Clinical trials suggests that SNS has sustained efficacy in a well selected
population of patients with refractory OAB, with moderate risks of procedure
related complications. SNS seems to be a safe, reversible and minimally
invasive therapy that does not preclude other treatment options. This therapy
might be an efficacious alternative to more invasive techniques. Although SNS
has the potential to become a well established treatment option in the
Netherlands, this therapy is not widely available so far. Reasons for this are
high costs of the device and procedure and the occurrence of technical
difficulties (Janknegt et al, 2001).
Also the use of Botulinum Type A (primarily BOTOX®) for OAB populations has
been reported. A few randomized controlled trials in idiopathic patients who
have not been adequately managed with conservative therapy have investigated
its efficacy, safety and durability (Brubaker, 2008; Sahai, 2007). These
studies support the potential utility of BOTOX® for patients with idiopathic
OAB.

So, Sacral Nerve Stimulation, as a minor invasive surgical intervention, and
botulinum toxin injection therapy for the treatment of OAB are momentarily
filling the gap between conservative treatment and major invasive surgery. So
far, SNS has already been registered in the Netherlands. Up to now, for the
indication OAB botulinum toxin injection therapy is not (yet) registered in the
Netherlands. Moreover, it seems that the injections only have a temporarily
efficacy and therefore must be repeated periodically each 6-9 months. For these
reasons it might be that SNS has superior efficacy to botulinum toxin injection
therapy and is more safe than the other option. To increase our knowledge and
to get more insight into this question we want to compare the efficacy and
safety of SNS with botulinum toxin injection therapy in adults patients with
idiopathic OAB.

References:
Teunissen TAM, Weel van C, Lagro-Janssen ALM. Urinary incontinence in older
people living in the community examining helpseeking
behaviour. Br J Gen Pract 2005; 55: 776-82.

Health Insurance Board/CVZ. GIPeilingen 2007. Ontwikkelingen genees- en
hulpmiddelengebruik; 2008 august. Report No.: nr. 29.

Chartier- Kastler E. Sacral Neuromodulation for treating the symptoms of OAB
and non-obstructive UR: >10 years of clinical experience. 2007 BJU International

Janknegt RA, Hassouna MM, Siegel SW, et al. Long-term effectiveness of sacral
nerve stimulation for refractory urge incontinence. Eur Urol 2001; 39(1):
101-106

Brubaker L, Richter HE, Visco A, Mahajan S, Nygaard I, Braun TM, Barber MD,
Menefee S,
Schaffer J, Weber AM, Wei J; Pelvic Floor Disorders Network. Refractory
idiopathic urge urinary incontinence and botulinum A injection. J Urol. 2008
Jul;180(1):217-22. Epub 2008 May 21

Sahai A, Khan MS, Dasgupta P. Efficacy of botulinum toxin-A for treating
idiopathic detrusor overactivity: results from a single center, randomized,
double-blind, placebo controlled trial. J Urol. 2007 Jun;177(6):2231-6

Primary objectives of INTACT III are:

1) to prospectively compare the efficacy of Sacral Nerve Stimulation (SNS) with
BOTOX® 100 U related to the Patient Perception of Bladder Condition (PPBC)
questionnaire (Coyne 2006) and the reduction of urinary incontinence episodes
(as measured with the 3 days micturition diary in patients with idiopathic OAB
with urinary incontinence whose symptoms have not been adequately managed with
conservative therapy, i.c. anticholinergic therapy or pelvic physiotherapy or
PTNS.

2) to prospectively compare adverse effects of Sacral Nerve Stimulation (SNS)
with BOTOX® 100 U.

Measurements will be executed after week 12 after the (first) treatment, after
6 and 12 months after treatment.

Secondary objectives of INTACT III
1) to prospectively compare the efficacy of Sacral Nerve Stimulation (SNS) with
BOTOX® 100 U related to a decrease of urgency (as measured with the PPIUS
questionnaire measuring decrease of patient*s perception of urgency), decrease
of frequency (number of voids/24 hrs as measured with the 3 days micturition
diary) and reduction volume involuntary loss of urine (as measured with the 3
days micturition diary,
2) to prospectively compare the efficacy of Sacral Nerve Stimulation (SNS) with
BOTOX® 100 U on quality of life (as measured with the Incontinence Quality of
Life Questionnaire (I-QoL), and on impact and severity of urinary incontinence
(as measured with the PRAFAB questionnaire (Hendriks 2007)
3) to prospectively compare the efficacy of Sacral Nerve Stimulation (SNS) with
BOTOX® 100 U on patient *s satisfaction as measured with the *patient
satisfaction questionnaire*, and on patient*s impression of improvement (as
measured with the *Behandeling Baat Schaal*,
in patients with idiopathic OAB with urinary incontinence whose symptoms have
not been adequately managed with conservative therapy, i.c. anticholinergic
therapy or pelvic physiotherapy or PTNS.

