Table 2.
Clinical efficacy/tolerability studies of trospium chloride in the management of urge urinary incontinence
| Reference | Duration (wk) | Regimens | N | Results (compared with baseline) |
|---|---|---|---|---|
| Stohrer et al 1991 | 3 | TC 20 mg bid | 27 | All patients had detrusor hyperreflexia due to spinal cord injury. TC significantly increased maximum cystometric capacity (median change 120 mL vs placebo 0 mL) (p < 0.001) and bladder compliance (10 vs 1 mL/cm H2O, p < 0.001), and reduced maximum detrusor pressure (–35.0 vs –2.5 cm H2O, p < 0.001). No significant intergroup differences were noted with maximum urine flow rate or residual urine volume (p = 0.8 for each). In the 6 patients with partial sensation who could complete a study diary, micturition intervals increased by approximately 30% with TC. Spontaneously reported AE occurred in 1 TC patient (constipation) and 5 Plac patients (nausea, dry mouth, tiredness plus decreased exercise capacity, constipation and nervousness plus constipation). |
| Plac bid | 28 | |||
| Cardozo et al 2000 | 3–3.5 | TC 20 mg bid | 104 | The study was stopped early as interim analysis demonstrated superiority of TC over Plac. By intent-to-treat analysis, the treatment effect of TC (TC effect-Plac effect) was +22.0 mL for maximum cystometric capacity (p = 0.0054), +45.0 mL for volume at first unsTable contraction (p = 0.0015), and +7.0 mL for volume at maximum contraction (p = 0.0113). The 2 treatments were not significantly different with respect to effect on bladder compliance, residual urine volume, or maximum detrusor pressure at first unsTable contraction. Investigators assessed 26 and 30 TC patients as markedly and slightly improved, respectively, while corresponding figures for Plac patients were 17 and 26 (patient assessments were similar). In a subgroup analysis of patients with bladder capacity ≥ 350 mL, the treatment effect of TC was again significant for maximum cystometric capacity (+58 mL, p < 0.001) and volume at first unsTable contraction (+90 mL, p < 0.001). AE occurred in 68% TC and 62% Plac patients. Xerostomia was the most frequent AE (43 TC and 18 Plac patients) followed by GI disorders. Dizziness occurred in 11 TC and 15 Plac, and headache in 25 TC and 36 Plac patients. Drug acceptability by the patient was noted as very good/good in 37/50% of TC and 29/40% of Plac patients (no statistical results for AE were available). |
| Plac bid | 104 | |||
| Frohlich et al 2002 | 3 | TC 20 mg bid | 314 | By intent-to-treat analysis, the treatment effect of TC over Plac was significant for maximum cystometric capacity (+52 mL, p < 0.0001), volume at first unsTable contraction (+48 mL, p = 0.0001) and volume at maximum contraction (+40 mL, p = 0.0042). Nonsignificant treatment effects were noted for maximum detrusor pressure at first unsTable contraction and residual urine volume. Per protocol analysis gave similar results. Clinical cure or marked improvement (per patient self-assessment) occurred in 47.9% and 19.7% of TC and Plac patients, respectively. The distributions of clinical responses (per patient self-assessment) were significantly different in the 2 groups (p < 0.0001, more cure/markedly improved with TC and more slightly improved/no improvement/worsened with Plac). The investigator assessment was similar to that of the patients. ≥ 1 AE occurred in 35.7% of TC and 38.9% of Plac patients. The most frequent AE were GI disorders (TC 21.7%, Plac 18.7%) and xerostomia was the most frequent individual AE (TC 14.0%, Plac 8.4%; p = 0.052). CNS disorders (mostly headache) occurred in 11.1% of TC and 17.7% of Plac patients (p = 0.033). The global judgments of tolerability by investigators and patients were similar (between treatments and between each other). |
| Plac bid | 203 | |||
| Junemann and Fusgen 1999 | 3 | TC 40 mg qd | 56 | The treatment effects of TC 40 mg qd and 40 mg bid over Plac were similar for maximum cystometric capacity (+45.3 and +61.4 mL, respectively; p = 0.0006 vs Plac for both), volume at first unsTable contraction (+53.5 and +75.2 mL, p = 0.0333 vs Plac for both), and volume at maximum contraction (+45.2 and +77.0 mL, p = 0.0015 vs Plac for both). Treatment effects for volume at first desire to urinate and residual urine volume were not significant. No data were available regarding the statistical comparison of the 2 active treatments. AE frequency was dose-dependent (Plac 28.3%, TC 40 mg qd 51%, TC 40 mg bid 64%) and were mainly the expected anticholinergic effects. |
| TC 40 mg bid | 56 | |||
| Plac | 58 | |||
