bonta for oab - comtecmed 4... · 2018-07-17 · bonta for oab noam d. kitrey, md, fecsm dept. of...

BoNTA for OAB

Noam D. Kitrey, MD, FECSM

Dept. of urology, Sheba medical center, ISRAEL

Chairman of the EAU UroTrauma guidelines panel

Financial and Other Disclosures

• Off-label use of drugs, devices, or other agents: None

• Data from IRB-approved human research is not presented

• I have no financial interests or relationships to disclose

1897 First isolation of

Botulinum toxin by van Ermengem

1960 First clinical use

(Dr. Alan Scott for strabismus)

2011 FDA approval - OnaBoNTA for

NDO

2013 FDA approval - OnaBoNTA for

refractory iOAB

2013 Nobel prize for Prof. James Rothman (Yale university) – BoNT mechanism of action

2015 AUA/SUFU guidelines:

OnaBoNTA (100u) as third-line treatment for refractory

OAB (standard, GrB)

1999 BTX-A into detrusor of NDO first

presented ICS meeting (Stöhrer and Schurch) 21 patients with SCI

onabotulinumtoxinA (Botox)

and

abobotulinumtoxinA (Dysport)

• different formulations

• cannot be considered generic equivalents due to different isolation, manufacturing, and stabilisation processes

BoNTA

SNARE

proteins

Synaptobrevin

(VAMP)

SNAP-25

Syntaxin

SYNAPTIC CLEFT

PRE-SYNAPSE

Receptor requires

SNARE complex for membrane

expression

2. Vesicle and terminal

membranes fuse

3a. Receptors delivered to membrane

insertion sites

3b. Neurotransmitter released

4. Mediators (e.g. SP) bind to

inserted receptors

1. SNARE proteins form

a complex

Adapted from Arnon et al. JAMA. 2001;285:1059–70.

Mechanism of action

Dmochowski et al. 2010 J Urol

• phase 2, multicenter, randomized, double-blind study

• 313 patients with idiopathic overactive bladder and urinary

urgency incontinence

• 50, 100, 150, 200 or 300 U intradetrusor onaboNTA or placebo


• A dose of 100 U appropriately balances

– symptom benefits with

– post-void residual urine volume

Week 2 Week 6 Week 12

Mea

n c

han

ge

fro

m b

asel

ine

(ep

iso

des

/day

) EMBARK study (phase III)

EMBARK Study Nitti VW et al. J Urol 2013 189 6):2186-93

Baseline values

Placebo: 5.39/day

BOTOX® 100 U: 5.49/day

0

–1.22

–0.95

–2.85** –3.11**

–2.80**

Placebo (n = 548)

BOTOX® 100 U (n = 557)

At week 12, BOTOX® led to a 51% reduction from baseline in UI episodes versus 18% with placebo (p < 0.001)

–1

–2

–3

–4

**p < 0.001 vs placebo.

–1.35 –1.40 –1.23

–2.89**

–3.56** –3.30**

-5

-4

-3

-2

-1

0

Week 2 Week 6 Week 12

Mea

n c

han

ge

fro

m b

asel

ine

(ep

iso

des

/day

) EMBARK study (phase III)


At week 12, BOTOX® led to a 37% reduction from baseline in daily urgency episodes versus 15% with placebo (p < 0.001)

Baseline values

Placebo: 8.31/day

BOTOX® 100 U: 8.82/day

**p < 0.001 vs placebo.

Placebo (n = 548)

BOTOX® 100 U (n = 557)

EMBARK study (phase III)


76%

Patients with 50% or 75% decrease in urinary incontinence

31.0 17.7 60.5 46.0 0

10

20

30

40

50

60

70 75% reduction

Patients with 100% decrease in urinary incontinence (‘DRY’)*

8.4 27.1 0

10

20

30

Column1

Pat

ien

ts (

%)

Pat

ien

ts (

%)

50% reduction

Placebo

(n = 548)

BOTOX® 100 U

(n = 557)

