Botulinum toxin-A for overactive bladder and detrusor overactivity Douglas Tincello Professor of Urogynaecology Prolapse & Incontinence Group, University of Leicester, UK Charity funding Moulton Charitable Trust & Wellbeing of Women Disclosures Drugs/placebo provided by Allergan Conduct/analysis independent of Allergan Other disclosures Grants and consultancies from Ethicon, Pfizer Funding and disclosures Tincello DG Kuwait Feb 16 th -18 th 2013
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Botulinum toxin-A for overactive bladder and detrusor overactivity Douglas Tincello Professor of Urogynaecology Prolapse & Incontinence Group, University.
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Botulinum toxin-A for overactive bladder and detrusor overactivity
Douglas Tincello
Professor of Urogynaecology Prolapse & Incontinence Group, University of Leicester, UK
Charity funding Moulton Charitable Trust & Wellbeing of Women
Disclosures Drugs/placebo provided by Allergan Conduct/analysis independent of Allergan
Other disclosures Grants and consultancies from Ethicon, Pfizer
Funding and disclosures
Tincello DG Kuwait Feb 16th -18th 2013
Background Botulinum toxin (BoNT-A)
Neurotoxin from Cl botulinum Neurogenic detrusor overactivity
Grade A evidence now exists Profound improvements in leakage, urgency,
urodynamics Idiopathic detrusor overactivity
Only 5 RCTs Most underpowered: premature end; small
groups International consensus for more data
(Apostolides 2009)Tincello DG Kuwait Feb 16th -18th 2013
Mode of action Neurotoxin from Clostridium botulinum
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
Thought to also affect sensory afferent fibres
Tincello DG Kuwait Feb 16th -18th 2013
Preparations BOTOX®
Manufactured by Allergan 100 IU per vial Most published studies use BOTOX ® “onabotulinum toxin A” (onaBoNT-A)
Dysport® Manufactured by Ipsen 500 IU per vial “apobotulinum toxin A” (apoBoNT-A)
Units are not equivalent
Tincello DG Kuwait Feb 16th -18th 2013
Evidence…and extrapolation
Botulinum toxin first used in neurogenic DO Reflex voiding and incontinence main issue Voiding function not an issue (catheters)
Care when extrapolating to idiopathic DO frequency and urgency main symptoms likely to be large placebo effect voiding problems will be important
4/52 144 ml, CI 101 to 216 reduction in frequency, leaks, urgency @12/52 33% required ISC
Brubaker 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% UTITincello DG Kuwait Feb 16th -18th 2013
Idiopathic: RCT data Flynn et al J Urol 2009;181:2608-15
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
(n= 44-57) 1˚ outcome: change in UUI episodes @ 12
weeks All doses better than placebo: No difference in primary analysis “pooled effects analysis”
50u worse than the rest; no dose response
Tincello DG Kuwait Feb 16th -18th 2013
European Consensus statement
Apostolidis Eur Urol 2009;55:100-120 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).
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).
Existing evidence is inconclusive for recommendations in neurogenic detrusor-sphincter dyssynergia, bladder pain syndrome, prostate diseases, and pelvic-floor disorders Tincello DG Kuwait Feb 16th -18th 2013
In the UK…NICE Guidelines “… 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…”
“… botulinum toxin in the management of detrusor overactivity of idiopathic aetiology deserves further evaluation…”Tincello DG Kuwait Feb 16th -18th 2013
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.”
Tincello DG Kuwait Feb 16th -18th 2013
Systematic reviews Mangera Eur Urol 2011; doi:
10.1016/j.eururo.2011.07.001 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-
(PGI-I) score of “a little better” or worse Verbal response of acceptable improvement Treatment stopped because of side effects 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)
Tincello DG Kuwait Feb 16th -18th 2013
Outcomes Primary
Urinary voiding frequency/24 hours at 6 months Minimum of two complete diary days accepted
Questionnaire data (3 and 6 months) ICIQ-SF & IQoL
Physical measures Complications Need for additional treatments Time to return of troublesome symptomsTincello DG Kuwait Feb 16th -18th 2013
Methods Randomised 1:1 to B0NT-A 200u or placebo Flexible or rigid cystoscopy Local, spinal or general anaesthetic
200 units; 20 injection sites @1ml per site Trigone sparing
Study power Solifenacin vs placebo
(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
womenTincello DG Kuwait Feb 16th -18th 2013
Six week visit = 118missing visit = 2 lost to follow up = 1withdrawn = 1
Three month visit = 102missing visit = 15lost to follow up = 1 (= 2)*withdrawn = 2 (= 3)
Six month visit = 116missing visit = 0 lost to follow up = 0 (= 2)*withdrawn = 1 (= 4)*
Six week visit = 114missing visit = 2lost to follow up = 0withdrawn = 2
Three month visit = 103missing visit = 11lost to follow up = 1 (= 1)*withdrawn = 1 (= 3)*
Six month visit = 111missing visit = 0lost to follow up = 2 (= 3)*withdrawn = 1 (= 4)*