- Email: [email protected]
Phase 3 Efficacy and Tolerability Study of OnabotulinumtoxinA for Urinary Incontinence From Neurogenic Detrusor Overactivity
Voiding Dysfunction
Phase 3 Efficacy and Tolerability Study of OnabotulinumtoxinA for Urinary Incontinence From Neurogenic Detrusor Overactivity David Ginsberg,*,† Angelo Gousse,‡ Veronique Keppenne, Karl-Dietrich Sievert,§ Catherine Thompson,§ Wayne Lam,§ Mitchell F. Brin, Brenda Jenkins§ and Cornelia Haag-Molkenteller§ From the University of Southern California (DG), Los Angeles and Allergan, Inc. (CT, WL, BJ, CHM) and University of California-Irvine, Irvine (MFB), California, Herbert Wertheim College of Medicine, Florida International University (AG), Miami, Florida, Université de Liège (VK), Liege, Belgium, and University of Tuebingen (KDS), Tuebingen Germany
Purpose: We assessed the efficacy, safety and effects on quality of life of onabotulinumtoxinA in patients with neurogenic detrusor overactivity. Materials and Methods: In this 52-week, international, multicenter, doubleblind, randomized, placebo controlled trial 416 patients with neurogenic detrusor overactivity and urinary incontinence (14 or more episodes per week) resulting from multiple sclerosis (227) and spinal cord injury (189) were treated with intradetrusor injections of onabotulinumtoxinA (200 or 300 U) or placebo. The primary end point was the change from baseline in the mean number of urinary incontinence episodes per week at week 6. Maximum cystometric capacity, maximum detrusor pressure during the first involuntary detrusor contraction and Incontinence Quality of Life total score were secondary end points. Adverse events were monitored. Results: OnabotulinumtoxinA at a dose of 200 U in 135 patients and 300 U in 132 decreased mean urinary incontinence at week 6 by 21 and 23 episodes per week, respectively, vs 9 episodes per week in 149 on placebo (each dose p ⬍0.001). Also, maximum cystometric capacity, maximum detrusor pressure during the first involuntary detrusor contraction and Incontinence Quality of Life score were significantly improved over values in the placebo group (each dose p ⬍0.001). Median time to patient re-treatment request was greater for onabotulinumtoxinA 200 and 300 U than for placebo (256 and 254 days, respectively, vs 92). The most common adverse events were urinary tract infection and urinary retention. Of patients who did not catheterize at baseline 10% on placebo, 35% on 200 U and 42% on 300 U initiated catheterization due to urinary retention.
Abbreviations and Acronyms AE ⫽ adverse event CIC ⫽ clean intermittent catheterization I-QOL ⫽ Incontinence Quality of Life IDC ⫽ involuntary detrusor contraction ITT ⫽ intent to treat MCC ⫽ maximum cystometric capacity MDP ⫽ maximum detrusor pressure MS ⫽ multiple sclerosis NDO ⫽ neurogenic detrusor overactivity PVR ⫽ post-void residual urine volume QOL ⫽ quality of life SCI ⫽ spinal cord injury UI ⫽ urinary incontinence UTI ⫽ urinary tract infection
Submitted for publication October 28, 2011. Study received ethics committee approval at each study site. Supported by Allergan, Inc., Irvine, California. * Correspondence: Department of Urology, University of Southern California, Norris Cancer Center, 1441 East Lake Ave., Suite 7416, Los Angeles, California 90033 (telephone: 323-865-3703; FAX: 323-865-0120; e-mail: [email protected]). † Financial interest and/or other relationship with Allergan, AMS/Boston Scientific, Medtronic, Tengion and Pfizer. ‡ Financial interest and/or other relationship with Allergan, Pfizer, Lilly and Astellas. § Financial interest and/or other relationship with Allergan.
0022-5347/12/1876-2131/0 THE JOURNAL OF UROLOGY® © 2012 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
AND
RESEARCH, INC.
Vol. 187, 2131-2139, June 2012 Printed in U.S.A. DOI:10.1016/j.juro.2012.01.125
www.jurology.com
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Conclusions: OnabotulinumtoxinA significantly improved neurogenic detrusor overactivity symptoms vs placebo. Clean intermittent catheterization initiation due to urinary retention appeared to increase in a dose dependent fashion. No clinically relevant benefit in efficacy or duration was identified for the 300 U dose over the 200 U dose. Key Words: urinary incontinence, botulinum toxin, onabotulinumtoxinA, spinal cord injuries, multiple sclerosis NEUROLOGICAL conditions such as SCI and MS often result in NDO.1,2 NDO can lead to urodynamically measured increased bladder storage pressures and UI, which can negatively impact QOL.3–7 Initial medical treatment for NDO consists mainly of anticholinergics, often with CIC. However, long-term anticholinergic treatment may be suboptimal, with patients stopping medication due to lack of efficacy and bothersome side effects. Primary side effects include dry mouth and constipation, which may be significant baseline problems in patients with neurological disease.8 –10 Early trials using onabotulinumtoxinA in patients with NDO demonstrated fewer UI episodes, improved urodynamic parameters and improved QOL.11,12 We describe a large, multicenter, prospective, placebo controlled trial designed to evaluate the safety and efficacy of 200 and 300 U onabotulinumtoxinA for UI resulting from NDO in patients with MS or SCI who were not adequately treated with anticholinergic therapy.
MATERIALS AND METHODS Study Design This global, multicenter, randomized, double-blind, placebo controlled, phase 3 trial (www.clinicaltrials.gov NCT00311376) was performed at 85 centers between September 2006 and May 2010 as part of the DIGNITY (Double-Blind Investigation of Purified Neurotoxin Complex in Neurogenic Detrusor Overactivity) Study program. The study included patients 18 to 80 years old with NDO 3 months or greater in duration and 14 or more UI episodes per week during screening who were not adequately treated with anticholinergic therapy. Patients had NDO, as demonstrated by IDC on urodynamics, secondary to SCI at T1 or below, or MS with an Expanded Disability Status Score of 6.5 or less using the Neurostatus web based, interactive test and certification tool, which provides standardized examinations and consistent definitions for scoring. Patients treated with anticholinergics at baseline continued at a stable dose throughout the study, while those not on anticholinergics remained off anticholinergics. Patients who did not perform CIC at baseline had to be willing to initiate CIC, if needed. Patients were excluded from analysis if they received previous treatment with any serotype botulinum toxin for urological conditions or surgery that might affect bladder function. Ethics committee approval was obtained at each study site and all patients provided written informed consent.
Patients were randomized 1:1:1 to receive 200 or 300 U onabotulinumtoxinA (Botox®) or placebo (0.9% saline). To maintain the blind, independent drug reconstitution was used. Using a rigid or flexible cystoscope we administered 30, 1 ml injections about 1 cm apart and 2 mm deep in the detrusor, sparing the trigone (fig. 1).12 Patients received no anesthesia, local anesthetic instillation without or with sedation, or general anesthesia. After initial treatment patients were evaluated at the clinic at weeks 2, 6 and 12 with followup every 6 weeks until re-treatment or study exit. Bladder diaries were collected before each followup. I-QOL13 responses were collected at baseline, posttreatment weeks 6 and 12, scheduled clinic visits and study exit. Urodynamic analysis was done at baseline and week 6 after each treatment. Patients could receive up to 2 treatments but could not request re-treatment sooner than 12 weeks after initial treatment. To qualify for re-treatment patients had to initiate the request and show less than a 50% decrease from baseline in the number of weekly UI episodes.
Efficacy and Safety Assessments The primary efficacy end point was the change from baseline in the number of weekly UI episodes 6 weeks after treatment, as collected in a 7-day bladder diary. Response was also categorized using the decrease in UI episodes per week from baseline, including 50% or greater (responder), 75% or greater and 100% (dry) at week 6. Secondary end points evaluated at week 6 included MCC, MDP during the first IDC and I-QOL total summary score. All urodynamic tracings were done according to International Con-
Figure 1. OnabotulinumtoxinA injections were administered cystoscopically in detrusor, sparing trigone.
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evaluated using the Hochberg procedure to adjust for multiple comparisons. As secondary end points, a hierarchical analysis strategy and the same ANCOVA model were used to evaluate changes from baseline. Median duration of the treatment effect was evaluated using Kaplan-Meier analysis as the time from day 1 to the patient request for re-treatment. Median time to patient qualification for retreatment was evaluated similarly. For treatment emergent AEs during treatment cycle 1 the Pearson chi-square test was used to evaluate the equality of proportions among groups. If 25% of the cells had an expected count of less than 5, the Fisher exact test was used. MS exacerbation was defined as a sudden worsening of MS symptoms or the appearance of new symptoms that lasted 24 hours or more and was separated from a previous exacerbation by at least 1 month. MS exacerbations were analyzed using annualized rates, that is the total number of exacerbation events divided by the total exposure time for all patients with MS.
tinence Society guidelines and were read by a blinded, independent central reviewer. AEs were assessed throughout the study. A report of UTI by the investigator did not distinguish asymptomatic from symptomatic UTIs. PVR was assessed in patients not on CIC. Recording urinary retention as an AE was based on investigator clinical judgment. CIC use was recorded in the diary and CIC initiation due to urinary retention was reported by the investigator. Bladder and renal ultrasound was done at specified time points and clinically significant changes from baseline were noted as AEs. The mouse protection assay14 was used to detect neutralizing antibodies against onabotulinumtoxinA at baseline, before re-treatment and at study exit.
