Transcript Factors Influencing Participation In Urogynaecological

Botulinum toxin-A for overactive
bladder and detrusor overactivity
Douglas Tincello
Professor of Urogynaecology
Prolapse & Incontinence Group, University of Leicester, UK
Funding and disclosures
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Charity funding
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Disclosures
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Moulton Charitable Trust & Wellbeing of Women
Drugs/placebo provided by Allergan
Conduct/analysis independent of Allergan
Other disclosures
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Grants and consultancies from Ethicon, Pfizer
Tincello DG Kuwait Feb 16th -18th 2013
Background
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Botulinum toxin (BoNT-A)
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Neurogenic detrusor overactivity
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Neurotoxin from Cl botulinum
Grade A evidence now exists
Profound improvements in leakage, urgency, urodynamics
Idiopathic detrusor overactivity
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Only 5 RCTs
 Most underpowered: premature end; small groups
International consensus for more data
 (Apostolides 2009)
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Mode of action
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Neurotoxin from Clostridium botulinum
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Inhibits presynaptic release of acetylcholine from nerves in
motor end plate (SNP-25)
Muscle paralysis of up to 9 months’ duration
Clinical recovery due to new growth of synaptic fibres to
new end plates
Large molecule does not diffuse
Local effect
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Thought to also affect sensory afferent fibres
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Preparations
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BOTOX®
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Dysport®
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Manufactured by Allergan
100 IU per vial
Most published studies use BOTOX ®
“onabotulinum toxin A” (onaBoNT-A)
Manufactured by Ipsen
500 IU per vial
“apobotulinum toxin A” (apoBoNT-A)
Units are not equivalent
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Evidence…and extrapolation
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Botulinum toxin first used in neurogenic DO
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Reflex voiding and incontinence main issue
Voiding function not an issue (catheters)
Care when extrapolating to idiopathic DO
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frequency and urgency main symptoms
likely to be large placebo effect
voiding problems will be important
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Data PubMed
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Neurogenic
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146 papers since 1998
 56 review articles
 4 systematic reviews (one paediatric)
 80 series/case reports/basic science papers
 3 randomised trials
Idiopathic
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65 papers since 2004
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27 review articles
3 systematic reviews (one with no analysis!)
37 series/case reports/basic science papers
4 randomised trials (plus RELAX trial)
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Neurogenic: RCT data
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Giannantoni J Urol 2004;172:240-3
Schurch J Urol 2005;174:196-200
Ehren Scand J Urol Nephrol 2007;41:335-40
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Idiopathic: RCT data
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Sahai
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J Urol 2007;177:2231-6
18 onaBoNT-A; 16 placebo
1º outcome change in cytometric capacity @ 4/52
144 ml, CI 101 to 216
reduction in frequency, leaks, urgency @12/52
33% required ISC
Brubaker
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J Urol 2008;180:217-22
RCT randomised 2:1 onaBoNT-A :placebo
“time to failure”
stopped by DMEC after 43 women
“benefit” in 65% active; 20% placebo group (373 vs 62 days)
43% retention (USS >200ml @ 4/52) & 75% UTI
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Idiopathic: RCT data
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Flynn et al J Urol 2009;181:2608-15
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15 patients 200iu/300iu onaBoNT-A vs placebo
1˚ outcome: symptoms at 6 weeks
Dmochowski et al J Urol 2010;184:2416-22
 Placebo or 50, 100, 150, 200, 300 iu onaBoNT-A
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(n= 44-57)
1˚ outcome: change in UUI episodes @ 12 weeks
All doses better than placebo:
No difference in primary analysis
“pooled effects analysis”
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50u worse than the rest; no dose response
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European Consensus statement
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Apostolidis Eur Urol 2009;55:100-120
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The use of botulinum neurotoxin type A is recommended in the
treatment of intractable symptoms of neurogenic detrusor
overactivity or idiopathic detrusor overactivity (grade A).
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Caution is recommended in IDO because the risk of voiding
difficulty and duration of effect have not yet been accurately
evaluated. Repeated treatment can be recommended in NDO
(grade B).
