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Optimal dose of botulinum toxin A for MS, Parkinson’s, and OAB Sender Herschorn, MD, FRCSC Division of Urology University of Toronto Botulinum Toxin 900kD complex COOH NH2 S-S Light Chain NH2 S-S Heavy Chain COOH Local, temporary inhibition of vesicle-mediated neurotransmission BoNT/A actions Efferent nerve terminal Afferent nerve Urothelial cell Kanai et al. N & U 2012, 31:300-8 Effect of BoNT/A Increase Bladder capacity Volume at first reflex detrusor contraction Compliance Decrease detrusor pressures during filling and voiding Improvement in urgency – thought to be afferently mediated Apostolidis et al. Eur Urol 2006; 49:644-650 BoNT/A for refractory patients Systematic review for NDO 18 studies with 698 patients 3 retrospective with series with >75 patients 3 prospective studies Majority were small open-label studies Overall BoNT/A provides clinically significant improvements in refractory NDO Karsenty et al. Eur Urol 2008; 53:275-287 Herschorn et al. J Urol 2011; 185:2229-2235 Leakage episodes Daily mean frequency of leakage episodes 5 4.5 4 3.5 3 2.5 2 1.5 1 0.5 0 * P<0.05 *** P<0.001 *** *** * § BL 6 24 36 48 § 60 BoNT/A Placebo § P<0.001 Compared to baseline Weeks afterWeeks initial injection after initial injection Herschorn et al. J Urol 2011; 185:2229-2235 Adverse events Botulinum toxin A (n=28) No. pts. (%) Placebo (n=29) No. pts. (%) Urinary tract infection 16 (57) 16 (55) Voiding difficulty/retention 6 (21) 2 (7) Headaches 6 (21) 5 (17) Nausea +/- vomiting 6 (21) 2 (7) Muscle weakness 3* (11) * 1 unrelated Herschorn et al. J Urol 2011; 185:2229-2235 Cruz F, et al. Eur Urol. 2011 Oct;60(4):742-50. NDO study design Multicentre (global), randomized, double-blind 52week study sponsored by Allergan, Inc 275 SCI or MS patients with UI due to NDO Not adequately managed by anticholinergics Up to 2 treatments of 300 U, 200 U or placebo Primary Endpoint: Number of UI episodes at week 6 Secondary Endpoints: Urodynamics, Incontinence Quality of Life (I-QOL) Cruz F, et al. Eur Urol. 2011 Oct;60(4):742-50. Significant Decrease in Urinary Incontinence Change in urinary incontinence episodes/week Baseline * * * * * * * p= <0.001 in pairwise comparison versus placebo Mean baselines: Placebo = 36.7/wk, 200 U = 32.5/wk, 300 U = 31.2/wk Cruz F, et al. Eur Urol. 2011 Oct;60(4):742-50. Significant Increase in MCC Change in MCC at 6 weeks * * * p= <0.001 in pairwise comparison versus placebo MCC: Maximum cystometric capacity Cruz F, et al. Eur Urol. 2011 Oct;60(4):742-50. Cruz F, et al. Eur Urol. 2011 Oct;60(4):742-50. Duration of Symptom Relief in Bladder Was Approximately 9 Months Based on time to patient request for re-treatment 300 U Median Median == 42.1 42.1 weeks weeks 200 U Median Median == 42.1 42.1 weeks weeks 29 weeks Placebo Median Median==13.1 13.1weeks weeks 0 10 20 Weeks 30 40 50 12 weeks was the earliest time point when patients were allowed to request treatment 6 months 9 months 1 year Cruz F, et al. Eur Urol. 2011 Oct;60(4):742-50. Adverse Events ≥ 5% in Any Treatment Group Adverse Events ≥ 5% (All of treatment cycle 1) Placebo (N=90) 200 U (N=91) 300 U (N=89) Overall 74.4 % 86.8 % 88.8 % UTI 40.0 % 56.0 % 64.0 % Urinary retention 3.3 % 19.8 % 31.5 % Hematuria 4.4 % 5.5 % 10.1 % Fatigue 1.1 % 8.8 % 3.4 % Dysuria 2.2 % 5.5 % 7.9 % Nasopharyngitis 3.3 % 6.6 % 6.7 % Constipation 2.2 % 5.5 % 6.7% Diarrhea 6.7 % 3.3 % 6.7 % Muscle spasms 1.1 % 4.4 % 6.7% Muscular weakness 1.1 % 6.6 % 4.5 % Pyrexia 3.3 % 6.6 % 1.1 % Arthralgia 5.6 % 3.3 % 1.1 % Influenza 0 5.5 % 1.1 % Urinary incontinence 2.2 % 5.5 % 1.1 % Pain in extremity 3.3 % 5.5 % 2.2 % Cruz F, et al. Eur Urol. 2011 Oct;60(4):742-50. 