Tables

Table 1.1: Dose-finding studies – summary of study characteristics

Table 1.2: Placebo-controlled studies – summary of study characteristics

Table 1.3: Active-controlled studies – summary of study characteristics

Table 1.4: Flexible dose studies & combined high dose AM - summary of study characteristics

Table 1.5: Miscellaneous studies - summary of study characteristics

Table 2.1: Placebo-controlled studies – efficacy outcomes

Table 2.2: Active-controlled studies – efficacy outcomes

Table 3.1: Placebo-controlled studies – tolerability and safety outcomes

Table 3.2: Active-controlled studies – tolerability and safety outcomes

Figure 1: Body of evidence

Antimuscarinics – NDO - Review Table 1.1: Dose-finding studies – summary of study characteristics

Treatment Patient L Age Author Study Design duration Treatment groups number Gender Diagnosis1 E (years) (weeks) (N) 1 x 15 mg Prop Neurogenic reflex IR(N=14) incontinence Prospective, 2 x 15 mg Prop IR 48/40/43/43 (posttraumatic, Mazur randomised, (N=21) 33 male years in the postoperative, 1b 3 66 (1994) parallel group, 3 x 15 mg Prop IR 33 female 4 treatment myelitis, multicentre (4) (N=17) arms myelodegenerative) 4 x 15 mg Prop IR (N=14) Placebo (N=19) 2 x 0.5 mg Tolt IR Prospective, Detrusor (N=20) randomised, hyperreflexia Van 2 x 1.0 mg Tolt IR 90 enrolled, parallel group, 48 male (MS 23, paraplegia. Kerrebroeck 1b 2 (N=16) 76 per 42 years double-blind, 42 female 20, quadriplegia 11, (1998) 2 x 2.0 mg Tolt IR protocol placebo-controlled, spinal cord diseases (N=18) multicentre (14) 8, miscellaneous 21) 2 x 4.0 mg Tolt IR (N=17) Prospective, Placebo (N=16) Detrusor randomised, 2 x 10 mg TC IR (N=16) Stöhrer 66 enrolled, hyperreflexia 1b parallel group, 2 2 x 20 mg TC IR (N=17) n.a. n.a. (1998) 63 analysed > 6 months in most double-blind, 2 x 40 mg TC IR (N=17) patients placebo-controlled 1 Terminology used by the original study authors has been retained Prop = Propiverine Tolt = Tolterodine TC = Trospium chloride

Antimuscarinics – NDO - Review Table 1.2: Placebo-controlled studies – summary of study characteristics

Treatment Patient Age Author L E Study Design duration Treatment groups number Gender Diagnosis1 (years) (weeks) (N) Prospective, Detrusor randomised, hyperreflexia in Stöhrer parallel group, 3 x 1 Placebo spinal cord 1b 3 60 n. a. n. a. (1990) double-blind, 3 x 5 mg Oxy IR injured patients placebo-controlled, and upper motor multicentre (2) neuron lesion Prospective, randomised, Spinal cord injury Placebo (N=32) A. M. Stöhrer parallel group, 61 enrolled 30 male, with consecutive 1b 3 2x20 mg TC IR 32.3 (TC) (1991) double-blind, 55 analysed 25 female detrusor (N=29) 34.2 (Plac.) placebo-controlled, hyperreflexia multicentre (3) Prospective, randomised, 30 ± 11.7 Detrusor Stöhrer parallel group, 3 x 1 Placebo 69 male, (Prop.) hyperreflexia and 1b 2 113 (1999) prospective, 3 x 15 mg Prop IR 44 female 29.2 ± 10.9 suprasacral double-blind, (Plac.) spinal cord injury multicentre (4) prospective, 2 weeks for randomised, each cross- Placebo (N=10) NDO due to SCI Ethans cross-over, over period, 14 enrolled 9 male, 40.5 2b 2 x 2 mg Tolt IR (7), MS (2), spina (2004) double-blind, intermediate 10 completed 1 female (range 21-63) (N=10) bifida (1) monocentre 4-day-wash- out.period prospective, Placebo (N=40), Amarenco randomised, NDO due to SCI 1b 4 Solifenacin n. a. n. a. 18 - 65 (2012) double-blind, (81) or MS (95) 1 x 10 mg (N=51) multicentre (n.a.) 1 Terminology used by the original study authors has been retained n.a. not applicable Oxy = Oxybutynin Tolt = Tolterodine TC = Trospium chloride