Statistical Analysis The study was powered at the 5% significance level to compare 2 doses of onabotulinumtoxinA vs placebo. Comparisons vs placebo focused on the initial 12 weeks after the first treatment before patients were eligible for retreatment. The safety population consisted of all randomized patients who received study drug, analyzed according to the dose received. The ITT population included all randomized patients. ANCOVA was done to assess efficacy in the ITT population with the baseline value as a covariate, and treatment arm, etiology at study entry, concurrent use/nonuse of anticholinergics and investigative site as factors using SAS®, version 9.2. Two pairwise comparisons (200 and 300 U onabotulinumtoxinA vs placebo at week 6) were
RESULTS Patients The ITT population consisted of 416 randomized patients, of whom 329 (79%) completed the 52-week study and 87 (21%) discontinued early, including 13 (3%) due to AEs (fig. 2). Table 1 lists demographic
Randomized = 416
Placebo = 149
OnabotA 200U = 135
OnabotA 300U = 132
Withdrawn = 4
Withdrawn = 5 Safety population = 407
Treatment Cycle 1 OnabotA 200U = 135
OnabotA 300U = 127
Discontinued = 14 (10%)
Discontinued = 16 (12%)
Discontinued = 22 (17%)
Completed = 19 (13%)
Completed = 45 (33%)
Completed = 36 (28%)
Entered 2 = 112 (77%)
Entered 2 = 74 (55%)
Entered 2 = 69 (54%)
OnabotA 200U = 74*
OnabotA 300U = 69*
Discontinued = 7 (10%)
Discontinued = 4 (6%)
Completed = 54 (73%)
Completed = 56 (81%)
Placebo = 145
Treatment Cycle 2 OnabotA 200U = 51*
OnabotA 300U = 46*
Discontinued = 6 (12%)
Discontinued = 5 (11%)
Completed = 45 (88%)
Completed = 39 (85%)
Figure 2. Patient flow through trial. OnabotA, onabotulinumtoxinA. Asterisk indicates numbers may not sum to total due to patients with opportunity to receive third treatment in earlier version of protocol and 15 who received placebo at treatment cycle 2 before amendment whose cycle 2 data were not analyzed.
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Table 1. Baseline demographic and clinical characteristics in ITT population Treatment Placebo
200 U
300 U
Totals
Overall No. pts Age: Mean ⫾ SD No. less than 40 (%) No. 40-64 (%) No. 65-74 (%) No. male (%) No. race (%): White Black Other No. anticholinergics (%) No. CIC (%)
149
135
46 ⫾ 13 45 (30) 95 (64) 9 (6) 73 (49)
46 ⫾ 14 48 (36) 73 (54) 14 (10) 55 (41)
138 (93) 5 (3) 6 (4) 83 (56) 89 (60)
117 (87) 12 (9) 6 (4) 66 (49) 71 (54)
132 47 ⫾ 12 40 (30) 83 (63) 9 (7) 43 (33)
416 46 ⫾ 13 133 (32) 251 (60) 32 (8) 171 (41)
117 (89) 7 (5) 8 (6) 68 (52) 73 (57)
372 (89) 24 (6) 20 (5) 217 (52) 233 (57)
Multiple sclerosis No. pts Mean ⫾ SD yrs since diagnosis No. anticholinergics (%) No. CIC (%) No. disease classification (%): Relapsing remitting Primary progressive Secondary progressive Progressive relapsing Mean ⫾ SD Expanded Disability Status Score No. pts Mean ⫾ SD yrs since injury No. anticholinergics (%) No. CIC (%) No. American Spinal Injury Association impairment scale (%): A B C D E
81 14 ⫾ 8 43 (53) 31 (38)
77 15 ⫾ 11 38 (49) 27 (36)
69 13 ⫾ 7 36 (52) 21 (31)
227 14 ⫾ 9 117 (51) 79 (35)
44 (54) 10 (12) 22 (27) 4 (5) 5.1 ⫾ 1.4 Spinal cord injury 68 10 ⫾ 12 40 (59) 58 (87)
50 (65) 5 (7) 18 (23) 4 (5) 5.2 ⫾ 1.3
37 (54) 8 (12) 19 (28) 5 (7) 5.0 ⫾ 1.4*
131 (58) 23 (10) 59 (26) 13 (6) 5.1 ⫾ 1.3
58 9⫾9 28 (48) 44 (77)
63 9⫾9 32 (51) 52 (84)
189 9 ⫾ 10 100 (53) 154 (83)
51 (75) 3 (4) 2 (3) 6 (9) 4 (6)
37 (64) 4 (7) 5 (9) 7 (12) 5 (9)
41 (65) 6 (10) 5 (8) 8 (13) 3 (5)
129 (68) 13 (7) 12 (6) 21 (11) 12 (6)
* In 68 patients.
and clinical characteristics of the ITT population and subgroups. UI Episodes Each onabotulinumtoxinA dose significantly decreased UI episodes compared with placebo 2, 6 and 12 weeks after treatment (p ⱕ0.008). There were no clinically relevant differences between the active dose groups (fig. 3, A). Similar results were seen in the MS and SCI subpopulations (fig. 3, B and C). At week 6 treatment resulted in a ⫺30%, ⫺67% and ⫺74% change from baseline in UI in the placebo, and 200 and 300 U onabotulinumtoxinA groups, respectively. Significantly more patients in the 2 onabotulinumtoxinA groups than the placebo group attained the 50% or greater responder threshold at week 6 for a reduction in weekly UI episodes (p ⱕ0.001). Furthermore, 36% and 41% of patients in the 200 and 300 U groups, respectively, achieved dry status (fig. 4).
Urodynamics and QOL Each onabotulinumtoxinA dose significantly increased MCC from baseline vs placebo (p ⬍0.001). There were no relevant differences between the active dose groups or by etiology (table 2). Each onabotulinumtoxinA dose significantly decreased MDP during the first IDC from baseline vs placebo (p ⬍0.001). Decreases were similar in the MS and SCI subpopulations (table 2). The proportion of patients without IDC at week 6 (maximum bladder filling 500 ml for urodynamics) was 19% (26 of 137), 64% (81 of 127) and 69% (77 of 111) in the placebo, and the onabotulinumtoxinA 200 and 300 U groups, respectively. Each onabotulinumtoxinA dose also significantly improved the I-QOL total summary score at week 6 compared with placebo (table 2). This significant improvement was maintained through week 12 in the overall population with increases from baseline
PHASE 3 EFFICACY AND TOLERABILITY STUDY OF ONABOTULINUMTOXINA
0
0
2
4
6
8
10
12
-5 -10 -15
*
-20
*
*
*
*
*
-25
*P=≤0.008 versus placebo
-30
C
Weeks Post-Treatment 0
0
2
4
6
8
10
12
-5 -10 -15 -20
*
* -25
* *P=<0.05 versus placebo
-30
*
Change From Baseline (episodes/week)
B
Weeks Post-Treatment
Change From Baseline (episodes/week)
Change From Baseline (epsiodes/week)
A
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Weeks Post-Treatment 0
2
4
6
8
10
12
0 -5 -10 -15 -20 -25 -30
* *
*
* *
*
*P=≤0.001 versus placebo
Figure 3. Change from baseline in weekly UI episodes after treatment cycle 1 at weeks 2, 6 and 12. A, ITT population. Orange curve indicates 149 patients on placebo. Purple curve indicates 135 patients on 200 U onabotulinumtoxinA. Red curve indicates 132 patients on 300 U onabotulinumtoxinA. B, MS population. Orange curve indicates 81 patients on placebo. Purple curve indicates 77 patients on 200 U onabotulinumtoxinA. Red curve indicates 69 patients on 300 U onabotulinumtoxinA. C, SCI population. Orange curve indicates 68 patients on placebo. Purple curve indicates 58 patients on 200 U onabotulinumtoxinA. Red curve indicates 63 patients on 300 U onabotulinumtoxinA.
of 9, 31 and 33 points in the placebo, and onabotulinumtoxinA 200 and 300 U groups, respectively (each treatment group vs placebo p ⬍0.001). The change from baseline in I-QOL score was analyzed in patients who did not perform CIC at baseline to determine whether subsequent initiation of CIC influenced QOL. In these patients the I-QOL improvement was similar whether they did or did not begin CIC after treatment (fig. 5). Effect Duration Re-treatment could not be requested before 12 weeks after treatment. Median time to patient request for re-treatment was 92 days (95% CI 87–107) for placebo, 256 (95% CI 212–296) for 200 U onabotulinumtoxinA and 254 (95% CI 211–337) for 300 U onabotulinumtoxinA (each treatment group vs 100
Placebo
*
Percentage of Patients
80
75%
OnabotA 200U
*
OnabotA 300U
77%
*
*
62% 63%
60
* 40
38%
* 41%
36% 26%
20 10%
0
≥50%
≥75%
100%
Responder Threshold (% decrease from baseline in UI) *P<0.001 vs placebo
Figure 4. Responder analysis for weekly UI episode decrease at week 6 vs baseline by treatment response thresholds in ITT population. OnabotA, onabotulinumtoxinA.