416 pts. – 227 MS, 189 SCI and DO 14+ UI episodes/wk 1o endpoint – ΔUI episodes/wk, 2o endpoints – MMC, MDP, IQOL; AEs 200U and 300U reduced UI episodes by 21 and 23/wk vs. 9 in placebo (P<0.001) Median time to retreatment was 256 and 254 days vs. 92 in placebo Most common AEs were UTI and retention IC initiated in 10% placebo, 35% 200U, and 42% 300U ® BOTOX Summary of Phase 3 Trials Studies demonstrated BOTOX® provided sustained benefits to patients with NDO in terms of: UI, urodynamic parameters, QOL 300 U dose provided no additional clinically relevant benefits compared with 200 U, but: 300 U associated with increase in PVR and more patients initiating catheterization Mostly in MS patients who were not using CIC Higher incidence of UTI and retention in 300 U group Approved dose is 200 U UTI: Urinary tract infection PVR: Post-void residual Long-term follow-up Two 24-week, randomised, multicentre, double-blind, placebo-controlled phase 3 studies First patient in 2009 Protocol amendment* Aug 2012 Final patient out Aug 2014 3-year, long-term follow-up study OnabotA 100U* OnabotA 100U vs placebo 24 weeks Up to 2 treatments Up to 3 years Multiple treatments, request for re-treatment initiated by patient *Originally, a dose increase from 100U to 150U was permitted from treatment 3 onwards. Since the 150U dose did not provide additional efficacy, the protocol was amended to allow only the 100U dose. The current analyses include data for the 100U dose only. OnabotA = onabotulinumtoxinA. Kennelly et al. Neurourol Urodyn epub 2015 Mean change from baseline in daily UI episodes (week 6) OnabotA consistently improved UI, volume/void, and QOL in patients with UI, with no new safety signals Kennelly et al. Neurourol Urodyn, 2015, epub 4-y efficacy and safety in completers To assess year to year consistency of outcomes in 227 pts. 1.4-1.5 treatments per year Reduction of UI -3.4 to -3.9 episodes/d (BL 4.3) High proportion ≥50% and 100% reductions (88.694.1% and 43.6-57.4%) Median duration of effect ≥9 mo. ≥26% experienced effect ≥12 mo. Most common AE was UTI Rovner et al. J Urol epub 2016 MS pilot study – 100U 12 patients (11 women, 1 man) At 6–7weeks, sig. improvement in bladder capacity, maximum detrusor pressure, urinary frequency urgency and pad use. At 12-14 weeks sig. improvement in frequency, nocturia, urgency and pad use. PVR sig. increased and reached 222 ml initially but decreased over time for 12 weeks - 3 patients needed to perform CIC No change in incontinence episodes 10/12 pts. were satisfied; mean duration 8 mo. Mehnert et al. J Urol, 2010; 184:1011-16 BoNT/A in Parkinson’s Disease 4 women with PD and 2 with MSA 200 U (OnabotA) in 20 sites Questionnaires, micturition diary, UD assessments At 1, 3, and 5 mo. all improved No UTI, 3 with PD had to strain to void, 2 with MSA needed daily CIC No systemic AEs Giannantoni et al. J Urol 2009; 182:1453-7 BoNT/A in Parkinson’s Disease 10 women and 6 men with PD 500 U (AbobotA) in 30 sites Questionnaire, Clinical, UD, Mict. Diary follow-up Every 3 mo. until 1y All parameters