Antimuscarinics – NDO - Review Table 1.3: Active-controlled studies – summary of study characteristics 1 Treatment Patient Age Author L E Study design Duration Treatment groups number Gender Diagnosis2 (years) (weeks) (N) Prospective, 2 x 20 mg TC IR randomised, Detrusor Madersbacher (N=52), 95 enrolled, 47 male, 32.8 (TC) 1b parallel group, 2 hyperreflexia (1995) 3 x 5 mg Oxy IR 88 analysed 48 female 31.3 (Oxy) double-blind, Due to SCI (N=43) multicentre (5) 3 x 5 mg Oxy IR Prospective, (N=19), Multiple sclerosis Gajewski 8 male, 1b randomised, 6 - 8 3 x 15 mg 34 n.a. with detrusor (1996) 26 female parallel group Propantheline IR hyperreflexia (N=15) Prospective, 8.4 mg/day Tolt IR, cross-over, NDO due to SCI Ethans 12.5 mg/day Oxy IR 14 enrolled, 9 male, 40.5 (range 2b open-label, 2 (7), MS (2), spina (2004) (Doses self-selected 10 completed 1 female 21-63) double-blind, bifida (1) by the patients) monocentre Prospective, NDO: SCI (122), randomised, 3 x 15 mg Prop IR myelitis (1), MS 131 enrolled, Stöhrer parallel group, (N=70), 99 male, 38.8 (Prop) (2), 1b 3 107 ITT, (2007) double-blind, 3 x 5 mg Oxy IR 32 female 37.7 (Oxy) myelodysplasia 91 PP multicentre (N=61) (4), spinal tumor (20) (2) Prospective, randomised, 41.4 Neurogenic Stöhrer parallel group, 3 x 15 mg Prop IR, 41 male, (Prop IR) 1b 3 66 detrusor (2009) double-blind, 1 x 45 mg Prop ER 25 female 40.9 overactivity multicentre (Prop ER) (6) 1 The results of the study of Amarenco (2012) comparing solifenacin and oxybutynin are not yet reported, so far only the comparison of solifenacin with placebo is reported 2 Terminology used by the original study authors has been retained n.a. not applicable Oxy = Oxybutynin Prop = Propiverine Tolt = Tolterodine TC = Trospium chloride

Antimuscarinics – NDO - Review Table 1.4: Flexible dose studies & combined high dose AM - summary of study characteristics Treatment Patient number Age Author L E Study design duration Treatment groups Gender Diagnosis1 (N) (years) (weeks) Flexible dose Prospective, Complete or incomplete SCI O’Leary open-label, dose- Dose titration: 4 male, 49.0 2a 12 10 with urodynamically defined (2003) titration, Oxy ER 10-30 mg 6 female (range 35-77) detrusor hyperreflexia monocentre Prospective, Neurogenic bladder: MS (22), Bennett open-label, dose- Dose titration: 10 male, 2a 12 39 46.3 ± 7.2 SCI (10), (2004) titration, Oxy ER 10-30 mg 29 female Morbus Parkinson (7) monocentre Prospective, 2 groups (doses self- Ethans open-label, 14 enrolled, 9 male, 40.5 NDO due to SCI (7), MS (2), 2b ≥ selected by the patients): (2004) double-blind, 2 10 completed 1 female (Range 21-63) spina bifida (1) Oxy IR + Tolt IR monocentre 2 groups (TC IR): Prospective, (1) standard dose: 36 ± 11 years double-blind , 45 mg/d (adjustable Menarini randomised, 80 enrolled 66 male, 1b 3 - 5 (2) adjustable dose: dose) NDO (2006) active-control, 10 female increase up to 90 or 135 36 ± 13 years parallel groups, mg/d dependent on (standard dose) multicentre (10) urodynamic response Group 1: Prospective, Solifenacin 10 mg Persu 19 males, SCI 10, MS 6, Morbus 2a open-label, 3 months Group 2: Dose increment 29 n. a. (2012) 10 female Parkinson 5, stroke 6 monocentre (n.a.) to Solifenacin 20 mg after one month 2 groups: Prospective, (1) Tolt ER 8 mg 15 male 34 NDO: 17 SCI, Horstmann (2006) 1b randomised. 4 weeks 21 (2) TC IR 90 mg 6 female (18 – 55) 3 MS, 1 MMC 2 parallel groups Combined high dose AM 3 groups: (1) Tolt 8 mg + Oxy 15-30 mg Amend n.a., 21 male NDO: 3 4 weeks (2) TC IR 90 mg + 27 35.7 (2008) (Open-label ?) 6 female SCI 21, MS 3, MMC 1. Tolt 4-8 mg (3) Oxy 30 mg + TC IR 45-90 mg 3 groups dependent on Variable Retrospective whether prior AM therapy 70% male, 39.3 SCI 49, MMC 13, Cameron (2009) 3 treatment 77 chart review or not and whether on 2 30% female (17.5 – 77.6) other diagnoses 15 periods or 3 AM during treatment Antimuscarinics – NDO - Review 1 Terminology used by the original study authors has been retained Oxy = Oxybutynin Tolt = Tolterodine TC = Trospium chloride