placebo p ⬍0.001, fig. 6). Median time to qualification for re-treatment was 96 days (95% CI 90 –127) for placebo, 295 (95% CI 253–338) for 200 U onabotulinumtoxinA and 337 (95% CI 294 –380) for 300 U onabotulinumtoxinA (each treatment group vs placebo p ⬍0.001). Safety and Tolerability Table 3 lists adverse events for the first 12 weeks and for treatment cycle 1, which had a median duration of 19.4, 43.9 and 44.0 weeks in the placebo, and 200 and 300 U groups, respectively. The most common AEs were UTI and urinary retention (table 4). UTI was reported as a serious AE in 8 patients since it led to hospitalization. One case of urosepsis was reported in the placebo group and 1 of pyelonephritis was noted in the 300 U group in treatment cycle 1. The UTI incidence was similar across all treatment groups in the SCI population but in the MS population it was higher after receiving onabotulinumtoxinA. Seven patients reported autonomic dysreflexia events during treatment cycle 1 (table 3). The event was considered related to the injection procedure since it occurred between days 1 and 5 in 6 patients. All cases resolved without sequelae within 24 hours. In patients who did not perform CIC at baseline, mainly those with MS, significant dose dependent increases from baseline in PVR were observed by week 2 in each onabotulinumtoxinA dose groups but not in the placebo group (p ⫽ 0.004, table 5). Week 2 was the first posttreatment time point at which the investigator assessed the patient. This represents the effect of treatment on PVR before the time that CIC could have been initiated. After active treatment approximately 50% of patients who did not use CIC at baseline began CIC for
35.1 ⫾ 18.1 10.8 ⫾ 18.4
50.9 ⫾ 38.1 ⫺2.4 ⫾ 43.4*
256 ⫾ 144 16 ⫾ 127
28.3 ⫾ 15.8 ⫺8.8 ⫾ 16.2
149
132 31.1 ⫾ 17.0 ⫺22.7 ⫾ 17.1* 256 ⫾ 145 168 ⫾ 170* 47.1 ⫾ 36.3 ⫺33.3 ⫾ 37.8* 32.2 ⫾ 18.6 32.9 ⫾ 23.9*
135 32.3 ⫾ 22.8 ⫺21.0 ⫾ 23.8* 252 ⫾ 154 151 ⫾ 171* 51.3 ⫾ 34.7 ⫺35.1 ⫾ 35.7* 34.0 ⫾ 18.0 26.9 ⫾ 26.8*
Proportion Requesting Retreatment
31.5 ⫾ 17.2 12.4 ⫾ 18.9
42.3 ⫾ 30.9 12.1 ⫾ 42.3
243 ⫾ 143 ⫺7.5 ⫾ 118
30.3 ⫾ 17.8 ⫺11.5 ⫾ 19
81
Placebo
31.3 ⫾ 17.7 ⫺23.8 ⫾ 18.3* 251 ⫾ 149 162 ⫾ 171* 36.8 ⫾ 28.2 ⫺29.0 ⫾ 33.2* 30.5 ⫾ 18.6 38.3 ⫾ 24.1*
260 ⫾ 161 142 ⫾ 179* 43.6 ⫾ 28.8 ⫺28.4 ⫾ 31.9* 33.5 ⫾ 17.1 28.0 ⫾ 28.0*
69
300 U Treatment
32.7 ⫾ 22.2 ⫺20.4 ⫾ 25.7
77
200 U Treatment
300 U Treatment
200 U Treatment
* p ⬍0.05 vs placebo. † Missing values were imputed with mean of nonmissing items at same visit.
No. pts UI (No./wk): Baseline Change from baseline MCC (ml): Baseline Change from baseline MDP at 1st IDC (cm H2O): Baseline Change from baseline I-QOL total summary score:† Baseline Change from baseline
Placebo
Mean ⫾ SD MS
Mean ⫾ SD Totals
Table 2. Change from baseline at week 6 during cycle 1 in urological and quality of life parameters in ITT population
34.5 ⫾ 19.4 25.4 ⫾ 25.2*
39.4 ⫾ 18.3 8.9 ⫾ 17.7
63
300 U Treatment
34.1 ⫾ 18.6 26.6 ⫾ 22.2*
58.4 ⫾ 40.8 ⫺36.3 ⫾ 41.4
262 ⫾ 142 175 ⫾ 169*
30.9 ⫾ 16.5 ⫺21.5 ⫾ 15.8*
Change From Baseline (Total Score)
61.6 ⫾ 39.1 ⫺41.0 ⫾ 38.4
242 ⫾ 147 163 ⫾ 160*
271 ⫾ 145 45 ⫾ 134 61.1 ⫾ 43.2 ⫺19.6 ⫾ 38.5
31.6 ⫾ 23.7 ⫺21.9 ⫾ 21.1*
58
200 U Treatment
25.9 ⫾ 12.8 ⫺5.7 ⫾ 11.2
68
Placebo
Mean ⫾ SD SCI
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I-QOL
40
*
30
*
0
0
2 4
90
180
* * *
20
*
10
0 * P<0.05 vs placebo
Weeks Post-Treatment
6 8
0.2
270
10
360
12
Placebo CIC-Y 200U OnabotA CIC-Y 300U OnabotA CIC-Y
Placebo CIC-N 200U OnabotA CIC-N 300U OnabotA CIC-N
Figure 5. I-QOL summary score in patients without CIC (CIC-N) at baseline. CIC-Y, CIC at baseline. OnabotA, onabotulinumtoxinA. Asterisk indicates p ⬍0.05 onabotulinumtoxinA vs placebo.
any reason during treatment cycle 1. Notably 22% of placebo treated patients also initiated CIC during treatment cycle 1 despite minimal increases in PVR. Since the protocol had no defined PVR at which to initiate CIC, initiating CIC due to urinary retention was based on investigator assessment. Of patients who did not use CIC at baseline the proportion in treatment cycle 1 who initiated CIC for urinary retention was 10% in the placebo group, and 35% and 42% in the 200 and 300 U dose groups, respectively. Seven patients discontinued the study due to nonfatal AEs during treatment cycle 1, including 4 in the 300 U group with UTI, bladder pain, breast
1.0
0.8
0.6
0.4
Placebo 200 U onabotA 300 U onabotA
0.0
450
Days Post-Treatment
Figure 6. Kaplan-Meier curve for time to patient request for re-treatment in ITT population. onabotA, onabotulinumtoxinA.
PHASE 3 EFFICACY AND TOLERABILITY STUDY OF ONABOTULINUMTOXINA
Table 3. Treatment emergent AEs during treatment cycle 1 No. Treatment (%) No. Placebo (%) No. pts Overall AE Serious AE AE with 5% or greater incidence: UTI Urinary retention Hematuria Pyrexia Overall AE Serious AE AE with 5% or greater incidence: UTI Urinary retention MS relapse* Muscular weakness† Bladder pain Diarrhea Headache Hypertension Nausea Hematuria Vulvovaginal mycotic infection Fatigue Pyrexia Other events of interest: Autonomic dysreflexia Constipation
145
200 U 135 (70) (3)
81 (64) 12 (9)
26 5 4 4
38 27 6 7
(28) (20) (4) (5)
36 (28) 21 (17) 6 (5) 2 (2)
113 17
(84) (13)
102 (80) 23 (18)
64 (50) 22 (17) 12 (9) 9 (7) 7 (6) 7 (6) 7 (6) 7 (6) 8 (6) 6 (5) 3 (4)
107 14
49 5 3 4 2 4 4 0 3 4 2
(34) (3) (2) (3) (1) (3) (3) (2) (3) (3)
66 (49) 27 (20) 1 (less than 1) 4 (3) 2 (2) 8 (6) 4 (3) 3 (2) 6 (4) 7 (5) 6 (8)
6 5
(4) (3)
8 10
(6) (7)
4 (3) 4 (3)
1 (less than 1)
3
(2)
3 (2)
5
6
(4)
5 (4)
(3)
* MS exacerbation was to have been reported as individual signs and symptoms. However, MS exacerbation (the preferred term was MS relapse) was recorded for 13 patients with serious and 3 with nonserious AEs, in addition to or instead of exacerbation signs and/or symptoms. † All patients with MS.
cancer and bladder calculus; 2 in the 200 U group with hydronephrosis and eschar; and 1 in the placebo group with influenza. None was considered by the investigator to be related to the study drug or procedure. Two deaths were reported, including 1 in treatment cycle 1 in the 300 U group and 1 in treatment cycle 2 in the 200 U group. Each death occurred more than 170 days after the last injection and were not considered treatment related. Table 4. UTI and urinary retention AEs by etiology
MS: UTI Urinary retention SCI: UTI Urinary retention
Treatment Placebo
127
94 4
(18) (3) (3) (3) Overall (74) (10)
Table 5. PVR at week 2 and CIC during treatment cycle 1 in patients with no CIC at baseline
300 U
1st 12 wks 83 (57) 12 (8)
No. Placebo (%)
No. 200 U (%)
No. 300 U (%)
80 22 (28) 4 (5) 65 27 (42) 1 (2)
76 38 (50) 22 (29) 59 28 (48) 5 (9)
67 34 (51) 19 (28) 60 30 (50) 3 (5)
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200 U
300 U
No. pts 58 60 55 PVR (ml): Mean ⫾ SD baseline 57 ⫾ 61 50 ⫾ 51 52 ⫾ 50 Mean ⫾ SD wk 2 7 ⫾ 55 106 ⫾ 165 169 ⫾ 300 change % Wk 2 PVR 200 ml 4 32 36 or greater No. CIC initiated (%): Urinary retention 6 (10) 21 (35) 23 (42) Any reason 13 (22) 28 (47) 27 (49)
p Value (KruskalWallis test)
0.926 0.004
The annualized MS exacerbation rate during treatment cycle 1 was 0.22, 0.14 and 0.37 in the placebo, and 200 and 300 U groups, respectively. No patient showed neutralizing antibodies against onabotulinumtoxinA after treatment(s).