BOTOX®

100 U

(n = 557)

Placebo

(n = 548)

Placebo

(n = 548)

BOTOX®

100 U

(n = 557)

EMBARK study (phase III)


The median duration of response after BOTOX® treatment,

based on patient request for re-treatment,

was 166 days (~6 months)

Platinum Priority – IncontinenceEditorial by Stephan Madersbacher on pp. 257–259 of this issue

Onabotul inum toxinA 100 U Sign if icant ly Im proves Al l Idiopathic

Overact ive Bladder Sym ptom s and Qual i t y of Li fe in Pat ients w ith

Overact ive Bladder and Ur inary Incont inence: A Random ised,

Double-Bl ind, Placebo-Cont rol led Tr ial

Christopher Chapple a,*, Karl-Dietr ich Sievert b, Scott MacDiarmid c, Vik Khullar d,

Piotr Radziszewski e, Christopher Nardo f, Catherine Thompson g, Jihao Zhou f,

Cornelia Haag-Molkenteller f

a Royal Hallamshire Hospital, Sheffield, UK; b University of Tuebingen, Tuebingen, Germany; c Alliance Urology Specialists, Greensboro, NC, USA; d Imperial

College, London, UK; e Department of Urology, Medical University of Warsaw, Warsaw, Poland; f Allergan, Inc., Irvine, CA, USA; g Allergan Ltd., Marlow, UK

EU RO PEA N U RO L O G Y 6 4 ( 2 0 1 3 ) 2 4 9 – 2 5 6

av a i l ab l e a t w w w .sc i en ced i r ec t . co m

j o u r n a l h o m ep ag e: w w w .eu r o p ean u r o l o g y .co m

Art icle info

Art icle history:

Accepted April 1, 2013

Published online ahead of

pr int on Apri l 10, 2013

Keywords:

Botulinum toxin

OnabotulinumtoxinA

Overact ive bladder

Urinary incont inence

Abst ract

Background: Overact ive bladder (OAB) syndrome w ith urinary incont inence (UI) is prevalent

in the populat ion and impairs health-related quality of l i fe (HRQOL).

Object ive: To assess the impact on efficacy, safety, and HRQOL of onabotulinumtoxinA

(BOTOX1 , Allergan, Inc.) treatment in pat ients w ith OAB w ith UI.

Design, sett ing, and par t i cipants: Thispivotal,mult icentre,double-blind,randomised,placebo-

controlled, phase 3 study enrolled patients w ith idiopathic OAB w ith 3 urgency UI episodes

over 3 d and 8 micturit ions per day w ho w ere inadequately managed by anticholinergics.

Intervent ion: OnabotulinumtoxinA at a 100 U dose (n = 277) or placebo (n = 271), adminis-

tered as 20 intradet rusor inject ions of 0.5 ml.

Outcome measurements and stat ist ical analysis: Co–primary end points w ere change from

baseline in the number of UI episodes per day and proport ion of pat ients reporting posit ive

treatment response on the treatment benefi t scale (TBS) at w eek 12. Addit ional end points

included other OAB symptoms (episodes of urinary urgency incontinence, micturit ion, urgency,

and nocturia) and HRQOL (Incontinence Quality of Life [I-QOL], King’s Health Quest ionnaire

[KHQ]).Safety assessments included adverse events (AEs),postvoid residual (PVR) urine volume,

and init iat ion of clean intermittent catheterisat ion (CIC).

Results and limitat ions: Onabotulinumtox inA signifi cant ly decreased UI episodes per day at

w eek 12 ( 2.95 for onabotulinumtoxinA versus 1.03 for placebo; p < 0.001). Reduct ions

from baseline in all other OAB symptoms w ere also significant ly greater follow ing onabotu-

l inumtoxinA compared w ith placebo ( p 0.01). Pat ients perceived a significant improvement

in their condit ion, as measured by patients w ith a posit ive treatment response on the TBS

(62.8% for onabot ulinumtoxinA versus 26.8% for placebo; p < 0.001). Clinically meaningful

improvement s from baseli ne in all I-QOL and KHQ mult i-i tem domains ( p < 0.001 versus

placebo) indicated posit ive impact on HRQOL. AEs w ere mainly local ised to the urinary tract.