Antimuscarinics – NDO - Review Table 1.5: Miscellaneous studies – summary of study characteristics continued

Patient Treatment Age Author LoE Trial Design Treatment number Gender Diagnosis1 Duration (years) (N) Prospective, Maders- Reflex bladder due to open-label, Trospium chloride IR 8 male Mean bacher 2a 2 weeks 29 transverse lesion of multicentre 2 x 20 mg 21 female age: 29 (1991) the spinal cord (3) Prospective, Propiverine IR Mazur open-label, 22 male Detrusor 2a 1 year 2 x 15 mg or 39 17 – 59 (1994) prospective 17 female hyperreflexia 3 x 15 mg multicentre Prospective, Carl 2a open-label, 12 weeks Darifenacin 15 mg 38 n.a. n.a. NDO due to MS (2006) monocentre Prospective, randomised, Acute NDO secondary to Geirsson double-blind, experiment Tolterodine IR 2 x 2 mg, 2b n.a. n.a. n.a. SCI or other (2006) cross-over, (single placebo pathology single-dose dose) vs. placebo Observational Spinelli Neurogenic 2b study, 6 weeks Solifenacin 1 x 10 - 15 mg 41 n.a. n.a. (2007) overactive bladder monocentre Retrospective Mean Male: Neurogenic bladder Tan Tolterodine2 18 Tolt Mean 3 open-label, follow-up female = dysfunction, (2009) Oxybutynin2 10 Oxy age: 44 monocentre 3 years 14:1 secondary to SCI Prospective, Yamanishi 47 enrolled 22 male 2a open-label, 12 weeks Tolterodine ER 4 mg 58 ± 20 NDO (2009) 43 completed 27 female monocentre Prospective, Van Rey 12 male 2a open-label, 8 weeks Solifenacin 5 mg and 10 mg 30 n.a. Multiple sclerosis (2011) 18 female monocentre Proietti Prospective 22 months 9 male, 2a Fesoterodine 4 mg 29 n. a. Multiple sclerosis (2012) study on average 20 female 1 Terminology used by the original study authors has been retained 2 Data missing on doses and galenic formulations Antimuscarinics – NDO - Review n.a. = not applicable Tolt = Tolterodine Oxy = Oxybutynin

Antimuscarinics – NDO - Review Table 2.1: Placebo-controlled studies – efficacy outcomes1

Stöhrer Stöhrer Stöhrer Ethans (1990) 2 (1991) (1999) (2004) Oxy IR TC IR Prop IR Tolt IR Placebo Placebo Placebo Placebo 3 x 5 mg 2 x 20 mg 3 x 15 mg 2 x 2 mg

60 overall 29 32 60 53 14 overall N Urodynamic parameters Max. pre 175 240 171 185 262 296 n.a. n.a. cystometric post 300 230 309 n.a. 366 289 322 244 bladder capacity post-pre + 125 - 10 + 138 - 17 + 104 - 7 n.a. n.a. (mL) pintra 0.0001 0.80 0.0001 n.a. n.a. n.a. pinter pOxy-Plac: < 0.0001 pTC-Plac:<0.001 pProp-Plac: n.a. pToltIR-Plac: n.a. Pre 90 85 101 82 81 92 Max. detrusor post 55 81 n.a. n.a. 54 92 pressure n.a. n.a. post-pre - 35 - 4 - 38 - 2 - 27 0 (cmH20) pintra 0.0001 0.013 0.001 n.a. pinter pOxy-Plac: < 0.0001 pTC-Plac:<0.001 pProp-Plac: 0.0001 pToltIR-Plac: n.a. Pre 17 13 34 20 50 59 post 32 16 n.a. n.a. 87 61 PVR (mL) n.a. n.a. post-pre + 15 + 3 + 15 + 15 + 37 + 2 pintra 0.0001 0.37 n.a. n.a. pinter pOxy-Plac: 0.012 pTC-Plac:0.80 pProp-Plac: 0.01 pToltIR-Plac: n.a. Clinical parameters Pre 1 2.8 (0.1-3.5) 3 (0-3.6) 3 Incontinence n.a. n.a. n.a. n.a. n.a. n.a. post n.a. n.a. post-pre n.a. n.a. Upper urinary n.a. n.a. n.a. n.a. n.a. n.a. n.a. n.a. tract QoL n.a. n.a. n.a. n.a. n.a. n.a. n.a. n.a.