DISCUSSION NDO can be caused by various neurological conditions. This study evaluated patients with SCI or MS. Each onabotulinumtoxinA dose (200 and 300 U) significantly decreased the frequency of UI episodes per week and improved urodynamic outcomes and QOL measures. The onset of action of onabotulinumtoxinA was rapid (within 2 weeks of injection) and sustained with a duration of effect (time to re-treatment request) of approximately 9 months. Average detrusor pressure during the first IDC decreased more than 33 cm H2O from a baseline of 50 cm H2O. Approximately two-thirds of onabotulinumtoxinA treated patients showed no evidence of NDO/IDC on post-injection urodynamics at week 6 with up to 500 ml bladder filling. Many initial studies that evaluated onabotulinumtoxinA for NDO included doses up to 300 U.15 This trial suggests that a dose of 200 U is sufficient and these results are consistent with those of a similarly designed trial.16 Efficacy and duration of effect were similar for the 2 doses but the 300 U dose showed an increased risk of urinary retention and elevated PVR in patients who did not catheterize. Since urinary retention is a risk of onabotulinumtoxinA detrusor injection, patients considering this treatment should be willing and able to perform CIC. However, estimating the true risk of urinary retention is a challenge. This was illustrated in the placebo arm, in which PVR remained stable throughout the study. However, 22% of patients on placebo who did not perform CIC at baseline began CIC during treatment cycle 1. This suggests that many patients who were not on CIC at baseline might have benefited from
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CIC before study entry and the need for CIC was due to voiding dysfunction inherent to neurogenic bladder. The difference between the proportion of patients initiating CIC for any reason after 200 U compared with the proportion initiating CIC in the placebo group was 25% (47% vs 22%). Similarly in those who initiated CIC due to urinary retention the difference in the rate in the 200 U dose and placebo groups was also approximately 25% (35% vs 10%). Thus, this may represent the true risk of CIC after onabotulinumtoxinA detrusor injection. The need to perform CIC did not negatively impact the outcome of onabotulinumtoxinA treatment. Improvements in the I-QOL score after onabotulinumtoxinA were similar with and without CIC. The 2 doses were well tolerated but the incidence of AEs was slightly lower in the 200 U group. The annualized MS exacerbation rate was low and within the expected range for the MS population.17,18 A recent study of approximately 46,000 patients with NDO showed that UTI was among the most commonly diagnosed conditions in this population, impacting 29% to 36% of patients.19 In the current series a similar 34% rate was observed in the placebo group. In patients with SCI, of whom most used CIC at baseline, the UTI rate was 42% in the placebo group and approximately 50% after active treatment. The increased incidence of UTIs in patients with MS after active treatment (28% on placebo and approximately 50% after active treatment), of whom most did not use CIC at baseline, was most likely associated with CIC initiation. A limitation is that this study was not designed specifically to assess repeat treatment. However, many patients received a second injection. Results are pending from the ongoing long-term 3-year study. Other limitations include the lack of protocol defined criteria for CIC initiation and no definition of symptomatic vs asymptomatic UTIs. OnabotulinumtoxinA is not interchangeable with other botulinum toxin preparations. The units of biological activity of onabotulinumtoxinA cannot be compared to or converted into units of any other botulinum toxin product.
CONCLUSIONS Treatment with 200 or 300 U onabotulinumtoxinA was well tolerated in patients with NDO. It significantly decreased weekly UI episodes and MDP, increased MCC and improved QOL compared to placebo treatment. No benefits in efficacy or duration of effect were observed for 300 U onabotulinumtoxinA compared with the 200 U dose. The 200 U onabotulinumtoxinA group had a more favorable safety profile.
ACKNOWLEDGMENTS Access to and use of Neurostatus is provided by Dr. Ludwig Kappos, Outpatient Clinic Neurology-Neurosurgery, University Hospital Basel and Franz Schnyder, Regarde, Basel, Switzerland. Dr. Alex Loeb, Evidence Scientific Solutions, Philadelphia, Pennsylvania assisted with the manuscript.
APPENDIX Principal Investigators Damien Bolton, Robert (Frank) Gardiner, Kym Horsell, Richard Millard, Helen O’Connell and Andrew Tan, Australia; Gustav Kiss and Helmut Madersbacher, Austria; Dirk Jan Maria Karine De Ridder, Karel Everaert, Veronique Keppenne and Jean Jacques Wyndaele, Belgium; Karen Ethans, Gary Gray, Anthony Skehan and Le Mai Tu, Canada; Milos Brodak, Vaclav Janda, Jan Krhut, Jan Mecl and Vladimir Student, Czech Republic; Pierre Denys, Gilles Karsenty and Jean-Marc Soler, France; Peter Martin Braun, Moritz Hamann, Paolo Fornara, Albert Kaufmann, Heinrich Schulte-Baukloh and Karl-Dietrich Sievert, Germany; Sharon English and John Tuckey, New Zealand; Jan Ilkowski, Zenona Jablonska, Rafal Kmieciak and Janusz Zajda, Poland; Oleg Apolikhin, Gregory Krivoborodov, Dmitry Pushkar and Olga Vorobyeva, Russia; Jozef Marko, Ivan Mincˇík and Jan Svihra, Slovak Republic; Christopher Reginald Chapple, Graham Conn and Clare Fowler, United Kingdom; Valentyn Kobets, Yuriy Sernyak, Petro Ivashchenko, Oleksandr Shulyak and Valerii Zaitsev, Ukraine; and Michael Albo, Yitzhak Berger, Jeffrey Davies Branch, Steven B. Brandes, Michael B. Chancellor, Lynn Conrad, Ananias Diokno, Roger R. Dmochowski, Jonathan M. Fialkov, Jenelle Foote, Jason P. Gilleran, David Ginsberg, Evan Robert Goldfischer, Howard Brian Goldman, Angelo Gousse, Richard Howard Greengold, Douglass S. Hale, Timothy C. Hlavinka, Michael Kennelly, Richard Kershen, Gary Lemack, Wendy W. Leng, L. Keith Lloyd, Kurt McCammon, Karen Noblett, Delbert C. Rudy, Peter K. Sand, Patrick J. Shenot, Steven W. Siegel, Christopher Patrick Smith, John J. Smith III, Jose R. Sotolongo, Jr., William D. Steers, William Sunter, Suzette Elisabeth Sutherland, George W. Tawil, Thomas Williams and Tracey Small Wilson, United States.
REFERENCES 1. Fowler CJ, Griffiths D and de Groat WC: The neural control of micturition. Nat Rev Neurosci 2008; 9: 453. 2. Chancellor MB, Anderson RU and Boone TB: Pharmacotherapy for neurogenic detrusor overactivity. Am J Phys Med Rehabil 2006; 85: 536. 3. Stohrer M, Blok B, Castro-Diaz D et al: EAU guidelines on neurogenic lower urinary tract dysfunction. Eur Urol 2009; 56: 81.
4. Foley SJ, McFarlane JP and Shah PJ: Vesicoureteric reflux in adult patients with spinal injury. Br J Urol 1997; 79: 888. 5. Hollingworth W, Campbell JD, Kowalski J et al: Exploring the impact of changes in neurogenic urinary incontinence frequency and conditionspecific quality of life on preference-based outcomes. Qual Life Res 2010; 19: 323. 6. Schurch B, Denys P, Kozma CM et al: Botulinum toxin A improves the quality of life of patients
with neurogenic urinary incontinence. Eur Urol 2007; 52: 850. 7. Schurch B, Denys P, Kozma CM et al: Reliability and validity of the Incontinence Quality of Life questionnaire in patients with neurogenic urinary incontinence. Arch Phys Med Rehabil 2007; 88: 646. 8. Jundt K, Schreyer K, Friese K et al: Anticholinergic therapy: do the patients take the pills prescribed? Arch Gynecol Obstet 2011; 284: 663.
PHASE 3 EFFICACY AND TOLERABILITY STUDY OF ONABOTULINUMTOXINA
9. DasGupta R and Fowler CJ: Bladder, bowel and sexual dysfunction in multiple sclerosis: management strategies. Drugs 2003; 63: 153. 10. Benevento BT and Sipski ML: Neurogenic bladder, neurogenic bowel, and sexual dysfunction in people with spinal cord injury. Phys Ther 2002; 82: 601. 11. Schurch B, Stohrer M, Kramer G et al: Botulinum-A toxin for treating detrusor hyperreflexia in spinal cord injured patients: a new alternative to anticholinergic drugs? Preliminary results. J Urol 2000; 164: 692. 12. Schurch B, de Seze M, Denys P et al: Botulinum toxin type a is a safe and effective treatment for neurogenic urinary incontinence: results of a single treatment, randomized, placebo controlled 6-month study. J Urol 2005; 174: 196.