Mean PVR w as higher in the onabotul inumtoxinA group (46.9 ml versus 10.1 ml at w eek 2;

p < 0.001); 6.9%of onabotulinumtoxinA patients versus 0.7%of placebo patients init iated CIC.

Conclusions: OnabotulinumtoxinA 100 U w as w el l tolerated and dem onstrated signifi cant

and clinically relevant improvement s in all OAB symptoms, pat ient- reported benefi t, and

HRQOL in pat ients inadequat ely managed by anticholinergi cs.

Tr ial registrat ion: ClinicalTrials.gov: NCT00910520.

# 2013 European Associat ion of Urology. Published by Elsevier B.V. All rights reserved.

* Correspondi ng author. Royal Hallamshire Hospital, Room H26, H-Floor, Glossop Road, Sheffield,

GB-S10 2JF, UK. Tel. +44 0 114 271 3048; Fax: +44 0 114 279 7841.

E-mail address: [email protected] (C. Chapple).

0302-2838/$ – see back matter # 2013 European Associat ion of Urology. Published by Elsevier B.V. All rights reserved.

ht tp://dx.doi .org/10.1016/j.eururo.2 013.04.001

Chapple C et al. Eur Urol 2013

Platinum Priority – Female Urology – IncontinenceEditorial by Bertil F.M. Blok on pp. 74–75 of this issue

Tw o-Year Outcom es of Sacral Neurom odulat ion Versus

Onabotul inum toxinA for Refractory Urgency Ur inary

Incont inence: A Random ized Tr ial

Cindy L. Amundsen a,*, Yuko M. Komesu b, Christopher Chermansky c, W. Thomas Gregory d,

Deborah L. Myerse, Emily F. Honeycutt f, Sandip P. Vasavada g, John N. Nguyen h,

Tracey S. Wilson i, Heidi S. Harvie j, Dennis Wallace f,

for the Pelvic Floor Disorders Network

a Department of Obstetrics and Gynecology, Duke University, Durham, North Carolina, USA; b Department of Obstetrics and Gynecology, University of New

Mexico, Albuquerque, New Mexico, USA; c Department of Urology, University of Pittsburgh, Pennsylvania, USA; d Department of Obstetrics and Gynecology,

Oregon Health & Science University, Portland, Oregon, USA; e Department of Obstetrics and Gynecology, Brown University, Providence, Rhode Island, USA;f Social, Statistical, and Environmental Sciences, RTI International, Research Triangle Park, North Carolina, USA; g Department of Urology, Cleveland Clinic,

Cleveland, Ohio, USA; h Department of Obstetrics and Gynecology, Kaiser Permanente San Diego, California, USA; i Department of Urology, University of

Alabama at Birmingham, Birmingham, Alabama, USA; j Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, Pennsylvania, USA

EU RO PEA N U RO L O GY 7 4 ( 2 0 1 8 ) 6 6 – 7 3

av a i l a b l e a t w w w .sc i en ced i r ec t . co m

j o u r n a l h o m ep ag e : w w w .eu r o p ean u r o l o g y .co m

Ar t icle info

Art icle history:

Accepted February 12, 2018

Associate Editor :

J.-N. Cornu

Stat ist ical Editor :

Andrew Vickers

Keywords:

Sacral neuromodulat ion

OnbotulinumtoxinA

InterStim

Urgency urinary incontinence

Botox

Abst ract

Background: Urgency urinary incont inence (UUI) is a chronic condit ion for w hich sacral

neuromodulat ion (SNM) (InterSt im/Medtronic) and onabotulinumtoxinA (BTX) (BotoxA/

Allergan) are ut i l ized. These therapies have not been compared over extended t ime.

