Archive for year: 2015

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

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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.

 

Read the full article
Tim Terry
Department Urology, Leicester General Hospital, Leicester

 

References
1 Lipshultz LI, Goldstein I, Seftel AD et al. Clinical efficacy of collagenase clostridium histolyticum in the treatment of Peyronie’s disease by subgroups: results from two large, randomised, placebo-controlled, phase 3 studies. BJU Int 2015; 116: 650–56

 

2 Honig SC. Intralesional collagenase in the treatment of Peyronie’s disease. Ther Adv Urol 2014; 6: 47–53

 

What’s the Diagnosis?

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Test yourself against our experts with our weekly quiz. You can type your answers here if you want to compare with our answers.

This patient presented with haematuria and was found to have stones.

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E-Cigarette Poll Results

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There has been considerable interest in the British Media about e-cigarettes and whether they should be prescribed for smokers whilat Liquido24e headlines in the USA suggested the manufacturers may face legal action for high levels of toxic chemicals (learn about liquid brands for vaporizers at Liquido24) – Do you feel e-cigarettes are a useful adjunct to help smokers stop?

E-Cigarette Poll Results

These e-cigarette poll results are in line with recent poll data from Consumer Reports in which more than 70% of smokers were interested in “tobacco alternatives” like e-cigarettes, while just over 20% were against, we also got data from different E-Cig Shop Services across the country, while possibly biased we do have some numbers to work with that are rather realistic to what we see on the real world every day, one of them is Oz Vape Loft leading supplier of everything required by vaping.

In a separate survey, Fusion found that more than 50% of those polled were considering switching to a more health-conscious lifestyle, like using e-cigarettes. The study was conducted in the summer of 2013, but only recently came to light.

And, as a note, I also found that, in a poll of smokers , only one-third would rather try an e-cigarette, compared to 40% who would rather continue using tobacco products.

So, are these people using e-cigarettes to quit smoking? Probably not. In fact, some experts think that e-cigarettes may help people quit by making their addiction harder to get off.

Article of the Month: Safety and efficacy of mirabegron as add-on therapy in patients with solifenacin-treated OAB (MILAI study)

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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.

Finally, the third post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a video from Prof. Osamu Yamaguchi discussing his paper. 

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

Safety and efficacy of mirabegron as add-on therapy in patients with overactive bladder treated with solifenacin: a postmarketing, open-label study in Japan (MILAI study)

Osamu Yamaguchi, Hidehiro Kakizaki*, Yukio Homma†, Yasuhiko Igawa‡, Masayuki Takeda§, Osamu Nishizawa, Momokazu Gotoh**, Masaki Yoshida††, Osamu Yokoyama‡‡, Narihito Seki§§, Akira Okitsu¶¶, Takuya Hamada¶¶, Akiko Kobayashi¶¶ and Kentarou Kuroishi¶¶

 

Division of Bioengineering and LUTD Research, School of Engineering, Nihon University, Koriyama, *Department of Urology, Asahikawa Medical University, Asahikawa, †Department of Urology, University of Tokyo Graduate School of Medicine, Tokyo, ‡Department of Continence Medicine, University of Tokyo Graduate School of Medicine, Tokyo, §Department of Urology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, ¶Department of Urology, Shinshu University, Matsumoto, **Department of Urology, Nagoya University Graduate School of Medicine, Nagoya, ††Department of Urology, National Centre 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

 

Read the full article
OBJECTIVE

To examine the safety and efficacy of mirabegron as ‘add-on’ therapy to solifenacin in patients with overactive bladder (OAB).