significantly better At 9 mo. 10 still improved, 12 prescribed medical therapy; 4 requested reinjection No pt. needed IC No neurological deterioration Kulaksizoglu et al. Parkinsonism & RD 2010; 16:531-4 BoNT/A in Parkinson’s Disease 7 women and 1 man 100 U OnabotA in 10 sites Clinical and UD assessments at 1, 3, and 6 mo. All pts. had improved parameters Increased PVR at 1 month but decreased at 3 and 6 months 2 women with PVR of 300 mL 2 women needed CIC No systemic AEs or PD deterioration Giannantoni et al. J Urol 2011; 186:960-4 BoNT/A in Parkinson’s Disease 12 men, 8 women 100 U OnabotA in 10-20 sites including the trigone At 3 months moderate to marked symptom relief At 6 months 59% had ≥50% incontinence decrease 3 men had PVR at 1 month 2 men given α-blockers 2 women had UTIs Anderson et al. Urology 2014; 83:22-7 Botulinum toxins OnabotulinumtoxinA (Botox/Botox Cosmetic), AbobotulinumtoxinA (Dysport) RimabotulinumtoxinB (Myobloc) IncobotulinumtoxinA (Xeomin) All are different pharmacologically and are not interchangeable http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ DrugSafetyInformationforHeathcareProfessionals/ucm174949.htm Conclusions - NDO BoNT/A intradetrusor injections are safe and effective for patients with refractory UI from NDO Patient selection on the basis of clinical and UD parameters Dosing 200 U for SCI and many MS patients 100 U for PD and if concerned about retention Systematic review for OAB Intravesical BoNT/A improves refractory OAB symptoms Significant risk of increased PVR and symptomatic urinary retention Optimal administration to be determined Anger et al. J Urol 2010; 183:2258 Phase 2 RCT for IOAB with Onabot – Dose response RCT with 313 patients followed for 36 weeks; placebo and 5 doses Primary efficacy variable at 12 weeks was weekly UUI episodes UUI episode decrease Doses ≥ 100 U durable efficacy; PVR increase related to dose Dmochowski et al. J Urol 2010; 184:2416-22 Phase 2 RCT for IOAB with Onabot - QoL RCT 313 patients (288 females) with 36 week follow-up 50 – 300 U King’s Health Questionnaire >100U Doses ≥ 100 U produced sig. QoL measurement improvements Fowler et al. Eur Urol 2012; 62:148-57 Objectives and Study Design To evaluate the efficacy and safety of onabotulinumtoxinA in patients with OAB and urinary incontinence who have been inadequately managed with anticholinergics Multicenter, randomized, placebo-controlled pivotal study Patients randomized to onabotulinumtoxinA 100 U or placebo in 1:1 ratio N= 557 (onabotulinumtoxinA 100 U = 280; placebo = 277) Total number of clinical sites = 72 24 weeks duration, primary timepoint week 12 Nitti et al. J. Urol 2013; 189:2186-93 Results: Percent Change from Baseline in All OAB Symptoms % Change at week 12 OAB symptom OnabotA 100 U Placebo Urinary incontinence episodes - 47.9 % - 12.5 % Micturition episodes - 16.9 % - 4.1 % Urgency episodes - 31.6 % - 10.0 % Nocturia episodes - 20.2 % + 0.2 % Nitti et al. J. Urol 2013; 189:2186-93 Results: Adverse Events ≥ 5% First 12 weeks Any time in treatment cycle 1 OnabotA 100 U Placebo OnabotA 100 U Placebo (N= 278) (N= 272) (N= 278) (N= 272) Urinary tract infection1 43 (15.5%) 16 (5.9%) 68 (24.5%) 25 (9.2%) Dysuria 34 (12.2%) 26 (9.6%) 40 (14.4%) 27 (9.9%) Bacteriuria 14 (5.0%) 5 (1.8%) 23 (8.3%) 10 (3.7%) Urinary retention2 15 (5.4%) 1 (0.4%) 16 (5.8%) 1 Hematuria 7 (2.5%) 15 (5.5%) 8 16 (5.9%) For