13. Patrick DL, Martin ML, Bushnell DM et al: Quality of life of women with urinary incontinence: further development of the incontinence quality of life instrument (I-QOL). Urology 1999; 53: 71. 14. Hatheway CL and Dang C: Immunogenicity of the neurotoxins of Clostridium botulinum. In: Therapy with Botulinum Toxin. Edited by J Jankovic and M Hallett. New York: Marcel Dekker 1994; pp 93–107. 15. Karsenty G, Denys P, Amarenco G et al: Botulinum toxin A (Botox) intradetrusor injections in adults with neurogenic detrusor overactivity/ neurogenic overactive bladder: a systematic literature review. Eur Urol 2008; 53: 275. 16. Cruz F, Herschorn S, Heesakkers J et al: Efficacy and safety of onabotulinumtoxinA in patients
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with urinary incontinence due to neurogenic detrusor overactivity: a randomized, double-blind, placebo-controlled trial. Eur Urol, 2011; 60: 742. 17. Johnson KP, Brooks BR, Cohen JA et al: Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. Copolymer 1 Multiple Sclerosis Study Group. Neurology 1995; 45: 1268. 18. Freedman MS: Long-term follow-up of clinical trials of multiple sclerosis therapies. Neurology 2011; 76: S26. 19. Manack A, Motsko SP, Haag-Molkenteller C et al: Epidemiology and healthcare utilization of neurogenic bladder patients in a US claims database. Neurourol Urodyn 2011; 30: 395.
Phase 3 Efficacy and Tolerability Study of OnabotulinumtoxinA for Urinary Incontinence From Neurogenic Detrusor Overactivity David Ginsberg,*,† Angelo Gousse,‡ Veronique Keppenne, Karl-Dietrich Sievert,§ Catherine Thompson,§ Wayne Lam,§ Mitchell F. Brin, Brenda Jenkins§ and Cornelia Haag-Molkenteller§ From the University of Southern California (DG), Los Angeles and Allergan, Inc. (CT, WL, BJ, CHM) and University of California-Irvine, Irvine (MFB), California, Herbert Wertheim College of Medicine, Florida International University (AG), Miami, Florida, Université de Liège (VK), Liege, Belgium, and University of Tuebingen (KDS), Tuebingen Germany
Purpose: We assessed the efficacy, safety and effects on quality of life of onabotulinumtoxinA in patients with neurogenic detrusor overactivity. Materials and Methods: In this 52-week, international, multicenter, doubleblind, randomized, placebo controlled trial 416 patients with neurogenic detrusor overactivity and urinary incontinence (14 or more episodes per week) resulting from multiple sclerosis (227) and spinal cord injury (189) were treated with intradetrusor injections of onabotulinumtoxinA (200 or 300 U) or placebo. The primary end point was the change from baseline in the mean number of urinary incontinence episodes per week at week 6. Maximum cystometric capacity, maximum detrusor pressure during the first involuntary detrusor contraction and Incontinence Quality of Life total score were secondary end points. Adverse events were monitored. Results: OnabotulinumtoxinA at a dose of 200 U in 135 patients and 300 U in 132 decreased mean urinary incontinence at week 6 by 21 and 23 episodes per week, respectively, vs 9 episodes per week in 149 on placebo (each dose p ⬍0.001). Also, maximum cystometric capacity, maximum detrusor pressure during the first involuntary detrusor contraction and Incontinence Quality of Life score were significantly improved over values in the placebo group (each dose p ⬍0.001). Median time to patient re-treatment request was greater for onabotulinumtoxinA 200 and 300 U than for placebo (256 and 254 days, respectively, vs 92). The most common adverse events were urinary tract infection and urinary retention. Of patients who did not catheterize at baseline 10% on placebo, 35% on 200 U and 42% on 300 U initiated catheterization due to urinary retention.
Abbreviations and Acronyms AE ⫽ adverse event CIC ⫽ clean intermittent catheterization I-QOL ⫽ Incontinence Quality of Life IDC ⫽ involuntary detrusor contraction ITT ⫽ intent to treat MCC ⫽ maximum cystometric capacity MDP ⫽ maximum detrusor pressure MS ⫽ multiple sclerosis NDO ⫽ neurogenic detrusor overactivity PVR ⫽ post-void residual urine volume QOL ⫽ quality of life SCI ⫽ spinal cord injury UI ⫽ urinary incontinence UTI ⫽ urinary tract infection
Submitted for publication October 28, 2011. Study received ethics committee approval at each study site. Supported by Allergan, Inc., Irvine, California. * Correspondence: Department of Urology, University of Southern California, Norris Cancer Center, 1441 East Lake Ave., Suite 7416, Los Angeles, California 90033 (telephone: 323-865-3703; FAX: 323-865-0120; e-mail: [email protected]). † Financial interest and/or other relationship with Allergan, AMS/Boston Scientific, Medtronic, Tengion and Pfizer. ‡ Financial interest and/or other relationship with Allergan, Pfizer, Lilly and Astellas. § Financial interest and/or other relationship with Allergan.
0022-5347/12/1876-2131/0 THE JOURNAL OF UROLOGY® © 2012 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
AND
RESEARCH, INC.
Vol. 187, 2131-2139, June 2012 Printed in U.S.A. DOI:10.1016/j.juro.2012.01.125
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Conclusions: OnabotulinumtoxinA significantly improved neurogenic detrusor overactivity symptoms vs placebo. Clean intermittent catheterization initiation due to urinary retention appeared to increase in a dose dependent fashion. No clinically relevant benefit in efficacy or duration was identified for the 300 U dose over the 200 U dose. Key Words: urinary incontinence, botulinum toxin, onabotulinumtoxinA, spinal cord injuries, multiple sclerosis NEUROLOGICAL conditions such as SCI and MS often result in NDO.1,2 NDO can lead to urodynamically measured increased bladder storage pressures and UI, which can negatively impact QOL.3–7 Initial medical treatment for NDO consists mainly of anticholinergics, often with CIC. However, long-term anticholinergic treatment may be suboptimal, with patients stopping medication due to lack of efficacy and bothersome side effects. Primary side effects include dry mouth and constipation, which may be significant baseline problems in patients with neurological disease.8 –10 Early trials using onabotulinumtoxinA in patients with NDO demonstrated fewer UI episodes, improved urodynamic parameters and improved QOL.11,12 We describe a large, multicenter, prospective, placebo controlled trial designed to evaluate the safety and efficacy of 200 and 300 U onabotulinumtoxinA for UI resulting from NDO in patients with MS or SCI who were not adequately treated with anticholinergic therapy.
MATERIALS AND METHODS Study Design This global, multicenter, randomized, double-blind, placebo controlled, phase 3 trial (www.clinicaltrials.gov NCT00311376) was performed at 85 centers between September 2006 and May 2010 as part of the DIGNITY (Double-Blind Investigation of Purified Neurotoxin Complex in Neurogenic Detrusor Overactivity) Study program. The study included patients 18 to 80 years old with NDO 3 months or greater in duration and 14 or more UI episodes per week during screening who were not adequately treated with anticholinergic therapy. Patients had NDO, as demonstrated by IDC on urodynamics, secondary to SCI at T1 or below, or MS with an Expanded Disability Status Score of 6.5 or less using the Neurostatus web based, interactive test and certification tool, which provides standardized examinations and consistent definitions for scoring. Patients treated with anticholinergics at baseline continued at a stable dose throughout the study, while those not on anticholinergics remained off anticholinergics. Patients who did not perform CIC at baseline had to be willing to initiate CIC, if needed. Patients were excluded from analysis if they received previous treatment with any serotype botulinum toxin for urological conditions or surgery that might affect bladder function. Ethics committee approval was obtained at each study site and all patients provided written informed consent.
Patients were randomized 1:1:1 to receive 200 or 300 U onabotulinumtoxinA (Botox®) or placebo (0.9% saline). To maintain the blind, independent drug reconstitution was used. Using a rigid or flexible cystoscope we administered 30, 1 ml injections about 1 cm apart and 2 mm deep in the detrusor, sparing the trigone (fig. 1).12 Patients received no anesthesia, local anesthetic instillation without or with sedation, or general anesthesia. After initial treatment patients were evaluated at the clinic at weeks 2, 6 and 12 with followup every 6 weeks until re-treatment or study exit. Bladder diaries were collected before each followup. I-QOL13 responses were collected at baseline, posttreatment weeks 6 and 12, scheduled clinic visits and study exit. Urodynamic analysis was done at baseline and week 6 after each treatment. Patients could receive up to 2 treatments but could not request re-treatment sooner than 12 weeks after initial treatment. To qualify for re-treatment patients had to initiate the request and show less than a 50% decrease from baseline in the number of weekly UI episodes.