PATIENTS AND METHODS

This multicentre, open-label, phase IV study enrolled patients aged ≥20 years with OAB, as determined by an OAB symptom score (OABSS) total of ≥3 points and an OABSS Question 3 score of ≥2 points, who were being treated with solifenacin at a stable dose of 2.5 or 5 mg once daily for at least 4 weeks. Study duration was 18 weeks, comprising a 2-week screening period and a 16-week treatment period. Patients meeting eligibility criteria continued to receive solifenacin (2.5 or 5 mg once daily) and additional mirabegron (25 mg once daily) for 16 weeks. After 8 weeks of treatment, the mirabegron dose could be increased to 50 mg if the patient’s symptom improvement was not sufficient, if he/she was agreeable to the dose increase, and the investigator judged that there were no safety concerns. Safety assessments included adverse events (AEs), laboratory tests, vital signs, 12-lead electrocardiogram, QT corrected for heart rate using Fridericia’s correction (QTcF) interval and post-void residual (PVR) volume. Efficacy endpoints were changes from baseline in OABSS total score, OAB questionnaire short form (OAB-q SF) score (symptom bother and total health-related quality of life [HRQL] score), mean number of micturitions/24 h, mean number of urgency episodes/24 h, mean number of urinary incontinence (UI) episodes/24 h, mean number of urgency UI episodes/24 h, mean volume voided/micturition, and mean number of nocturia episodes/night. Patients were instructed to complete the OABSS sheets at weeks −2, 0, 8 and 16 (or at discontinuation), OAB-q SF sheets at weeks 0, 8 and 16 (or at discontinuation) and patient voiding diaries at weeks 0, 4, 8, 12 and 16 (or at discontinuation).

RESULTS

Overall incidence of drug-related treatment-emergent AEs (TEAEs) was 23.3%. Almost all TEAEs were mild or moderate. The most common TEAE was constipation, with similar incidence in the groups receiving a dose increase to that observed in the groups maintained on the original dose. Changes in PVR volume, QTcF interval, pulse rate and blood pressure were not considered to be clinically significant and there were no reports of urinary retention. Significant improvement was seen for changes in efficacy endpoints from baseline to end of treatment (EOT) in all groups (patients receiving solifenacin 2.5 or 5 mg + mirabegron 25 or 50 mg).

CONCLUSIONS

Add-on therapy with mirabegron 25 mg once daily for 16 weeks, with an optional dose increase to 50 mg at week 8, was well tolerated in patients with OAB treated with solifenacin 2.5 mg or 5 mg once daily. There were significant improvements from baseline to EOT in OAB symptoms with combination therapy with mirabegron and solifenacin. Add-on therapy with mirabegron and an antimuscarinic agent, such as solifenacin, may provide an attractive therapeutic option.

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Editorial: Combining solifenacin and mirabegron for OAB management

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Overactive bladder (OAB) is one of the most frequent LUTS in both sexes, and is associated with significant bother and impact on quality of life [1]. In many cases, no underlying cause is found and OAB is stated as being ‘idiopathic’. Until recently, the first-line management of idiopathic OAB has been based on the use of antimuscarinics, solifenacin being one of the most prescribed drugs; however, the long-term adherence to antimuscarinics has been shown to be rather low because of lack of efficacy, treatment switch or adverse events, or for mixed reasons [2].

A few years ago, β3-adrenergics were successfully introduced as an alternative to antimuscarinics for OAB management. The efficacy of β3-adrenergics has been shown and they are associated with a new safety profile that differs from that of antimuscarinics [3]. Mirabegron, the most widely used β3-adrenergic drug, has thus gained popularity in clinical practice. Given that β3-adrenergics and anticholinergics have a distinct mechanism of action, the combination of both drugs has been seen as a possible option and has been tested through a huge randomized controlled trial [4].

In the present issue of BJUI, Yamaguchi et al. [5] report the results of the MILAI study, an open-label phase IV trial assessing the effects of mirabegron as an add-on therapy in patients treated for OAB with solifenacin. They found that the addition of mirabegron to solifenacin generated only mild to moderate adverse events, and led to promising efficacy results; however, this study, which the authors call a preliminary study, raises a number of questions that remain completely unanswered.

First, even if seen as fluctuant, idiopathic OAB is considered to be a chronic disease. Long-term results must be seen as a critical issue in the field, and there is no guarantee that the short-term data presented in the MILAI study will stand the test of time in terms of efficacy and adherence.

Second, the study raises an important question about the optimum use of mirabegron in idiopathic OAB. Should it be a first-line option, a secondary option after antimuscarinics (available for treatment switch), or an add-on therapy, as it is presented in the present trial? There might be some room for each of these pathways depending on the patient history and characteristics, and the results obtained under antimuscarinics. From that point of view, the MILAI study is probably too weak to identify factors associated with failure of the combination therapy. Further studies should better detail patient inclusion criteria (because ‘failure’ of antimuscarinics is a heterogeneous concept), as well as characteristics of non-responders. In the present study, these two points are not detailed, and the study provides only a global statistically significant improvement, paving the way for additional research. A better understanding of the mechanism of action of the treatment combination would be of great value to move forward and enable better patient selection.