any reason 13 (4.6%) 21 (7.6%) 31 (11.1%) 34 (12.3%) Due to adverse events 4 2 5 4 Adverse event (2.9%) (0.4%) Discontinuations 1 Defined 2 Defined (1.4%) (0.7%) (1.8%) (1.4%) as positive urine culture with bacteriuria count of > 105 CFU/mL and leukocyturia of > 5/hpf as PVR ≥ 200 mL with symptoms that required CIC, or PVR ≥ 350 mL with CIC regardless of symptoms Nitti et al. J. Urol 2013; 189:2186-93 European and U.S. RCT BL: PBO 5.7±3.9 BoNT/A 5.5±3.8 IQoL 548 pt. PBO 271, BoNT/A 277 239 vs. 250 completed Chapple et al. Eur Urol 2013, 64:249-256 Adverse events Chapple et al. Eur Urol 2013, 64:249-256 Systematic review and meta-analysis 8 studies (6 RCTs) with 1320 patients Sig. UI episodes, daily frequency, MCC, voided volume 29.2% vs. 7.95% became dry Only localized AEs - Sig. UTI and retention vs. placebo Cui et al. N&U, 2015; 34:413-9 Repeat BoNT/A injections Review of multiple studies Overall objective and subjective (patient reported) efficacy outcomes after first injection sustained after repeated injections Dowson et al. Nat Rev Urol 2010; 7:661-667 Efficacy and safety at 3.5 years Pts. who completed either of two 24-wk trials entered for 3.5 years Data analysed by treatment (up to 6) and by treatment subgroup of 1-6 treatments 74-83% reported improved or greatly improved symptoms after each treatment Consistent reductions in daily UI episodes (3-4/day) and urgency episodes (3-4/day) Median duration of effect 7.6 months No new safety signals: UTI (13.5%-17%), de novo IC (4% to 0.6%) Nitti et al. J Urol, 2016; 196:791-800 Long-term use of BoNT/A 137 patients (idiopathic 104; neuropathic 33) followed for ≥36 months Real life study, idiopathic dose was 200 or 300u, CIC started for PVR 150 ml Mohee A, et al BJUI 2013; 111:106-13 Durability of BoNT/A Retrospective review over a 7-year period in 136 patients Mean time for patients requesting additional treatment: For first 5 cycles varied between 8.5 and 10.4 mo. Longest time between 3rd and 4th cycles Between 5th and 6th – 5.5mo. and between 6th and 7th – 5.25 mo. (p=0.015) 80% discontinued treatment over time Chohan et al. IUJ, 2015; 26:1605-12 Long-term patient satisfaction First 100 patients treated from 2004-2010 72 complete data for questionnaires 49 continued; 23 discontinued High satisfaction among those who continued Discontinuation mainly for lack of efficacy 44% no further treatment 39% back to anti-muscarinics 13% other Malde et al. BJUI 2015; 116:443-9 Number of injections sites and outcome Single blind RCT in 67 patients 100U BoNT/A diluted in 10mL NS injected in 10, 20, or 40 sub-urothelial sites under GA At 1, 3, and 6 months No sig. difference in GRA, symptoms, UDS findings and AEs Liao et al. N&U 2016 Aug;35(6):717-23. Retention rate Retrospective study in 160 patients (121 women and 39 men) treated with 100U or 200U of BoNT/A 56(35%) had retention and needed CIC for ~16 weeks (1-40) After 1st injection associated with preop PVR and bladder capacity After 2nd injection associated with preop PVR, BoNT/A dose, and previous retention Osborn et al. N&U, 2015; 34:675-8 OnabotA for OAB RCT evidence of efficacy in patients refractory to or intolerant of oral medications Notable AEs are UTI and risk of retention which is dose related Emerging data of long-term persistence of efficacy and safety Limited comparisons to other therapies Currently recommended does is 100 U