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Article of the Week: CCH in the Treatment of Peyronie’s disease

Every Month the Editor-in-Chief selects an Article of the Month from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

If you only have time to read one article this week, it should be this one.

Clinical Efficacy of Collagenase Clostridium Histolyticum in the Treatment of Peyronie’s Disease by Subgroups: Results From Two Large, Double-Blind, Randomized, Placebo-Controlled, Phase 3 Studies

Larry I. Lipshultz, Irwin Goldstein*, Allen D. Seftel, Gregory J. Kaufman, Ted M. Smith‡, James P. Tursi‡ and Arthur L. Burnett§

 

Scott Department of Urology, Baylor College of Medicine, Houston, TX, *San Diego Sexual Medicine, Alvarado Hospital, San Diego, CA,Cooper University Hospital, Camden, NJ, Auxilium Pharmaceuticals, Inc., Chesterbrook, PA, and §Johns Hopkins Medicine, Baltimore, MD, USA

 

OBJECTIVE

To examine the efficacy of intralesional collagenase Clostridium histolyticum (CCH) in defined subgroups of patients with Peyronie’s disease (PD).

PATIENTS AND METHODS

The efficacy of CCH compared with placebo, assessed from baseline to week 52, was examined in subgroups of participants from the Investigation for Maximal Peyronie’s Reduction Efficacy and Safety Studies (IMPRESS) I and II. The subgroups were defined according to: severity of penile curvature deformity at baseline (30–60° [n = 492] and 61–90° [n = 120]); PD duration (1 to ≤2 [n = 201], >2 to ≤4 [n = 212] and >4 years [n = 199]); degree of plaque calcification (no calcification [n = 447], non-contiguous stippling [n = 103] and contiguous calcification that did not interfere with injection of CCH [n = 62]); and baseline erectile function (International Index of Erectile Function [IIEF] scores 1–5 [n= 22], 6–16 [n = 106] and ≥17 [n = 480]).

RESULTS

Reductions in penile curvature deformity and PD symptom bother were observed in all subgroups. Penile curvature deformity reductions were significantly greater with CCH than with placebo for the following subgroups: baseline penile curvature 30–60° and 61–90°; disease duration >2 to ≤4 years and >4 years; no calcification; and IIEF score ≥17 (high IIEF-erectile function score; P < 0.05 for all). PD symptom bother reductions were significantly greater in the CCH group for: penile curvature 30–60°; disease duration >4 years; no calcification; and IIEF score 1–5 (no sexual activity) and ≥17 (P < 0.05 for all).

CONCLUSIONS

In this analysis, clinical efficacy of CCH treatment for reducing penile curvature deformity and PD symptom bother was found across subgroups. In the IMPRESS I and II overall, adverse events (AEs) were typically mild or moderate, although treatment-related serious AEs, including corporal rupture or penile haematoma, occurred. Future studies could be considered to directly assess the efficacy and safety of CCH treatment in defined subgroups of PD patients, with the goal of identifying predictors of optimum treatment success.

Editorial: Intralesional Collagenase injections in PD patients : do they IMPRESS and can we afford them?

The study by Lipshultz et al. [1] is a post hoc reworking of the results of the Investigation for Maximal Peyronie’s Reduction Efficacy and Safety Studies (IMPRESS) I and II phase 3 trials (each included 418 randomised patients) of intralesional injections of collagenase clostridium histolyticum (CCH) in patients with Peyronie’s disease (PD). The intention being to identify specifically, which subgroups of patients with PD might do best with CCH treatment compared with their matched placebo controls, as determined by reductions in penile curvature deformity and Peyronie’s Disease Questionnaire (PDQ) PD Symptom Bother score at study week 52 compared with baseline.

In both IMPRESS studies, CCH-treated patients showed statistically greater mean improvements vs placebo for reduction of penile curvature and PDQ PD Symptom Bother score. The current authors [1] have reassessed these previous results using four patient cohort variables, namely, baseline penile curvature, duration of PD, degree of penile calcification, and baseline erectile function severity, which were then further divided using various descriptors.

The results show that intralesional CCH significantly reduced baseline penile curvature in both the 30–60 and 61–90° curvature cohorts (P < 0.001 and P <0.008, respectively). Additionally, significant penile curvature improvements occurred with intralesional CCH when PD duration was >2 to <4 years and >4 years (P < 0.001).

CCH treatment in patients with PD with no penile calcification show statistically significant improvements in reducing baseline penile curvature and PDQ PD Symptom Bother score but this was not seen for either the noncontiguous stippling or contiguous calcification patient subgroups. Significant improvements in penile curvature occurred with intralesional CCH in patients with PD with a baseline International Index of Erectile Function (IIEF) score of >17 (P < 0.001) and the PDQ PD Symptom Bother score was also significantly reduced in these patients. Although these results are statistically meaningful, the clinical benefits are less readily discernible considering 12.5° was the largest difference in the reduction of mean penile curvature in all subgroups when comparing intralesional CCH to placebo at week 52. Similarly, although statistically significant changes in the PDQ PD Symptom Bother score were reported for intralesional CCH for the subgroups with duration of disease of >4 years, no penile calcification, and IIEF of >17, it is unclear what clinical benefit would accrue with a maximal change of 1.4 in any of the randomised subgroups.