| Hofner et al 2000 | 52 | TC 20 mg bid | 177 | Per protocol analysis revealed statistically-indistinguishable treatment effects for the 2 drugs while both drugs produced significant effects compared with baseline (maximum cystometric capacity: +115 mL for TC and +119 mL for Oxy; volume at first unsTable contraction: +66 mL for TC and +49 mL for Oxy; volume at first desire to urinate: +86 mL for TC and +75 mL for Oxy). Frequency fell 31% on TC and 34% on Oxy. The number of incontinent episodes fell by approximately 1 per day with both drugs. AE occurred in 64.8% of TC and 76.7% of Oxy recipients (p < 0.01). Treatment-emergent AE (ie, those judged to be possibly, probably, or definitely drug-related) occurred in 47.9% of TC and 58.9% of Oxy recipients (p = 0.02). GI AE occurred in 39% of TC and 51% of Oxy recipients (p = 0.02), while xerostomia occurred in 33% of TC and 50% of Oxy recipients (p < 0.01). Tolerability of treatment was judged very good by 63% of TC and 42% of Oxy recipients (p = 0.004). The investigator assessment of tolerability was similar to that of the patients, favoring TC (p = 0.008). |
| Oxy 5 mg bid | 58 | |||
| Madersbacher et al 1995 | 2 | TC 20 mg bid | 88a | All patients had detrusor hyperreflexia due to spinal cord injury. The treatment effects of the 2 drugs were statistically indistinguishable from each other but both agents produced significant effects (p < 0.001) compared with baseline (maximum cystometric capacity; +97 mL for TC and +163 mL for Oxy; maximum voiding detrusor pressure: –35.4 cm H2O for TC and –38 cm H2O for Oxy; bladder compliance: +17 mL/cm H2O for TC and +22.6 mL/cm H2O for Oxy; residual urine volume: +76.5 mL for TC and +114.1 mL for Oxy). The frequency of hyperreflexive waves fell over time in both groups in a similar pattern (p = 0.16). Premature study withdrawal occurred in 16% of Oxy and 6% of TC patients and occurred earlier in the Oxy compared with TC groups (after means of 7 and 14 days on treatment, respectively). However the reasons for withdrawal were not listed, making interpretation of these data difficult. The only AE mentioned was xerostomia, which occurred in 54% of TC (4% being severe) and 56% of Oxy (23% being severe) patients. |
| Oxy 5 mg tid | ||||
| Junemann and Al-Shukri 2000 | 3 | TC 20 mg bid | 57 | The change from baseline in number of frequency episodes over 24 h was –3.4, –2.6, and –1.9, and Tolt 2 mg bid 63 for TC, Tolt, and Plac recipients (p = NS for Tolt vs Plac and p = 0.01 for TC vs Plac but no data Al-Shukri Plac bid 60 for TC vs Tolt). AE occurred in 34, 32, and 15% of TC, Tolt, and Plac recipients, respectively, 2000 with corresponding rates of mild xerostomia of 85, 84, and 42% in those who had that AE. |
| Tolt 2 mg bid | 63 | |||
| Plac bid | 60 | |||
| Zinner et al 2004 | 12 | TC 20 mg bid | 253 | By intent-to-treat analysis, at 12 weeks TC was superior to Plac in reducing urinary frequency/24 h (by –2.4 and –1.3 events, p ≤ 0.001), urge incontinence episodes/24 h (by –59 and –44%, p ≤ 0.0001), urge micturitions/24 h (–2.3 and –1.1 events, p ≤ 0.0001), diurnal micturitions/24 h (–1.9 and –1.0 events, p ≤ 0.0001), nocturnal micturitions/24 h (–0.5 and –0.3 events, p ≤ 0.05) and increasing urine volume/micturition (by +32.1 and +7.7 mL, p ≤ 0.0001). The superiority of TC over Plac was apparent as early as the week 4 visit. TC also reduced the impact of incontinence on QOL more than did Plac (measured by Incontinence Impact Questionnaire; for all patients by –54 and –36 points, p ≤ 0.05; for females by –59 and –36 points, p ≤ 0.05; for males by –33 and –35 points, NS). The subscores significantly improved by TC were travel, social relationships, and emotional health (all p ≤ 0.05). The results of other TC were travel, social relationships, and emotional health (all p ≤ 0.05). The results of other end point analyses demonstrated no significant differences between males and females. The five commonest AE were dry mouth (TC 22%, Plac 7%), constipation (10% and 4%), headache (7% and 5%), abdominal pain (3% and 1%), and diarrhea (3% and 5%) (no statistical results available). Mean increase in heart rate in trospium chloride recipients was 3 beats/minute compared with placebo. |
| Plac bid | 256 | |||
| Anonymous (Study 2) 2004 | 12 | TC 20 mg bid | 323 | By intent-to-treat analysis, TC was superior to Plac in reducing urinary frequency/24 h (by –2.7 and –1.8 events, p < 0.001) and urge incontinence episodes/week (by –16.1 and –12.1 2004 events, p < 0.001) and increasing urine volume/micturition (by +35.6 and +9.4 mL, p < 0.001). The superiority of TC over Plac was apparent as early as the week 4 visit. Pooled AE data (Zinner et al 2004 + this study) are available in Table 3. Mean increase in heart rate in trospium chloride recipients was 4 beats/minute compared with placebo. |
| Plac bid | 325 |
a
The number in each group was not given. 95 patients enrolled but data were evaluated in only 88 patients. Randomization was 1:1, so it was likely that approximately equal numbers were in the two groups.
Abbreviations: TC, trospium chloride; Plac, placebo; AE, adverse event; bid, twice daily; GI, gastrointestinal; CNS, central nervous system; qd, once daily; Oxy, oxybutynin immediate-release; Tolt, tolterodine immediate-release; tid, three times daily; NS, not significant; QOL, quality-of-life.