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Existing evidence is inconclusive for recommendations in
neurogenic detrusor-sphincter dyssynergia, bladder pain
syndrome, prostate diseases, and pelvic-floor disorders
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In the UK…NICE Guidelines
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“… only in women who have not responded to
conservative treatments, and who are willing and able
to self-catheterise. Women should be informed about
the lack of long-term data. There should be special
arrangements for audit or research. The use of
botulinum toxin A for this indication is outside the UK
marketing authorisation for the product…”
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“… botulinum toxin in the management of detrusor
overactivity of idiopathic aetiology deserves further
evaluation…”
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Recent systematic reviews
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Anger
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J Urol 2010;183:2258-64
23 studies included; IDO and OAB; Only 3 RCTs included
“…results in a significant improvement in OAB symptoms
and QOL among patients who experience treatment failure
or do not tolerate medical therapy”
“.. nearly 9-fold increase in odds of retention”
“..study limited by…lack of RCTs…(with) extreme
heterogeneity in…outcome measures”
“… several questions remain concerning the optimal
administration of BoNT-A for the patient with OAB.
Clearly more level I data from randomized controlled trials
are needed to guide management.”
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Systematic reviews
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Mangera Eur Urol 2011; doi: 10.1016/j.eururo.2011.07.001
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RCTs and non-RCT of level II evidence
No meta-analysis done
IDO: 4 RCTs, 2 non-RCTs
“High level data support the use of onaBoNT-A”
“onaBoNT-A much better studied than apoBoNT-A”
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The RELAX study…
Approval
May 2005
Additional
centres
Jan 2008
1st patient
July 2006
Sahai
J Urol
2007
34 pts
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Additional
2 centres
Jun 2009
Brubaker
J Urol
2008
43 pts
Flynn
J Urol
2009
15 pts
Last
patient
Feb 2010
Dm’ski
J Urol
2010
313 pts
Eligibility criteria
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Urodynamically proven (DOA) (within 2 years)
8 weeks treatment with any licensed anticholinergic
Refractory to treatment
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(PGI-I) score of “a little better” or worse
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Verbal response of acceptable improvement
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Treatment stopped because of side effects
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Previous treatments ineffective
At least 8 voids per 24 hours
At least 2 urgency episodes per 24 hours
(defined as “moderate” or higher on USS)
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Outcomes
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Primary
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Urinary voiding frequency/24 hours at 6 months
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Minimum of two complete diary days accepted
Secondary
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Diary data (6 weeks, 3 and 6 months)
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Questionnaire data (3 and 6 months)
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Urge episodes, incontience episodes & Urgency severity score
ICIQ-SF & IQoL
Physical measures
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Complications
Need for additional treatments
Time to return of troublesome symptoms
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Methods
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Randomised 1:1 to B0NT-A 200u or placebo
Flexible or rigid cystoscopy
Local, spinal or general anaesthetic
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200 units; 20 injection sites @1ml per site
Trigone sparing
Study power
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Solifenacin vs placebo
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(Chapple et al BJU Int 2004;93:303-10)
Voiding frequency 9.7±3.5 vs 10.99±4.2
Effect size 1.29 voids/24 hours
220 patients in total; 10% drop out = 240 women
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Screened =
415
eligible = 283
ineligible = 132
Results
Losses before randomisation = 43
Self-withdrawal =
23
Clinical withdrawal = 7
Lost to follow up = 13
Allocation
&
treatment
Botulinum toxin
Follow up
Placebo
122
randomised =
treated as allocated = 122
not treated =
0
Six week visit =
missing visit =
lost to follow up =
withdrawn =
Three month visit =