1 The study of Amarenco (2012) is not included in this table, because detailed results are not given 2 Values ot the urodynamic parameters according to figures provided by authors. 3 Tolterodine significantly superior to placebo in reduction of incontinence episodes n.a. not applicable Oxy = Oxybutynin Prop = Propiverine Tolt = Tolterodine TC = Trospium chloride Antimuscarinics – NDO - Review

Antimuscarinics – NDO - Review Table 2.2: Active-controlled studies – efficacy outcomes

Gajewski Madersbacher Stöhrer Stöhrer Ethans (1986) (1995) (2007) (2009) (2004) Propan- Tolt IR Oxy IR Oxy IR TC IR Oxy IR Prop IR Prop IR Prop ER Oxy IR theline IR 8.4 3x5 mg 3x5 mg 2x20 mg 3x5 mg 3x15 mg 3x15 mg 1x45 mg 12.5 mg/day 3x15 mg mg/day N 19 15 43 52 45 46 33 33 14 overall Urodynamic parameters Pre 138 163 188 215 164 198 124 107 n.a. n.a. Max. cystometric post 282 198 351 312 298 309 229 204 562 454 bladder capacity post-pre + 144 + 35 + 166 + 97 + 134 +110 + 104 + 98 n.a. n.a. (mL) pintra 0.001 0.001 * * * * n.a. n.a. pinter pTC-Oxy: 0.06 pProp-Oxy: n.s. pPropIR-PorpER:n.s. pOxy-Tolt: n.s. Pre 82 82 69 57 66 67 Max. detrusor post 44 53 43 38 42 44 pressure n.a. n.a. n.a. n.a. post-pre - 38 - 29 - 26 - 19 - 24 - 23 (cmH20) pintra 0.001 0.001 * * * * pinter pTC-Oxy: 0.63 pProp-Oxy: n.s. pPropIR-PorpER:n.s. pre 48 49 65 73 PVR post 154 128 149 141 n.a. n.a. n.a. n.a. (mL) post-pre + 106 + 79 + 84 + 68 + 18 + 17 pintra 0.001 0.001 * * * * pinter pTC-Oxy : 0.18 pProp-Oxy: n.s. pPropIR-PorpER:n.s. Clinical parameters pre n.a. n.a. 3.3 3.9 79.3 % 80.6 % post n.a. n.a. 2.0 2.3 65.5 % 41.9 % 0.5 0.6 Incontinence post-pre - 1.0 - 0.5 n.a. n.a. - 1.3 - 1.6 - 13.8 % - 38.7 % (0 – 1.3) (0 – 1.7) pintra n.a. n.a < 0.05 < 0.05 n.a. n.a.

pinter pProp-Oxy: 0.54 Both groups were comparable (n.s.) in reduction of incontinence episodes / day Upper urinary n.a. n.a. n.a. n.a. n.a. n.a. n.a. n.a. n.a. n.a. tract QoL n.a. n.a. n.a. n.a. n.a. n.a. n.a. n.a. n.a. n.a. n.a. not applicable Oxy = Oxybutynin Prop = Propiverine Tolt = Tolterodine TC = Trospium chloride

Antimuscarinics – NDO - Review Table 3.1: Placebo-controlled studies – tolerability and safety outcomes 1