Importantly, the IMPRESS I and II studies were not designed for subgroup analysis and despite combining these studies some of the specified PD subgroups contained in the present paper contain too few subjects to allow a valid statistical analysis of CCH efficacy. This has prompted the authors to conclude that further adequately powered prospective, randomised studies should be conducted to further clarify which PD characteristics offer optimal patient benefit with CCH treatment. The outcomes of these future studies might then optimise healthcare expenditure for a non-surgical treatment (consisting of eight penile injections and modelling), which shows therapeutic promise for patients with PD but potentially has significant consumer cost issues, which may be prohibitive unless some clinician guidelines exist for the use of CCH treatment. This has relevance as the USA Food and Drug Administration has already approved the use of intralesional CCH for the treatment of adult men with PD, who at the start of therapy have a palpable plaque and a curvature deformity of ≥30° [2].

Importantly, the outcomes of the patients with PD in the IMPRESS studies were only reported to week 52 of the study, which begs the questions as to how long any clinical benefit might last in patients who initially respond to intralesional CCH and whether these patients once having relapsed might respond to adjuvant injections.

 

Tim Terry
Department Urology, Leicester General Hospital, Leicester

 

References

Article of the week: Mirabegron is an effective treatment for OAB

Every week the Editor-in-Chief selects the Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

If you only have time to read one article this week, it should be this one.

Phase III, randomised, double-blind, placebo-controlled study of the β3-adrenoceptor agonist mirabegron, 50 mg once daily, in Japanese patients with overactive bladder

Osamu Yamaguchi, Eiji Marui*, Hidehiro Kakizaki, Yukio Homma, Yasuhiko Igawa§, Masayuki Takeda, Osamu Nishizawa**, Momokazu Gotoh††, Masaki Yoshida‡‡, Osamu Yokoyama§§, Narihito Seki¶¶, Yasushi Ikeda*** and Sumito Ohkawa***

Division of Bioengineering and LUTD Research, School of Engineering, Nihon University, Koriyama, *Department of Human Arts Sciences, University and Graduate School of Human Arts Sciences, Saitama, Department of Urology, Asahikawa Medical University, Asahikawa, Department of Urology, The University of Tokyo Graduate School of Medicine, Tokyo, §Department of Continence Medicine, The University of Tokyo Graduate School of Medicine, Tokyo, Department of Urology, University of Yamanashi, Yamanashi, **Department of Urology, Shinshu University, Matsumoto, ††Department of Urology, Nagoya University Graduate School of Medicine, Nagoya, ‡‡Department of Urology, National Center for Geriatrics and Gerontology, Obu, §§Department of Urology, University of Fukui Faculty of Medical Sciences, Fukui, ¶¶Department of Urology, Kyushu Central Hospital of the Mutual Aid Association of Public School Teachers, Fukuoka, and ***Astellas Pharma Inc., Tokyo, Japan

Registered at clinicaltrials.gov (NCT00966004)

OBJECTIVE

• To evaluate the efficacy and safety of the β3-adrenoceptor agonist mirabegron, in a Japanese population with overactive bladder (OAB).

PATIENTS AND METHODS

• This randomised, double-blind, placebo-controlled phase III study enrolled adult patients experiencing OAB symptoms for ≥24 weeks. Patients with ≥ 8 micturitions/24 h and ≥1 urgency episode/24 h or ≥1 urgency incontinence episode/24 h were randomised to once-daily placebo, mirabegron 50 mg or tolterodine 4 mg (as an active comparator, without testing for non-inferiority of efficacy and safety) for 12 weeks.

• The primary endpoint was the change in the mean number of micturitions/24 h from baseline to final assessment. Secondary endpoints included micturition variables related to urgency and/or incontinence and quality-of-life domain scores on the King’s Health Questionnaire.

• Safety assessments included adverse events (AEs), post-void residual urine volume, laboratory variables, vital signs and 12-lead electrocardiogram.

RESULTS

• A total of 1139 patients were randomised to receive placebo (n = 381), mirabegron 50 mg (n = 380) or tolterodine 4 mg (n = 378). Demographic and baseline characteristics were similar among the treatment groups.

• At final assessment, mirabegron was significantly superior to placebo in terms of mean [sd] change from baseline in number of micturitions/24 h (–1.67 [2.212] vs -0.86 [2.354]; P < 0.001) and mean [sd] change from baseline in number of urgency episodes/24 h (–1.85 [2.555] vs –1.37 [3.191]; P = 0.025), incontinence episodes/24 h (–1.12 [1.475] vs –0.66 [1.861]; P = 0.003), urgency incontinence episodes/24 h (–1.01 [1.338] vs –0.60 [1.745]; P = 0.008), and volume voided/micturition (24.300 [35.4767] vs 9.715 [29.0864] mL; P < 0.001).

• The incidence of AEs in the mirabegron group was similar to that in the placebo group. Most AEs were mild and none were severe.