missing visit =
lost to follow up =
withdrawn =
118
2
1
1
102
15
1 (= 2)*
2 (= 3)
116
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Ineligibility (132)
Failed entry screen =
Not DO alone
Exclusion criteria -=
Unwilling to learn ISC =
Not interested =
Failed symptom severity =
(void threshold = 25)
(leak threshold = 5)
Unknown reason =
Six month visit =
missing visit =
0
lost to follow up =
0 (= 2)*
Kuwait withdrawn
Feb 16th =-18th 2013
1 (= 4)*
118
randomised =
treated as allocated = 118
not treated =
0
Six week visit =
missing visit =
lost to follow up =
withdrawn =
114
2
0
2
Three month visit =
missing visit =
lost to follow up =
withdrawn =
103
Six month visit =
missing visit =
lost to follow up =
withdrawn =
111
11
1 (= 1)*
1 (= 3)*
0
2 (= 3)*
1 (= 4)*
3
40
20
16
14
30
9
Groups at randomisation
Treatment group
Placebo group
(n=122)
(n=118)
60.7 (50.8 to 67.8)
58.2 (51.5 to 69.2)
Body mass index > 30 (n, %)
49 (40.2%)
50 (43.5%)
Caucasian
118 (96.7%)
109 (93.9%)
Previous continence surgery (n, %)
44 (36.1%)
46 (39%)
10.3 (9.3 to 12.7)
10.7 (9.3 to 13.3)
Incontinence episodes/24hours
6.2 (3.7 to 8.3)
6.2 (3.0 to 8.7)
Urgency episodes/24 hours
8.0 (5.7 to 10.3)
7.7 (6.0 to 9.7)
Urgency severity score (IUSS)
2.1 (1.7 to 2.4)
2.1 (1.7 to 2.3)
6 (4.9%)
8 (6.8%)
ICIQ score
17.0 (14.0 to 19.0)
16.0 (13.0 to 18.0)
I-QoL score
24.4 (11.4 to 38.6)
23.3 (12.5 to 34.1)
Age
Voiding frequency/24hours
Continent (n, %)
Primary outcome
Treatment group
(n=100)*
Placebo group
(n=99)*
p-value
8.33
9.67
0.0001
(6.83 to 10.00)
(8.37 to11.67)
Primary outcome
Urinary frequency /24 hr
* In data window
Voiding frequency
12
10
8
6
BoNT-A
Placebo
4
2
0
Baseline
6 weeks
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3 months
6 months
Treatment group
Placebo group
p-value
(n=100)*
(n=99)*
Urgency episode/24 hr
3.83
(1.17 to 6.67)
6.33
(4.00 to 8.67)
<0.0001
Urgency severity score
1.50
(1.00 to 2.00)
1.90
(1.50 to 2.30)
0.0006
Leakage episode/24 hr
1.67
(0.00 to 5.33)
6.00
(1.33 to 8.33)
<0.0001
31 (31)
12 (12.1)
Secondary outcomes
Continent (n, %)
9
8
Urgency episodes
7
6
7
40
BoNT-A
5
35
Placebo
4
4
3
2
1
0
30
25
20
15
2
BoNT-A
1
Placebo
0
10
BoNT-A
5
Placebo
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6 weeks
months Feb
6 months
Baseline
Baseline
45
6
5
3
Leakage episodes
0.002
Continent (%)
0
6 weeks
3 months
6 months
Baseline
6 weeks
3 months
6 months
Treatment group
Placebo group
(n=100)*
(n=99)*
Quality of life outcomes
p-value
ICIQ score
10.00
(4.00 to 15.00)
15.00
<0.0001
(11.00 to 18.00)
I-QoL score
55.11
(23.30 to 78.41)
27.27
<0.0001
(18.18 to 46.59)
100
ICIQ score
20
18
80
16
70
14
12
60
10
50
8
40
6
30
4
2
IQoL score
90
BoNT-A
20
Placebo
10
0
0
Baseline
6 weeks
3 months
6 months
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BoNT-A
Placebo
Baseline
6 weeks
3 months
6 months
0.25
0.50
0.75
1.00
Time to return of symptoms
0.00
Placebo
BoNT-A
0
Number at risk
Placebo 118
BoNT-A 120
1
2
3
4
5
Time to Recurrence of Symptoms (months)
6
16
70
9
42
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14
65
12
55
11
54
9
50
Adverse events
At six weeks
Treatment
Group
Placebo
Group
(n=118)
(n=113)
Urinary tract
infection
35 (30%)
10 (9%)
Voiding
difficulty
19 (16%)
ISC
Use of
additional
treatment
At six months
Odds ratio
Treatment
Group
Placebo
Group
(n=116)
(n=110)
4.34
(1.95 to 10.37)
36 (31%)
12 (11%)
3.68
(1.72 to 8.25)
5 (4%)
4.1
(1.42 to 16.70)
10 (9%)
1 (1%)
10.28
(1.41 to 450)
16 (14%)
5 (4%)
3.39
(1.13 to 12.20)
18 (16%)
4 (4%)
4.87
(1.52 to 20.33)
8 (7%)
22 (20%)
0.30
(0.11 to 0.75)
16 (14%)
35 (32%)
0.34
(0.16 to 0.69)
(95% CI)
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Odds ratio
(95% CI)
Conclusions
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RCT data confirms clinical effect on OAB/DO symptoms
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Mean reduction in voiding 25%
Reduction urgency episodes/leakage episodes over 50%
Continence achieved in a third of women at six months
Quality of life improvement less than symptom improvement
Robust safety data
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Few adverse events
Urinary tract infection in a third of women (30%)
Voiding difficulty requiring ISC in 1 in 6 women (16%) at six months
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So where are we now?
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BoNT-A is an effective treatment
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Significant risk of voiding dysfunction
More effective than oral medication
Some questions remain
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Equally effective in OAB without confirmation of DO?
Is it safe/ethical/valid assumption that OAB = DO ???
What is the optimum dose?
Is BoNT-A truly cost-effective?
What about dosing frequency?
Tolerance?
Life long therapy?
Tincello DG Kuwait Feb 16th -18th 2013