Efficacy and Safety Assessments The primary efficacy end point was the change from baseline in the number of weekly UI episodes 6 weeks after treatment, as collected in a 7-day bladder diary. Response was also categorized using the decrease in UI episodes per week from baseline, including 50% or greater (responder), 75% or greater and 100% (dry) at week 6. Secondary end points evaluated at week 6 included MCC, MDP during the first IDC and I-QOL total summary score. All urodynamic tracings were done according to International Con-
Figure 1. OnabotulinumtoxinA injections were administered cystoscopically in detrusor, sparing trigone.
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evaluated using the Hochberg procedure to adjust for multiple comparisons. As secondary end points, a hierarchical analysis strategy and the same ANCOVA model were used to evaluate changes from baseline. Median duration of the treatment effect was evaluated using Kaplan-Meier analysis as the time from day 1 to the patient request for re-treatment. Median time to patient qualification for retreatment was evaluated similarly. For treatment emergent AEs during treatment cycle 1 the Pearson chi-square test was used to evaluate the equality of proportions among groups. If 25% of the cells had an expected count of less than 5, the Fisher exact test was used. MS exacerbation was defined as a sudden worsening of MS symptoms or the appearance of new symptoms that lasted 24 hours or more and was separated from a previous exacerbation by at least 1 month. MS exacerbations were analyzed using annualized rates, that is the total number of exacerbation events divided by the total exposure time for all patients with MS.
tinence Society guidelines and were read by a blinded, independent central reviewer. AEs were assessed throughout the study. A report of UTI by the investigator did not distinguish asymptomatic from symptomatic UTIs. PVR was assessed in patients not on CIC. Recording urinary retention as an AE was based on investigator clinical judgment. CIC use was recorded in the diary and CIC initiation due to urinary retention was reported by the investigator. Bladder and renal ultrasound was done at specified time points and clinically significant changes from baseline were noted as AEs. The mouse protection assay14 was used to detect neutralizing antibodies against onabotulinumtoxinA at baseline, before re-treatment and at study exit.
Statistical Analysis The study was powered at the 5% significance level to compare 2 doses of onabotulinumtoxinA vs placebo. Comparisons vs placebo focused on the initial 12 weeks after the first treatment before patients were eligible for retreatment. The safety population consisted of all randomized patients who received study drug, analyzed according to the dose received. The ITT population included all randomized patients. ANCOVA was done to assess efficacy in the ITT population with the baseline value as a covariate, and treatment arm, etiology at study entry, concurrent use/nonuse of anticholinergics and investigative site as factors using SAS®, version 9.2. Two pairwise comparisons (200 and 300 U onabotulinumtoxinA vs placebo at week 6) were
RESULTS Patients The ITT population consisted of 416 randomized patients, of whom 329 (79%) completed the 52-week study and 87 (21%) discontinued early, including 13 (3%) due to AEs (fig. 2). Table 1 lists demographic
Randomized = 416
Placebo = 149
OnabotA 200U = 135
OnabotA 300U = 132
Withdrawn = 4
Withdrawn = 5 Safety population = 407
Treatment Cycle 1 OnabotA 200U = 135
OnabotA 300U = 127
Discontinued = 14 (10%)
Discontinued = 16 (12%)
Discontinued = 22 (17%)
Completed = 19 (13%)
Completed = 45 (33%)
Completed = 36 (28%)
Entered 2 = 112 (77%)
Entered 2 = 74 (55%)
Entered 2 = 69 (54%)
OnabotA 200U = 74*
OnabotA 300U = 69*
Discontinued = 7 (10%)
Discontinued = 4 (6%)
Completed = 54 (73%)
Completed = 56 (81%)
Placebo = 145
Treatment Cycle 2 OnabotA 200U = 51*
OnabotA 300U = 46*
Discontinued = 6 (12%)
Discontinued = 5 (11%)
Completed = 45 (88%)
Completed = 39 (85%)
Figure 2. Patient flow through trial. OnabotA, onabotulinumtoxinA. Asterisk indicates numbers may not sum to total due to patients with opportunity to receive third treatment in earlier version of protocol and 15 who received placebo at treatment cycle 2 before amendment whose cycle 2 data were not analyzed.
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Table 1. Baseline demographic and clinical characteristics in ITT population Treatment Placebo
200 U
300 U
Totals
Overall No. pts Age: Mean ⫾ SD No. less than 40 (%) No. 40-64 (%) No. 65-74 (%) No. male (%) No. race (%): White Black Other No. anticholinergics (%) No. CIC (%)
149
135
46 ⫾ 13 45 (30) 95 (64) 9 (6) 73 (49)
46 ⫾ 14 48 (36) 73 (54) 14 (10) 55 (41)
138 (93) 5 (3) 6 (4) 83 (56) 89 (60)
117 (87) 12 (9) 6 (4) 66 (49) 71 (54)
132 47 ⫾ 12 40 (30) 83 (63) 9 (7) 43 (33)
416 46 ⫾ 13 133 (32) 251 (60) 32 (8) 171 (41)
117 (89) 7 (5) 8 (6) 68 (52) 73 (57)
372 (89) 24 (6) 20 (5) 217 (52) 233 (57)
Multiple sclerosis No. pts Mean ⫾ SD yrs since diagnosis No. anticholinergics (%) No. CIC (%) No. disease classification (%): Relapsing remitting Primary progressive Secondary progressive Progressive relapsing Mean ⫾ SD Expanded Disability Status Score No. pts Mean ⫾ SD yrs since injury No. anticholinergics (%) No. CIC (%) No. American Spinal Injury Association impairment scale (%): A B C D E
81 14 ⫾ 8 43 (53) 31 (38)
77 15 ⫾ 11 38 (49) 27 (36)
69 13 ⫾ 7 36 (52) 21 (31)
227 14 ⫾ 9 117 (51) 79 (35)
44 (54) 10 (12) 22 (27) 4 (5) 5.1 ⫾ 1.4 Spinal cord injury 68 10 ⫾ 12 40 (59) 58 (87)
50 (65) 5 (7) 18 (23) 4 (5) 5.2 ⫾ 1.3
37 (54) 8 (12) 19 (28) 5 (7) 5.0 ⫾ 1.4*
131 (58) 23 (10) 59 (26) 13 (6) 5.1 ⫾ 1.3
58 9⫾9 28 (48) 44 (77)
63 9⫾9 32 (51) 52 (84)
189 9 ⫾ 10 100 (53) 154 (83)
51 (75) 3 (4) 2 (3) 6 (9) 4 (6)
37 (64) 4 (7) 5 (9) 7 (12) 5 (9)
41 (65) 6 (10) 5 (8) 8 (13) 3 (5)
129 (68) 13 (7) 12 (6) 21 (11) 12 (6)
* In 68 patients.
and clinical characteristics of the ITT population and subgroups. UI Episodes Each onabotulinumtoxinA dose significantly decreased UI episodes compared with placebo 2, 6 and 12 weeks after treatment (p ⱕ0.008). There were no clinically relevant differences between the active dose groups (fig. 3, A). Similar results were seen in the MS and SCI subpopulations (fig. 3, B and C). At week 6 treatment resulted in a ⫺30%, ⫺67% and ⫺74% change from baseline in UI in the placebo, and 200 and 300 U onabotulinumtoxinA groups, respectively. Significantly more patients in the 2 onabotulinumtoxinA groups than the placebo group attained the 50% or greater responder threshold at week 6 for a reduction in weekly UI episodes (p ⱕ0.001). Furthermore, 36% and 41% of patients in the 200 and 300 U groups, respectively, achieved dry status (fig. 4).
Urodynamics and QOL Each onabotulinumtoxinA dose significantly increased MCC from baseline vs placebo (p ⬍0.001). There were no relevant differences between the active dose groups or by etiology (table 2). Each onabotulinumtoxinA dose significantly decreased MDP during the first IDC from baseline vs placebo (p ⬍0.001). Decreases were similar in the MS and SCI subpopulations (table 2). The proportion of patients without IDC at week 6 (maximum bladder filling 500 ml for urodynamics) was 19% (26 of 137), 64% (81 of 127) and 69% (77 of 111) in the placebo, and the onabotulinumtoxinA 200 and 300 U groups, respectively. Each onabotulinumtoxinA dose also significantly improved the I-QOL total summary score at week 6 compared with placebo (table 2). This significant improvement was maintained through week 12 in the overall population with increases from baseline
PHASE 3 EFFICACY AND TOLERABILITY STUDY OF ONABOTULINUMTOXINA
0
0
2
4
6
8
10
12
-5 -10 -15
*
-20
*
*
*
*
*
-25
*P=≤0.008 versus placebo
-30
C
Weeks Post-Treatment 0
0
2
4
6
8
10
12
-5 -10 -15 -20
*
* -25
* *P=<0.05 versus placebo
-30
*
Change From Baseline (episodes/week)
B
Weeks Post-Treatment
Change From Baseline (episodes/week)
Change From Baseline (epsiodes/week)
A
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Weeks Post-Treatment 0
2
4
6
8
10
12
0 -5 -10 -15 -20 -25 -30
* *
*
* *
*
*P=≤0.001 versus placebo
Figure 3. Change from baseline in weekly UI episodes after treatment cycle 1 at weeks 2, 6 and 12. A, ITT population. Orange curve indicates 149 patients on placebo. Purple curve indicates 135 patients on 200 U onabotulinumtoxinA. Red curve indicates 132 patients on 300 U onabotulinumtoxinA. B, MS population. Orange curve indicates 81 patients on placebo. Purple curve indicates 77 patients on 200 U onabotulinumtoxinA. Red curve indicates 69 patients on 300 U onabotulinumtoxinA. C, SCI population. Orange curve indicates 68 patients on placebo. Purple curve indicates 58 patients on 200 U onabotulinumtoxinA. Red curve indicates 63 patients on 300 U onabotulinumtoxinA.