CONCLUSIONS

• Mirabegron 50 mg once daily is an effective treatment for OAB symptoms, with a low occurrence of side effects in a Japanese population.

 

Editorial: Mirabegron the first β3-adrenoceptor agonist for OAB: a summary of the phase III studies

The study reported in this edition of BJUI details the results of a large phase III study conducted in Japan contrasting 50 mg mirabegron, the new β3-adrenoceptor agonist, to placebo with tolterodine as an active comparator [1]. This adds to the body of knowledge already provided by phase III evaluations reported from Europe [2], where tolterodine was also used as an active comparator and North America [3], where the efficacy of 25–100 mg was compared with placebo [4]. As the first in this new class of compounds with a mechanism of action that is distinct from that of the antimuscarinic agents, which are the mainstay of overactive bladder (OAB) therapy to date, there is clearly interest in the efficacy and in particular the safety of this new class of compound. This has been evaluated in a long-term safety study [5].

This paper [1] confirms the findings evident in these other publications, which suggest a favourable short- and long-term tolerability profile for mirabegron in patients with OAB. In particular, excluding typical anticholinergic side-effects, such as dry mouth, which occurred with a similar incidence with mirabegron as placebo, but was reported in 13.3% of tolterodine patients, there was no evidence of any cardiotoxicity with mirabegron, which is consistent with a previous pooled analysis of the European and North American studies [6]. In this pooled analysis, mirabegron was associated with mean increases of 0.4–0.6 mmHg in blood pressure and ≈1 beat/min in heart rate, both reversible upon treatment discontinuation. In the long-term study, the changes in heart rate seen with mirabegron 50 mg were less than those seen with tolterodine. Changes in vital signs did not result in more cardiovascular-related adverse events in patients treated with mirabegron compared with those treated with placebo or tolterodine in both the pooled 12-week and the 1-year long-term studies. In addition, there was one case of urinary retention with mirabegron in the pooled 12-week studies; the incidence being less than placebo or tolterodine. Clearly from the evidence now available, mirabegron has an efficacy similar to that seen with tolterodine and significantly better than placebo for most of the symptoms of the OAB symptom complex. In conclusion, mirabegron is well-tolerated and as efficacious as anticholinergic therapy. Further analyses of the phase III data has shown that mirabegron is effective in both naïve patients and those that have failed to either tolerate or respond to a previous anticholinergic therapy [7].

Future work should include an adequately powered direct comparison to antimuscarinic therapy. Furthermore, data on the combination of mirabegron and an antimuscarinic have already shown potential benefit in a phase II study, and this should be explored further [8]. Other interesting areas to explore will be the use of this therapy in both male patients and patients with neurogenic bladder dysfunction.

Christopher Chapple
Department of Urology, The Royal Hallamshire Hospital, Sheffield Teaching Hospitals, Sheffield, UK

 

References

  1. Yamaguchi O, Marui E, Kakizaki H et al. Phase III, randmised, double-blind, placebo-controlled study of the β3 -adrenoceptor agonist mirabegron, 50 mg once daily, in Japanese patients with overactive bladder. BJU Int 2014; 113: 951–960.
  2. Khullar V, Amarenco G, Angulo JC et al. Efficacy and tolerability of mirabegron, a β(3)-adrenoceptor agonist, in patients with overactive bladder: results from a randomised European-Australian phase 3 trial. Eur Urol 2013; 63: 283–295
  3. Nitti VW, Auerbach S, Martin N, Calhoun A, Lee M, Herschorn S. Results of a randomized phase III trial of mirabegron in patients with overactive bladder. J Urol 2013; 189: 1388–1395
  4. Herschorn S, Barkin J, Castro-Diaz D et al. A phase III, randomized, double-blind, parallel-group, placebo-controlled, multicentre study to assess the efficacy and safety of the β3 adrenoceptor agonist, mirabegron, in patients with symptoms of overactive bladder. Urology 2013; 82: 313–320
  5. Chapple CR, Kaplan SA, Mitcheson D et al. Randomized double-blind, active-controlled phase 3 study to assess 12-month safety and efficacy of mirabegron, a β(3)-adrenoceptor agonist, in overactive bladder. Eur Urol 2013; 63: 296–305
  6. Nitti VW, Khullar V, van Kerrebroeck P et al. Mirabegron for the treatment of overactive bladder: a prespecified pooled efficacy analysis and pooled safety analysis of three randomised, double-blind, placebo-controlled, phase III studies. Int J Clin Pract 2013; 67: 619–632
  7. Khullar V, Cambronero J, Angulo JC et al. Efficacy of mirabegron in patients with and without prior antimuscarinic therapy for overactive bladder: a post hoc analysis of a randomized European-Australian Phase 3 trial. BMC Urol 2013; 13: 45
  8. Abrams P, Kelleher C, Staskin D et al. Combination treatment with mirabegron and solifenacin in patients with overactive bladder: efficacy and safety results from a randomised, double-blind, dose-ranging, phase 2 study (symphony). Eur Urol 2014. doi: 10.1016/j.eururo.2014.02.012

 

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