Object ive: To compare UUI episodes (UUIE) over 24 mo follow ing SNM or BTX.

Design, sett ing, and par t icipants: Mult icenter, open-label, randomized, extension trial

(February 2012–July 2016) at nine US medical centers involving 386 w omen w ith 6

UUIE over 3 d inadequately managed by medicat ions. Part icipants w ere clinical re-

sponders to treatment : 50%reduct ion in UUIEs after SNM placement or 1 mo post BTX.

Intervent ion: SNM (n = 194) versus 200 U BTX (n = 192). SNM reprogrammings occurred

throughout the 24 mo. After 6 mo, tw o addit ional BTX inject ions w ere allow ed.

Outcome measurements and stat ist ical analysis: Primary outcome: change in mean

daily UUIE over 24 mo. Secondary outcomes: no UUIE, 75%and 50%UUIE reduct ion;

Overact ive Bladder Quest ionnaire Short Form; Urinary Distress Inventory short form;

Incont inence Impact Quest ionnaire; Pat ient Global Impression of Improvement; Over-

act ive Bladder Sat isfact ion of Treatment Quest ionnaire; and adverse events (AEs).

Primary analysis used a linear mixed model.

Results and limitat ions: Outcome data w ere available for 260/298 (87%) clinical re-

sponders. No difference in decreased mean UUIE was found over 24 mo ( 3.88 vs 3.50

episodes/d,95% confidence interval [CI] = 0.14–0.89; p = 0.15), w ith no differences in

UUI resolut ion, 75%or 50%UUIEreduct ion. BTX group maintained higher sat isfact ion

(mean difference = 9.14, 95%CI = 14.38– 3.90; p < 0.001), t reatment endorsement

(mean difference = 12.16, 95% CI = 17.7– 6.63; p < 0.001) through 24 mo. Other

secondary measures did not differ. Recurrent urinary tract infect ions (UTIs) w ere higher

* Corresponding author. 5324 McFarland Drive, Suite 310, Durham , North Carolina 27707, USA.

Tel. +1 919 401 1006; Fax: +1 919 401 1033.

E-mail address: [email protected] (C.L. Amundsen).

ht tps://doi.org/10.1016/j.eururo.2018.02.011

0302-2838/© 2018 European Associat ion of Urology. Published by Elsevier B.V. All r ights reserved.

• 56 Adult OAB studies

• 16 Level 1+2 studies (1380 pts.)

• 40 level 3 studies (2673 pts.)

Allergan data

93.5% Not on CIC

Did not initiate CIC

Used CIC for ≤ 6 weeks

Used CIC for > 6 and ≤ 12 weeks



Used CIC for > 24 weeks

2.5%

1.3%

0.4% 1.4%

0.9% 6.5% CIC = 6.5% (36/552 patients)

Patients requiring CIC at any point during treatment cycle

• Greater symptomatic and urodynamic improvements with 200

IU compared with 100 IU.

• At the cost of a greater ISC frequency that was 24–31% for 200

IU compared with 7–10% for 100 IU ( p < 0.001)

• prospective, multicenter, long-term (3.5-year) study

• 131 centers

• 839 pts entered – 430 completed extension study

Nitti at al. 2016 J Urol

• Durable and meaningful improvements in urinary symptoms and QOL

• The median duration of effect was 7.6 months

• The rate of de novo catheterization

– after the first treatment was 4.0%

– 0.6% to 1.7% after subsequent treatments


Carlson et al. 2017 Can J Urol

• “Real world” study

• 81 patients with repeated injections

• No difference between first and repeat injections in

outcomes and safety

• ~50% became dry

• Significant improvements in PRO

Carlson et al. 2017 Can J Urol

• ~10% remain on anti-cholinergics

• Some use them to “bridge the gap”