of 9, 31 and 33 points in the placebo, and onabotulinumtoxinA 200 and 300 U groups, respectively (each treatment group vs placebo p ⬍0.001). The change from baseline in I-QOL score was analyzed in patients who did not perform CIC at baseline to determine whether subsequent initiation of CIC influenced QOL. In these patients the I-QOL improvement was similar whether they did or did not begin CIC after treatment (fig. 5). Effect Duration Re-treatment could not be requested before 12 weeks after treatment. Median time to patient request for re-treatment was 92 days (95% CI 87–107) for placebo, 256 (95% CI 212–296) for 200 U onabotulinumtoxinA and 254 (95% CI 211–337) for 300 U onabotulinumtoxinA (each treatment group vs 100
Placebo
*
Percentage of Patients
80
75%
OnabotA 200U
*
OnabotA 300U
77%
*
*
62% 63%
60
* 40
38%
* 41%
36% 26%
20 10%
0
≥50%
≥75%
100%
Responder Threshold (% decrease from baseline in UI) *P<0.001 vs placebo
Figure 4. Responder analysis for weekly UI episode decrease at week 6 vs baseline by treatment response thresholds in ITT population. OnabotA, onabotulinumtoxinA.
placebo p ⬍0.001, fig. 6). Median time to qualification for re-treatment was 96 days (95% CI 90 –127) for placebo, 295 (95% CI 253–338) for 200 U onabotulinumtoxinA and 337 (95% CI 294 –380) for 300 U onabotulinumtoxinA (each treatment group vs placebo p ⬍0.001). Safety and Tolerability Table 3 lists adverse events for the first 12 weeks and for treatment cycle 1, which had a median duration of 19.4, 43.9 and 44.0 weeks in the placebo, and 200 and 300 U groups, respectively. The most common AEs were UTI and urinary retention (table 4). UTI was reported as a serious AE in 8 patients since it led to hospitalization. One case of urosepsis was reported in the placebo group and 1 of pyelonephritis was noted in the 300 U group in treatment cycle 1. The UTI incidence was similar across all treatment groups in the SCI population but in the MS population it was higher after receiving onabotulinumtoxinA. Seven patients reported autonomic dysreflexia events during treatment cycle 1 (table 3). The event was considered related to the injection procedure since it occurred between days 1 and 5 in 6 patients. All cases resolved without sequelae within 24 hours. In patients who did not perform CIC at baseline, mainly those with MS, significant dose dependent increases from baseline in PVR were observed by week 2 in each onabotulinumtoxinA dose groups but not in the placebo group (p ⫽ 0.004, table 5). Week 2 was the first posttreatment time point at which the investigator assessed the patient. This represents the effect of treatment on PVR before the time that CIC could have been initiated. After active treatment approximately 50% of patients who did not use CIC at baseline began CIC for
35.1 ⫾ 18.1 10.8 ⫾ 18.4
50.9 ⫾ 38.1 ⫺2.4 ⫾ 43.4*
256 ⫾ 144 16 ⫾ 127
28.3 ⫾ 15.8 ⫺8.8 ⫾ 16.2
149
132 31.1 ⫾ 17.0 ⫺22.7 ⫾ 17.1* 256 ⫾ 145 168 ⫾ 170* 47.1 ⫾ 36.3 ⫺33.3 ⫾ 37.8* 32.2 ⫾ 18.6 32.9 ⫾ 23.9*
135 32.3 ⫾ 22.8 ⫺21.0 ⫾ 23.8* 252 ⫾ 154 151 ⫾ 171* 51.3 ⫾ 34.7 ⫺35.1 ⫾ 35.7* 34.0 ⫾ 18.0 26.9 ⫾ 26.8*
Proportion Requesting Retreatment
31.5 ⫾ 17.2 12.4 ⫾ 18.9
42.3 ⫾ 30.9 12.1 ⫾ 42.3
243 ⫾ 143 ⫺7.5 ⫾ 118
30.3 ⫾ 17.8 ⫺11.5 ⫾ 19
81
Placebo
31.3 ⫾ 17.7 ⫺23.8 ⫾ 18.3* 251 ⫾ 149 162 ⫾ 171* 36.8 ⫾ 28.2 ⫺29.0 ⫾ 33.2* 30.5 ⫾ 18.6 38.3 ⫾ 24.1*
260 ⫾ 161 142 ⫾ 179* 43.6 ⫾ 28.8 ⫺28.4 ⫾ 31.9* 33.5 ⫾ 17.1 28.0 ⫾ 28.0*
69
300 U Treatment
32.7 ⫾ 22.2 ⫺20.4 ⫾ 25.7
77
200 U Treatment
300 U Treatment
200 U Treatment
* p ⬍0.05 vs placebo. † Missing values were imputed with mean of nonmissing items at same visit.
No. pts UI (No./wk): Baseline Change from baseline MCC (ml): Baseline Change from baseline MDP at 1st IDC (cm H2O): Baseline Change from baseline I-QOL total summary score:† Baseline Change from baseline
Placebo
Mean ⫾ SD MS
Mean ⫾ SD Totals
Table 2. Change from baseline at week 6 during cycle 1 in urological and quality of life parameters in ITT population
34.5 ⫾ 19.4 25.4 ⫾ 25.2*
39.4 ⫾ 18.3 8.9 ⫾ 17.7
63
300 U Treatment
34.1 ⫾ 18.6 26.6 ⫾ 22.2*
58.4 ⫾ 40.8 ⫺36.3 ⫾ 41.4
262 ⫾ 142 175 ⫾ 169*
30.9 ⫾ 16.5 ⫺21.5 ⫾ 15.8*
Change From Baseline (Total Score)
61.6 ⫾ 39.1 ⫺41.0 ⫾ 38.4
242 ⫾ 147 163 ⫾ 160*
271 ⫾ 145 45 ⫾ 134 61.1 ⫾ 43.2 ⫺19.6 ⫾ 38.5
31.6 ⫾ 23.7 ⫺21.9 ⫾ 21.1*
58
200 U Treatment
25.9 ⫾ 12.8 ⫺5.7 ⫾ 11.2
68
Placebo
Mean ⫾ SD SCI
2136 PHASE 3 EFFICACY AND TOLERABILITY STUDY OF ONABOTULINUMTOXINA
I-QOL
40
*
30
*
0
0
2 4
90
180
* * *
20
*
10
0 * P<0.05 vs placebo
Weeks Post-Treatment
6 8
0.2
270
10
360
12
Placebo CIC-Y 200U OnabotA CIC-Y 300U OnabotA CIC-Y
Placebo CIC-N 200U OnabotA CIC-N 300U OnabotA CIC-N
Figure 5. I-QOL summary score in patients without CIC (CIC-N) at baseline. CIC-Y, CIC at baseline. OnabotA, onabotulinumtoxinA. Asterisk indicates p ⬍0.05 onabotulinumtoxinA vs placebo.
any reason during treatment cycle 1. Notably 22% of placebo treated patients also initiated CIC during treatment cycle 1 despite minimal increases in PVR. Since the protocol had no defined PVR at which to initiate CIC, initiating CIC due to urinary retention was based on investigator assessment. Of patients who did not use CIC at baseline the proportion in treatment cycle 1 who initiated CIC for urinary retention was 10% in the placebo group, and 35% and 42% in the 200 and 300 U dose groups, respectively. Seven patients discontinued the study due to nonfatal AEs during treatment cycle 1, including 4 in the 300 U group with UTI, bladder pain, breast
1.0
0.8
0.6
0.4
Placebo 200 U onabotA 300 U onabotA
0.0
450
Days Post-Treatment
Figure 6. Kaplan-Meier curve for time to patient request for re-treatment in ITT population. onabotA, onabotulinumtoxinA.