Finally, one of the upcoming challenges will be to integrate mirabegron as an add-on therapy in the world of male LUTS, including benign prostatic obstruction, where β3-adrenergics probably have an important role to play. As underlined by the authors, several studies are on the way, and their results (in a male population) are urgently awaited.

After having been successfully introduced in most countries in the western world, the new life of mirabegron has begun (including post-marketing studies, extensions of market authorizations, potentially new indications, combination therapy). The future will tell us whether this success story will continue.

Read the full article
Jean-Nicolas Cornu 
Department of Urology, Tenon Hospital, Hopitaux Universitaires Paris-EST, Assistance publique Hopitaux de Paris, Universite Pierre et Marie Curie Paris 6, Paris, France

 

References
1 Agarwal A, Eryuzlu LN, Cartwright R et al. What is the most bothersome lower urinary tract symptom? Individual- and population- level perspectives for both men and women. Eur Urol 2014; 65: 1211–7

2 Veenboer PW, Bosch JL. Long-term adherence to antimuscarinic therapy in everyday practice: a systematic review. J Urol 2014; 191: 1003–8

3 Maman K, Aballea S, Nazir J et al. Comparative efficacy and safety of medical treat ment s for the management of o veractive bl adder: a syste matic literature review and mixed treatment comparison. Eur Urol 2014; 65: 755–65

 

4 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; 67: 577–88

 

5 Yamaguchi O, Kakizaki H, Homma Y et al. Safety and efficacy of mirabegron as add-on therapy in patients with overactive bladder treated with solifenacin: a post-marketing, open-label study in Japan (MILAI study). BJU Int 2015; 116: 612–22

 

 

Video: Safety and efficacy of mirabegron as ‘add-on’ therapy in patients with OAB treated with solifenacin

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Safety and efficacy of mirabegron as add-on therapy in patients with overactive bladder treated with solifenacin: a postmarketing, open-label study in Japan (MILAI study)

Osamu Yamaguchi, Hidehiro Kakizaki*, Yukio Homma†, Yasuhiko Igawa‡, Masayuki Takeda§, Osamu Nishizawa, Momokazu Gotoh**, Masaki Yoshida††, Osamu Yokoyama‡‡, Narihito Seki§§, Akira Okitsu¶¶, Takuya Hamada¶¶, Akiko Kobayashi¶¶ and Kentarou Kuroishi¶¶

 

Division of Bioengineering and LUTD Research, School of Engineering, Nihon University, Koriyama, *Department of Urology, Asahikawa Medical University, Asahikawa, †Department of Urology, University of Tokyo Graduate School of Medicine, Tokyo, ‡Department of Continence Medicine, University of Tokyo Graduate School of Medicine, Tokyo, §Department of Urology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, ¶Department of Urology, Shinshu University, Matsumoto, **Department of Urology, Nagoya University Graduate School of Medicine, Nagoya, ††Department of Urology, National Centre 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

 

Read the full article
OBJECTIVE

To examine the safety and efficacy of mirabegron as ‘add-on’ therapy to solifenacin in patients with overactive bladder (OAB).

PATIENTS AND METHODS

This multicentre, open-label, phase IV study enrolled patients aged ≥20 years with OAB, as determined by an OAB symptom score (OABSS) total of ≥3 points and an OABSS Question 3 score of ≥2 points, who were being treated with solifenacin at a stable dose of 2.5 or 5 mg once daily for at least 4 weeks. Study duration was 18 weeks, comprising a 2-week screening period and a 16-week treatment period. Patients meeting eligibility criteria continued to receive solifenacin (2.5 or 5 mg once daily) and additional mirabegron (25 mg once daily) for 16 weeks. After 8 weeks of treatment, the mirabegron dose could be increased to 50 mg if the patient’s symptom improvement was not sufficient, if he/she was agreeable to the dose increase, and the investigator judged that there were no safety concerns. Safety assessments included adverse events (AEs), laboratory tests, vital signs, 12-lead electrocardiogram, QT corrected for heart rate using Fridericia’s correction (QTcF) interval and post-void residual (PVR) volume. Efficacy endpoints were changes from baseline in OABSS total score, OAB questionnaire short form (OAB-q SF) score (symptom bother and total health-related quality of life [HRQL] score), mean number of micturitions/24 h, mean number of urgency episodes/24 h, mean number of urinary incontinence (UI) episodes/24 h, mean number of urgency UI episodes/24 h, mean volume voided/micturition, and mean number of nocturia episodes/night. Patients were instructed to complete the OABSS sheets at weeks −2, 0, 8 and 16 (or at discontinuation), OAB-q SF sheets at weeks 0, 8 and 16 (or at discontinuation) and patient voiding diaries at weeks 0, 4, 8, 12 and 16 (or at discontinuation).