Stöhrer Stöhrer Stöhrer Ethans (1990) (1991) (1999) (2004) Oxy IR TC IR Prop IR Tolt IR Placebo Placebo Placebo Placebo 3 x 5 mg 2 x 20 mg 3 x 15 mg 2 x 2 mg 70 % 13 % 1 / 29 (3 %) 7 / 32 n.a. n.a. n.a. n.a. Adverse events (22 %) 1.7 0.7 22 / 60 4 / 53 (0 - 6.7) (0 - 2.4) >50 % - Dry mouth n.a. n.a. n.a. (37 %) (8 %) Visual Visual analogue analogue scale scale - Methodology of Spontaneously reported Actively prompted n.a. n.a. assessing AE Discontinuations 2 / 29 4 / 32 8 / 60 3 / 53 2 3 n.a. n.a. (7 %) (13 %) (13 %) (5.6 %)

1 The study of Amarenco (2012) comparing solifenacin and placebo is not included in this table, because detailed results are not given n.a. not applicable Oxy = Oxybutynin Prop = Propiverine Tolt = Tolterodine TC = Trospium chloride

Antimuscarinics – NDO - Review Table 3.2: Active-controlled studies – tolerability and safety outcomes 1

Gajewski Madersbacher Stöhrer Stöhrer Ethans (1986) (1995) (2007) (2009) (2004) Propan- Tolt IR Oxy IR Oxy IR TC IR Oxy IR Prop IR Prop IR Prop ER Oxy IR theline IR 8.4 3x5 mg 3x5 mg 2x20 mg 3x5 mg 3x15 mg 3x15 mg 1x45 mg 12.5 mg/day 3x15 mg mg/day 13/19 8/15 Almost comparable in 48/61 48/70 Adverse events 48.5 % 36.4 % n.a. n.a. (68 %) (53 %) both groups (78.7 %) (68.6 %) 22 (56 %), 26 (54 %), 41/61 33/70 4.4 2.6 - Dry mouth n.a. n.a. in 23 % in 4 % (67.2 %) (47.1 %) 24.2 % 27.3 % (0.3 – 6.6) (0 – 8.8) severe severe pProp-Oxy: 0.02 Visual analogue scale - Methodology of n.a. Actively prompted Actively prompted Spontaneously n.a. assessing AE reported 4 / 19 4 / 15 9/61 16/70 Discontinuations 7 (16 %) 3 (6 %) n.a. n.a. n.a. n.a. (22 %) (27 %) (15%) (23%)

1 The study of Amarenco (2012) comparing solifenacin and oxybutynin is not included in this table, because detailed results are not given n.a. not applicable Oxy = Oxybutynin Prop = Propiverine Tolt = Tolterodine TC = Trospium chloride

Antimuscarinics – NDO - Review Figure 1: Body of evidence* References reviewed (346)

Inclusion: Exclusion: not suitable, Inclusion: Literature because no data given, Hand search (4) search (26) ongoing study, mixed patient populations, overview only, non-oral administration (316)

Dose-Finding: Placebo-controlled: Active-controlled: Flexible+combined Various: 3 studies, 222 pat. 5 studies, 339 pat. 5 studies, 340 pat. high dose: 9 studies, 281 pat. Prop (1)10 Oxy (1)13 Oxy (4)16,18-20 8 studies, 297 pat. Dar (1)32 TC (1)12 Prop (1)14 Prop (2)20,21 Oxy (4)16,22,23,27 Fes (1)36 Tolt (1)11 Sol (1)17 TC (1)18 Sol (1)25 Oxy (1)37 TC (1)15 PT (1)19 TC (3)24,26,27 Prop (1)35 Tolt (1)16 Tolt (3)16,26,27 Sol (2)33,34 TC (1)29 Tolt (3)30,31,37 28 – no details given

Randomised controlled trials:16 studies, 1002 pat. Open-label studies: 14 studies, 477 pat. Dar (0) Sol (1)17 Dar (1)32 Sol (3)25,33,34 Fes (0) TC (5)12,15,18,24,26 Fes (1)36 TC (2)27,29 Oxy (5)13,16,18,19, 20 Tolt (4)11,16,26,30 Oxy (5)16,22,23,27,37 Tolt (4)16,27,31,37 Prop (4)10,14,20,21 PT (1)19 Prop (1)35 * Due to „double counting“ (e.g. for active-controlled studies or studies administering two antimuscarinics concomitantly) the counts within the boxes, adding up all antimuscarinic treatment arms, can be deviant to the number of studies given in the respective headings. Dar = Darifenacin Fes = Fesoterodine Oxy = Oxybutynin Prop = Propiverine Sol = Solifenacin TC = Trospium chloride Tolt = Tolterodine PT= Propantheline

Antimuscarinics – NDO - Review