Measurements will be executed after week 12 after the (first) treatment, after
6 and 12 months after treatment.

Clinical hypotheses
SNS is more effective than BOTOX® 100 U as assessed by the difference between
treatment groups in the proportion of idiopathic OAB patients with a positive
treatment response on the Patient Perception of Bladder Condition (PPBC) at
Week 12 after (first) treatment and at 6 months and at 12 months after
treatment.

SNS is more effective than BOTOX® 100 U improving the symptoms of idiopathic
OAB as measured by the difference between treatment groups in the reduction of
urinary incontinence episodes at Week 12 after (first) treatment and at 6
months and at 12 months after treatment.

Overall study design
In case of a new signed informed consent, and in- and exclusion criteria
fulfilled, unsuccessful patients after INTACT II (progress less than two
categories on the PPBC or < 50 % less Incontinence episodes frequency (IEFs)
may enter INTACT III (see Flowchart 1). The setting of INTACT III is the region
of South- Limburg, with participation of GPs and urologists, with study support
from the PcCM of MUMC+.

This will be a mono-centre, single-blind, randomized, pragmatic, parallel-group
study to assess the efficacy and safety of SNS (Group 1) compared to a single
treatment of BOTOX® (Group 2) followed by a second treatment (if applicable)
with BOTOX® (Group 2) in patients with idiopathic OAB with urinary
incontinence whose symptoms have not been adequately managed with conservative
therapy, i.c. anticholinergic therapy or pelvic physiotherapy or PTNS.
Following a qualification period of 3 to 6 weeks, patients meeting the study
inclusion/exclusion criteria will be randomly assigned to one of two treatment
arms (SNS or BOTOX® 100 U) in a ratio of 1:1 with a random permuted block size
of four. To conceal treatment allocation, an independent research assistant
prepared a computer-generated randomisation list and treatment allocation. In
case of randomization to Group 1 the department of urology and the Pelvic care
Center Maastricht of MUMC will perform the SNS, if randomized to Group 2 botox
injections will be performed at the department of urology of MUMC. Patients
will be stratified according to the number of urgency incontinence episodes
reported at baseline, <= 9 or > 9 episodes, over the 3-day micturition diary
completed during the qualification period. Because there can be differences in
underlying causes of the health problem OAB in relation to gender patients will
be stratified according to gender as well.
Patients in group 2 will be eligible to receive a second BOTOX® treatment if
all the predefined Treatment 2 criteria are met (see Section 5.9.2.5).

One randomization number will be assigned to each patient prior to the first
treatment and will be associated with one of the following treatment sequences:
A) Group 1: SNS
B) Group 2: BOTOX® 100 U (Treatment 1)/BOTOX® 100 U (Treatment 2)
Patients will be followed regularly for safety and efficacy at post-treatment
visits, Week 15/16 and Week 52 post treatment in both groups and in Group 2
also at Week 24-27 and Week 40. In both groups follow-up is 52 weeks. Patients
in Group 2 will complete up to 3 treatments, in case the first and/or the
second treatment was not sufficiently successful (see section 5.9.2.5 for
qualification for Treatment 2 (Botox 2)) with a maximum study participation
duration of 52 weeks (if a patient qualifies for Treatment 2 (Botox 2) at week
24 and received Treatment 2 (Botox 2) at week 27, and - if necessary -
qualified for Treatment 3 (Botox 3) at week 51 and received Treatment 3 (Botox
3) at week 52).

Total duration of the complete study (INTACT I, II & III) is 4 years.

Estimation of problems to be expected
There are no big problems with respect to diagnostics and therapy to be
expected. All methods used are usual care diagnostical and treatment
procedures. Phase 3 has an experimental character because of the randomisation
procedure, and only outcome measures based on micturition diaries and
questionnaires are used. Besides the urodynamic investigation and the
cystoscopy, both regular, in general acceptable but invasive diagnostical
procedures, especially the treatment methods during phase 3 are invasive.
But, based on literature and own experience we do not expect major problems
regarding this.


For further information about the study design of phase 3, please see Appendix
20.