RESULTS

Overall incidence of drug-related treatment-emergent AEs (TEAEs) was 23.3%. Almost all TEAEs were mild or moderate. The most common TEAE was constipation, with similar incidence in the groups receiving a dose increase to that observed in the groups maintained on the original dose. Changes in PVR volume, QTcF interval, pulse rate and blood pressure were not considered to be clinically significant and there were no reports of urinary retention. Significant improvement was seen for changes in efficacy endpoints from baseline to end of treatment (EOT) in all groups (patients receiving solifenacin 2.5 or 5 mg + mirabegron 25 or 50 mg).

CONCLUSIONS

Add-on therapy with mirabegron 25 mg once daily for 16 weeks, with an optional dose increase to 50 mg at week 8, was well tolerated in patients with OAB treated with solifenacin 2.5 mg or 5 mg once daily. There were significant improvements from baseline to EOT in OAB symptoms with combination therapy with mirabegron and solifenacin. Add-on therapy with mirabegron and an antimuscarinic agent, such as solifenacin, may provide an attractive therapeutic option.

Read more articles of the week

Article of the Week: Nerve-sparing surgery – In vivo periprostatic nerve tracking using MPM in a rat model

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Every Week the Editor-in-Chief selects an 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.

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

Real-time in vivo periprostatic nerve tracking using multiphoton microscopy in a rat survival surgery model: a promising pre-clinical study for enhanced nerve-sparing surgery

Matthieu Durand*, **, Manu Jain*‡, Amit Aggarwal†, Brian D. Robinson*‡, Abhishek Srivastava*, Rebecca Smith†, Prasanna Sooriakumaran§, Joyce Loeffler**, Chris Pumill††, Jean Amiel**, Daniel Chevallier**, Sushmita Mukherjee† and Ashutosh K. Tewari*

 

*Department of Urology, †Department of Biochemistry, ‡Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York-Presbyterian Hospital, New York, NY, ††Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA, §Surgical Intervention Trials Unit, University of Oxford, Oxford, UK, ¶Karolinska Institute, Stockholm, Sweden, and **Department of Urology, Hopital Archet 2, Centre Hospitalier Universitaire de Nice, University of Nice Sophia-Antipolis, Nice, France

 

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OBJECTIVES

To assess the ability of multiphoton microscopy (MPM) to visualise, differentiate and track periprostatic nerves in an in vivo rat model, mimicking real-time imaging in humans during RP and to investigate the tissue toxicity and reproducibility of in vivo MPM on prostatic glands in the rat after imaging and final histological correlation study.

MATERIALS AND METHODS

In vivo prostatic rat imaging was carried out using a custom-built bench-top MPM system generating real-time three-dimensional histological images, after performing survival surgery consisting of mini-laparotomies under xylazine/ketamine anaesthesia exteriorising the right prostatic lobe. The acquisition time and the depth of anaesthesia were adjusted for collecting multiple images in order to track the periprostatic nerves in real-time. The rats were then monitored for 15 days before undergoing a new set of imaging under similar settings. After humanely killing the rats, their prostates were submitted for routine histology and correlation studies.

RESULTS

In vivo MPM images distinguished periprostatic nerves within the capsule and the prostatic glands from fresh unprocessed prostatic tissue without the use of exogenous contrast agents or biopsy sample. Real-time nerve tracking outlining the prostate was feasible and acquisition was not disturbed by motion artefacts. No serious adverse event was reported during rat monitoring; no tissue damage due to laser was seen on the imaged lobe compared with the contralateral lobe (control) allowing comparison of their corresponding histology.

CONCLUSIONS

For the first time, we have shown that in vivo tracking of periprostatic nerves using MPM is feasible in a rat model. Development of a multiphoton endoscope for intraoperative use in humans is currently in progress and must be assessed.

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