botulinum toxin-a for overactive bladder and detrusor overactivity douglas tincello professor of...

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


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


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


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)


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


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% 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


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

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.”


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”


The RELAX study…

ApprovalMay 2005

1st patientJuly 2006

Additional centres

Jan 2008

Additional 2 centresJun 2009

Last patient

Feb 2010

Sahai J Urol 200734 pts

Brubaker J Urol 200843 pts

Flynn J Urol 200915 pts

Dm’ski J Urol 2010

313 pts


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)


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 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)*

Follow up

Screened = 415 eligible = 283 ineligible = 132

Botulinum toxin randomised = 122treated as allocated = 122not treated = 0

Placeborandomised = 118treated as allocated = 118not treated = 0

Allocation &

treatment

Ineligibility (132)Failed entry screen = 3Not DO alone 40Exclusion criteria -= 20Unwilling to learn ISC =

16Not interested = 14Failed symptom severity =

30(void threshold = 25)(leak threshold = 5)

Unknown reason = 9

Losses before randomisation = 43Self-withdrawal = 23Clinical withdrawal = 7Lost to follow up = 13

Results


Groups at randomisationTreatment group

(n=122)

Placebo group

(n=118)

Age 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%)

Voiding frequency/24hours 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)

Continent (n, %) 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)

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

Baseline 6 weeks 3 months 6 months0

2

4

6

8

10

12 Voiding frequency

BoNT-A



Treatment group

(n=100)*

Placebo group

(n=99)*

p-value

Secondary outcomes

Urgency episode/24 hr3.83

(1.17 to 6.67)6.33

(4.00 to 8.67)<0.0001

Urgency severity score1.50

(1.00 to 2.00)1.90

(1.50 to 2.30)0.0006

Leakage episode/24 hr1.67

(0.00 to 5.33)6.00

(1.33 to 8.33)<0.0001

Continent (n, %) 31 (31) 12 (12.1) 0.002


1

2

3

4

5

6

7

8

9

Urgency episodes

BoNT-A

Placebo


1

2

3

4

5

6

7

Leakage episodes

BoNT-A

Placebo


5

10

15

20

25

30

35

40

45 Continent (%)BoNT-A

Placebo

Quality of life outcomesTreatment group

(n=100)*

Placebo group

(n=99)*

p-value

ICIQ score10.00

(4.00 to 15.00)15.00

(11.00 to 18.00) <0.0001

I-QoL score55.11

(23.30 to 78.41)27.27

(18.18 to 46.59) <0.0001


2

4

6

8

10

12

14

16

18

20 ICIQ score

BoNT-A


10

20

30

40

50

60

70

80

90

100

IQoL score

BoNT-A


Time to return of symptoms

0.0

00

.25

0.5

00

.75

1.0

0C

umu

latr

ive

Pro

bab

ility

120 70 65 55 54 50 42BoNT-A118 16 14 12 11 9 9Placebo

Number at risk

0 1 2 3 4 5 6Time to Recurrence of Symptoms (months)

PlaceboBoNT-A


At six weeks At 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


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 monthsTincello DG Kuwait Feb 16th -18th 2013

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


botulinum toxin-a for overactive bladder and detrusor overactivity douglas tincello professor of...

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