INTERVENTION PHASE 3 = INTACT III

In case of insufficient success within the identified protocollized period
phase 3 of the study will follow. The urologist will choose between SNS and
botox injections. For this project this means randomization between SNS and
botox injections. SNS treatment and botox injections will be executed in the
MUMC. If cured the patient will also have evaluations at 6 and 12 months. For
treatment with botox see paragraphs 'Treatment procedure' and 'Intervention'
of het INTACT III protocol (Appendix 20).

SNS
SNS is a rehabilitative treatment to be used to treat selected patients with
OAB (Siegel 2000, Aboseif 2007) . In this technique, low-intensity electrical
impulses are generated by an implantable neurostimulator (INS) (also referred
to as an implantable pulse generator (IPG)), and delivered via a conducting
electrode to one of the lower sacral nerves (usually S3) involved in the
control of lower urinary tract function.
SNS treatment is based on the protocol that has been (partly) developed within
the department of urology of the MUMC+. This has been described in the document
Nieuwe DBC Urologie Neuromodulatie met een geïmplanteerd neurostimulatie
systeem voor de behandeling van patiënten met functistoornissen van de lagere
urinewegen (Messelink et al. 2008). For more details see paragraphs 'Treatment
procedure' and 'Intervention' of het INTACT III protocol (Appendix 20).
The neurostimulator will be programmed and interrogated externally by the
physician with a magnetic programming device. With the use of the hand-held
patient programmer, the patient can stop and start the INS, as well as increase
and decrease the amplitude of the stimulation. Before the system is permanently
implanted, a test with a permanent lead (two-stage procedure) will be carried
out to identify whether or not the candidates is suitable for the permanent
implant. The test phase will lasts 1-6 weeks. The patient qualifies for
permanent implant if during the test phase, the patient reports at least 50%
improvement in the micturition diary variables and lower urinary tract symptoms
(as recorded in the micturition diary). The permanent implant of the system is
by a minimally invasive technique which will be performed at the *Dagcentrum*
of the MUMC.

Botox injections
Each vial of BOTOX® (Botulinum ToxinType A) Purified NeurotoxinComplex,
(formulation no. 9060X), contains: 100 units (U) of Clostridium botulinum
toxinType A, 0.5 mg albumin (human), and 0.9 mg sodium chloride in a sterile,
vacuum-dried form without a preservative. One unit (U) corresponds to the
calculated median lethal intraperitoneal dose (LD50) in mice. The botulinum
toxin injections will also be administred at the *Dagcentrum* of the MUMC+. A
flexible or rigid cystoscope may be used for study treatment administration.
BOTOX® injections are administered as a minimally invasive technique which will
be performed at the *Dagcentrum* of the MUMC. The urologist will receive one 10
mL syringe pre-filled with 10 mL of study medication and one 1 mL syringe
pre-filled with saline from the independent reconstitutor. The 10 mL of study
drug will be administered as 20 injections each of 0.5 mL.


References
Bent AE, Gousse AE, Hendrix SL, Klutke CG, Monga AK, Yuen CK et al. Validation
of a two-item quantitative questionnaire for the triage of women with urinary
incontinence. Obstet Gynecol. 2005;106:767-73

ZonMw final report. The effects of involving a nurse practitioner in primary
care for adult patients with urinary incontinence.
Programme DoelmatigheidsOnderzoek 2003-2006 Subsidy round round 04, 2008

Faber E, Custers JWH, Berghmans LCM, van Dongen JJAM, Van Groeningen COM,
Grupping-Morel MHM et al. Landelijke Eerstelijns Samenwerkings Afspraak
Incontinentie voor urine. Huisarts Wetensch. 2007;:50:S9-S12

Ref Botox

Messelink EJ, Heesakkers JPFA, van Koeveringe GA, Koldewijn EL. Neuromodulatie
met een geïmplanteerd neurostimulatie systeem voor de
behandeling van patiënten met functiestoornissen van de lage urinewegen.
Dossier Nieuwe DBC Urologie Juni 2008

The following risks van occur during the study period

# urinary retention for which CIC is required

# increased PVR for which CIC is required in case of the following criteria:
**Patient has a PVR of >= 350 mL (regardless of symptoms), OR
**Patient has a PVR >= 200 mL and < 350 mL and the patient reports associated
symptoms i.e. voiding difficulties, sensation of bladder fullness that in the
investigator*s opinion require CIC

# urinary tract infection (UTI)
An adverse event of UTI will be recorded if both the following criteria are
fulfilled, regardless of patient symptoms:
**A positive urine culture result with a bacteriuria count of >105 CFU/mL
**Leukocyturia of >5/hpf

# hinder/oversensibility/pain at location of tined lead of permanent SNS
implant or infection/inflammation at those sites