1. 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

2. 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 16 th -18 th 2013

3. 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 16 th -18 th 2013

4. 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 16 th -18 th 2013

5. 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 Tincello DG Kuwait Feb 16 th -18 th 2013

6. Data PubMed  Neurogenic  146 papers since 1998  56 review articles  4 systematic reviews (one paediatric)  80 series/case reports/basic science papers  3 randomised trials  Idiopathic  65 papers since 2004  27 review articles  3 systematic reviews (one with no analysis!)  37 series/case reports/basic science papers  4 randomised trials (plus RELAX trial) Tincello DG Kuwait Feb 16 th -18 th 2013

7. Neurogenic: RCT data  Giannantoni J Urol 2004;172:240-3  Schurch J Urol 2005;174:196-200  Ehren Scand J Urol Nephrol 2007;41:335-40 Tincello DG Kuwait Feb 16 th -18 th 2013

8. Idiopathic: RCT data  Sahai 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 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 Tincello DG Kuwait Feb 16 th -18 th 2013

9. 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 o naBoNT-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 16 th -18 th 2013

10. 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 16 th -18 th 2013

11. 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 16 th -18 th 2013

12. Recent systematic reviews  Anger 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.” Tincello DG Kuwait Feb 16 th -18 th 2013

13. 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-A”  “onaBoNT-A much better studied than apoBoNT-A” Tincello DG Kuwait Feb 16 th -18 th 2013

14. The RELAX study… Tincello DG Kuwait Feb 16 th -18 th 2013

15. Eligibility criteria  Urodynamically proven (DOA) (within 2 years)  8 weeks treatment with any licensed anticholinergic  Refractory to treatment  (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 16 th -18 th 2013

16. Outcomes  Primary  Urinary voiding frequency/24 hours at 6 months  Minimum of two complete diary days accepted  Secondary  Diary data (6 weeks, 3 and 6 months)  Urge episodes, incontience episodes & Urgency severity score  Questionnaire data (3 and 6 months)  ICIQ-SF & IQoL  Physical measures  Complications  Need for additional treatments  Time to return of troublesome symptoms Tincello DG Kuwait Feb 16 th -18 th 2013

17. 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 women Tincello DG Kuwait Feb 16 th -18 th 2013

18. Six week visit = 118 missing visit = 2 lost to follow up = 1 withdrawn = 1 Three month visit = 102 missing visit = 15 lost to follow up = 1 (= 2)* withdrawn = 2 (= 3) Six month visit = 116 missing visit = 0 lost to follow up = 0 (= 2)* withdrawn = 1 (= 4)* Six week visit = 114 missing visit = 2 lost to follow up = 0 withdrawn = 2 Three month visit = 103 missing visit = 11 lost to follow up = 1 (= 1)* withdrawn = 1 (= 3)* Six month visit = 111 missing visit = 0 lost to follow up = 2 (= 3)* withdrawn = 1 (= 4)* Follow up Screened = 415 eligible = 283 ineligible = 132 Botulinum toxin randomised = 122 treated as allocated =122 not treated = 0 Placebo randomised = 118 treated as allocated =118 not treated = 0 Allocation & treatment Ineligibility (132) Failed entry screen = 3 Not DO alone 40 Exclusion criteria -=20 Unwilling to learn ISC =16 Not interested = 14 Failed symptom severity =30 (void threshold = 25) (leak threshold = 5) Unknown reason = 9 Losses before randomisation = 43 Self-withdrawal = 23 Clinical withdrawal = 7 Lost to follow up = 13 Results Tincello DG Kuwait Feb 16 th -18 th 2013

19. Groups at randomisation Treatment group (n=122) Placebo group (n=118) Age60.7 (50.8 to 67.8)58.2 (51.5 to 69.2) Body mass index > 30 (n, %)49 (40.2%)50 (43.5%) Caucasian118 (96.7%)109 (93.9%) Previous continence surgery (n, %)44 (36.1%)46 (39%) Voiding frequency/24hours10.3 (9.3 to 12.7)10.7 (9.3 to 13.3) Incontinence episodes/24hours6.2 (3.7 to 8.3)6.2 (3.0 to 8.7) Urgency episodes/24 hours8.0 (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) Continent (n, %)6 (4.9%)8 (6.8%) ICIQ score17.0 (14.0 to 19.0)16.0 (13.0 to 18.0) I-QoL score24.4 (11.4 to 38.6)23.3 (12.5 to 34.1)

20. Treatment group (n=100)* Placebo group (n=99)* p-value Primary outcome Urinary frequency /24 hr 8.33 (6.83 to 10.00) 9.67 (8.37 to11.67) 0.0001 * In data window Primary outcome Tincello DG Kuwait Feb 16 th -18 th 2013

21. Treatment group (n=100)* Placebo group (n=99)* p-value Secondary outcomes 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 Continent (n, %)31 (31)12 (12.1)0.002

22. Quality of life outcomes Treatment group (n=100)* Placebo group (n=99)* p-value ICIQ score 10.00 (4.00 to 15.00) 15.00 (11.00 to 18.00) <0.0001 I-QoL score 55.11 (23.30 to 78.41) 27.27 (18.18 to 46.59) <0.0001 Tincello DG Kuwait Feb 16 th -18 th 2013

23. Time to return of symptoms Tincello DG Kuwait Feb 16 th -18 th 2013

24. At six weeksAt six months Treatment Group (n=118) Placebo Group (n=113) Odds ratio (95% CI) Treatment Group (n=116) Placebo Group (n=110) Odds ratio (95% CI) Urinary tract infection 35 (30%)10 (9%) 4.34 (1.95 to 10.37) 36 (31%)12 (11%) 3.68 (1.72 to 8.25) Voiding difficulty 19 (16%)5 (4%) 4.1 (1.42 to 16.70) 10 (9%)1 (1%) 10.28 (1.41 to 450) ISC 16 (14%)5 (4%) 3.39 (1.13 to 12.20) 18 (16%)4 (4%) 4.87 (1.52 to 20.33) Use of additional treatment 8 (7%)22 (20%)0.30 (0.11 to 0.75) 16 (14%)35 (32%)0.34 (0.16 to 0.69) Adverse events Tincello DG Kuwait Feb 16 th -18 th 2013

25. Conclusions  RCT data confirms clinical effect on OAB/DO symptoms  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  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 Tincello DG Kuwait Feb 16 th -18 th 2013

26. So where are we now?  BoNT-A is an effective treatment  Significant risk of voiding dysfunction  More effective than oral medication  Some questions remain  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? Probably 100 units Tincello DG Kuwait Feb 16 th -18 th 2013