PHASE 3 EFFICACY AND TOLERABILITY STUDY OF ONABOTULINUMTOXINA
Table 3. Treatment emergent AEs during treatment cycle 1 No. Treatment (%) No. Placebo (%) No. pts Overall AE Serious AE AE with 5% or greater incidence: UTI Urinary retention Hematuria Pyrexia Overall AE Serious AE AE with 5% or greater incidence: UTI Urinary retention MS relapse* Muscular weakness† Bladder pain Diarrhea Headache Hypertension Nausea Hematuria Vulvovaginal mycotic infection Fatigue Pyrexia Other events of interest: Autonomic dysreflexia Constipation
145
200 U 135 (70) (3)
81 (64) 12 (9)
26 5 4 4
38 27 6 7
(28) (20) (4) (5)
36 (28) 21 (17) 6 (5) 2 (2)
113 17
(84) (13)
102 (80) 23 (18)
64 (50) 22 (17) 12 (9) 9 (7) 7 (6) 7 (6) 7 (6) 7 (6) 8 (6) 6 (5) 3 (4)
107 14
49 5 3 4 2 4 4 0 3 4 2
(34) (3) (2) (3) (1) (3) (3) (2) (3) (3)
66 (49) 27 (20) 1 (less than 1) 4 (3) 2 (2) 8 (6) 4 (3) 3 (2) 6 (4) 7 (5) 6 (8)
6 5
(4) (3)
8 10
(6) (7)
4 (3) 4 (3)
1 (less than 1)
3
(2)
3 (2)
5
6
(4)
5 (4)
(3)
* MS exacerbation was to have been reported as individual signs and symptoms. However, MS exacerbation (the preferred term was MS relapse) was recorded for 13 patients with serious and 3 with nonserious AEs, in addition to or instead of exacerbation signs and/or symptoms. † All patients with MS.
cancer and bladder calculus; 2 in the 200 U group with hydronephrosis and eschar; and 1 in the placebo group with influenza. None was considered by the investigator to be related to the study drug or procedure. Two deaths were reported, including 1 in treatment cycle 1 in the 300 U group and 1 in treatment cycle 2 in the 200 U group. Each death occurred more than 170 days after the last injection and were not considered treatment related. Table 4. UTI and urinary retention AEs by etiology
MS: UTI Urinary retention SCI: UTI Urinary retention
Treatment Placebo
127
94 4
(18) (3) (3) (3) Overall (74) (10)
Table 5. PVR at week 2 and CIC during treatment cycle 1 in patients with no CIC at baseline
300 U
1st 12 wks 83 (57) 12 (8)
No. Placebo (%)
No. 200 U (%)
No. 300 U (%)
80 22 (28) 4 (5) 65 27 (42) 1 (2)
76 38 (50) 22 (29) 59 28 (48) 5 (9)
67 34 (51) 19 (28) 60 30 (50) 3 (5)
2137
200 U
300 U
No. pts 58 60 55 PVR (ml): Mean ⫾ SD baseline 57 ⫾ 61 50 ⫾ 51 52 ⫾ 50 Mean ⫾ SD wk 2 7 ⫾ 55 106 ⫾ 165 169 ⫾ 300 change % Wk 2 PVR 200 ml 4 32 36 or greater No. CIC initiated (%): Urinary retention 6 (10) 21 (35) 23 (42) Any reason 13 (22) 28 (47) 27 (49)
p Value (KruskalWallis test)
0.926 0.004
The annualized MS exacerbation rate during treatment cycle 1 was 0.22, 0.14 and 0.37 in the placebo, and 200 and 300 U groups, respectively. No patient showed neutralizing antibodies against onabotulinumtoxinA after treatment(s).
DISCUSSION NDO can be caused by various neurological conditions. This study evaluated patients with SCI or MS. Each onabotulinumtoxinA dose (200 and 300 U) significantly decreased the frequency of UI episodes per week and improved urodynamic outcomes and QOL measures. The onset of action of onabotulinumtoxinA was rapid (within 2 weeks of injection) and sustained with a duration of effect (time to re-treatment request) of approximately 9 months. Average detrusor pressure during the first IDC decreased more than 33 cm H2O from a baseline of 50 cm H2O. Approximately two-thirds of onabotulinumtoxinA treated patients showed no evidence of NDO/IDC on post-injection urodynamics at week 6 with up to 500 ml bladder filling. Many initial studies that evaluated onabotulinumtoxinA for NDO included doses up to 300 U.15 This trial suggests that a dose of 200 U is sufficient and these results are consistent with those of a similarly designed trial.16 Efficacy and duration of effect were similar for the 2 doses but the 300 U dose showed an increased risk of urinary retention and elevated PVR in patients who did not catheterize. Since urinary retention is a risk of onabotulinumtoxinA detrusor injection, patients considering this treatment should be willing and able to perform CIC. However, estimating the true risk of urinary retention is a challenge. This was illustrated in the placebo arm, in which PVR remained stable throughout the study. However, 22% of patients on placebo who did not perform CIC at baseline began CIC during treatment cycle 1. This suggests that many patients who were not on CIC at baseline might have benefited from
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PHASE 3 EFFICACY AND TOLERABILITY STUDY OF ONABOTULINUMTOXINA
CIC before study entry and the need for CIC was due to voiding dysfunction inherent to neurogenic bladder. The difference between the proportion of patients initiating CIC for any reason after 200 U compared with the proportion initiating CIC in the placebo group was 25% (47% vs 22%). Similarly in those who initiated CIC due to urinary retention the difference in the rate in the 200 U dose and placebo groups was also approximately 25% (35% vs 10%). Thus, this may represent the true risk of CIC after onabotulinumtoxinA detrusor injection. The need to perform CIC did not negatively impact the outcome of onabotulinumtoxinA treatment. Improvements in the I-QOL score after onabotulinumtoxinA were similar with and without CIC. The 2 doses were well tolerated but the incidence of AEs was slightly lower in the 200 U group. The annualized MS exacerbation rate was low and within the expected range for the MS population.17,18 A recent study of approximately 46,000 patients with NDO showed that UTI was among the most commonly diagnosed conditions in this population, impacting 29% to 36% of patients.19 In the current series a similar 34% rate was observed in the placebo group. In patients with SCI, of whom most used CIC at baseline, the UTI rate was 42% in the placebo group and approximately 50% after active treatment. The increased incidence of UTIs in patients with MS after active treatment (28% on placebo and approximately 50% after active treatment), of whom most did not use CIC at baseline, was most likely associated with CIC initiation. A limitation is that this study was not designed specifically to assess repeat treatment. However, many patients received a second injection. Results are pending from the ongoing long-term 3-year study. Other limitations include the lack of protocol defined criteria for CIC initiation and no definition of symptomatic vs asymptomatic UTIs. OnabotulinumtoxinA is not interchangeable with other botulinum toxin preparations. The units of biological activity of onabotulinumtoxinA cannot be compared to or converted into units of any other botulinum toxin product.
CONCLUSIONS Treatment with 200 or 300 U onabotulinumtoxinA was well tolerated in patients with NDO. It significantly decreased weekly UI episodes and MDP, increased MCC and improved QOL compared to placebo treatment. No benefits in efficacy or duration of effect were observed for 300 U onabotulinumtoxinA compared with the 200 U dose. The 200 U onabotulinumtoxinA group had a more favorable safety profile.
ACKNOWLEDGMENTS Access to and use of Neurostatus is provided by Dr. Ludwig Kappos, Outpatient Clinic Neurology-Neurosurgery, University Hospital Basel and Franz Schnyder, Regarde, Basel, Switzerland. Dr. Alex Loeb, Evidence Scientific Solutions, Philadelphia, Pennsylvania assisted with the manuscript.
APPENDIX Principal Investigators Damien Bolton, Robert (Frank) Gardiner, Kym Horsell, Richard Millard, Helen O’Connell and Andrew Tan, Australia; Gustav Kiss and Helmut Madersbacher, Austria; Dirk Jan Maria Karine De Ridder, Karel Everaert, Veronique Keppenne and Jean Jacques Wyndaele, Belgium; Karen Ethans, Gary Gray, Anthony Skehan and Le Mai Tu, Canada; Milos Brodak, Vaclav Janda, Jan Krhut, Jan Mecl and Vladimir Student, Czech Republic; Pierre Denys, Gilles Karsenty and Jean-Marc Soler, France; Peter Martin Braun, Moritz Hamann, Paolo Fornara, Albert Kaufmann, Heinrich Schulte-Baukloh and Karl-Dietrich Sievert, Germany; Sharon English and John Tuckey, New Zealand; Jan Ilkowski, Zenona Jablonska, Rafal Kmieciak and Janusz Zajda, Poland; Oleg Apolikhin, Gregory Krivoborodov, Dmitry Pushkar and Olga Vorobyeva, Russia; Jozef Marko, Ivan Mincˇík and Jan Svihra, Slovak Republic; Christopher Reginald Chapple, Graham Conn and Clare Fowler, United Kingdom; Valentyn Kobets, Yuriy Sernyak, Petro Ivashchenko, Oleksandr Shulyak and Valerii Zaitsev, Ukraine; and Michael Albo, Yitzhak Berger, Jeffrey Davies Branch, Steven B. Brandes, Michael B. Chancellor, Lynn Conrad, Ananias Diokno, Roger R. Dmochowski, Jonathan M. Fialkov, Jenelle Foote, Jason P. Gilleran, David Ginsberg, Evan Robert Goldfischer, Howard Brian Goldman, Angelo Gousse, Richard Howard Greengold, Douglass S. Hale, Timothy C. Hlavinka, Michael Kennelly, Richard Kershen, Gary Lemack, Wendy W. Leng, L. Keith Lloyd, Kurt McCammon, Karen Noblett, Delbert C. Rudy, Peter K. Sand, Patrick J. Shenot, Steven W. Siegel, Christopher Patrick Smith, John J. Smith III, Jose R. Sotolongo, Jr., William D. Steers, William Sunter, Suzette Elisabeth Sutherland, George W. Tawil, Thomas Williams and Tracey Small Wilson, United States.
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