• 16.7% of SIC in de-novo group

• Double-blind BoNTA Vs. Solifenacin

• 472 screened but only 118+113 completed 6m

Visco et al. N Eng J Med 2012

Visco et al. N Eng J Med 2012

Amundsen CL et al. 2016 JAMA

• ROSETTA trial

• Multicenter, open-label, randomized trial

• 2012-2015 at 9 US medical centers

• 381 women with refractory urgency urinary

incontinence

• 200u of OnaBotNT-A Vs. SMN

• 6 months follow-up


• OnaBoNTA provided a small but statistically significant greater

reduction in episodes of UUI than sacral neuromodulation

• No significant difference for quality of life or for the subscales

for treatment preference, convenience, or adverse effects

• OnaBoNTA increased the risk of urinary tract infections and

need for self-catheterizations

Amundsen CL et al. 2018 Euro Urol

• planned 24-mo extension trial compared efficacy,

AEs, and satisfaction with therapy in women

randomized to either SNM or BTX 200 units

• Cross-over permissible

• BotNT re-injections permissible


Two-Year Outcom es of Sacral Neurom odulat ion Versus















Ar t icle info

Art icle history:


Associate Editor :

J.-N. Cornu


Andrew Vickers

Keywords:

Sacral neuromodulation

OnbotulinumtoxinA

InterStim


Botox

Abst ract



Allergan) are uti l ized. These therapies have not been compared over extended t ime.


Design, sett ing, and part icipants: Mult icenter, open-label, randomized, extension trial




















Tel. +1 919 401 1006; Fax: +1 919 401 1033.



0302-2838/© 2018 European Associat ion of Urology. Published by Elsevier B.V. All rights reserved.

















Ar t icle info

Art icle history:


Associate Editor :

J.-N. Cornu


Andrew Vickers

Keywords:


OnbotulinumtoxinA

InterStim


Botox

Abst ract

























Tel. +1 919 401 1006; Fax: +1 919 401 1033.





















Ar t icle info

Art icle history:


Associate Editor :

J.-N. Cornu


Andrew Vickers

Keywords:


OnbotulinumtoxinA

InterStim


Botox

Abst ract

























Tel. +1 919 401 1006; Fax: +1 919 401 1033.




















Ar t icle info

Art icle history:


Associate Editor :

J.-N. Cornu


Andrew Vickers

Keywords:


OnbotulinumtoxinA

InterStim


Botox

Abst ract

























Tel. +1 919 401 1006; Fax: +1 919 401 1033.





• sustained and similar reductions in mean daily UUIE

• BTX more likely complete resolution of UUIE in the first 6m

• BTX had higher satisfaction and treatment endorsement throughout the 24m

• No significant difference QoL measures, global assessment of improvement, or adverse effects subscales.

• The use of UUI medications or the alternate trial therapy was comparable

















Ar t icle info

Art icle history:


Associate Editor :

J.-N. Cornu


Andrew Vickers

Keywords:


OnbotulinumtoxinA

InterStim


Botox

Abst ract

























Tel. +1 919 401 1006; Fax: +1 919 401 1033.




















Ar t icle info

Art icle history:


Associate Editor :

J.-N. Cornu


Andrew Vickers

Keywords:


OnbotulinumtoxinA

InterStim


Botox

Abst ract

























Tel. +1 919 401 1006; Fax: +1 919 401 1033.




Based on

• 9 RCT placebo controlled

• 4 RCT active groups

• 35 Observational studies

Limitations

• Short follow-up in most studies

• Variability in

– doses

– injection sites

– adverse events

Take Home Messages

• BoNTA significantly improves refractory iOAB symptoms

• Improves quality of life

• Simple (mostly office) procedure

• CIC 6-10% (for 100 units)

• Increased UTI risk

• Sustained efficacy and tolerability over repeated

treatments

BoNTA for OAB

Noam D. Kitrey, MD, FECSM

Dept. of urology, Sheba medical center, ISRAEL

Chairman of the EAU UroTrauma guidelines panel

bonta for oab - comtecmed 4... · 2018-07-17 · bonta for oab noam d. kitrey, md, fecsm dept. of...

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