Florian M E Wagenlehner1, J W Olivier van Till2, Jos G A Houbiers3, Reynaldo V Martina4, Dirk P Cerneus3, Joost H J M Melis3, Antoni Majek5, Egils Vjaters6, Michael Urban7, Henrikas Ramonas8, Daniel A Shoskes9, J Curtis Nickel10. 1. Clinic for Urology, Pediatric Urology and Andrology, Justus-Liebig-University, Giessen, Germany. 2. Astellas Pharma Europe B.V., Leiden, The Netherlands. Electronic address: olivier.vantill@astellas.com. 3. Astellas Pharma Europe B.V., Leiden, The Netherlands. 4. Biostatistics Department, University of Liverpool, Liverpool, United Kingdom. 5. Centrum Medyczne Szpital Sw Rodziny Sp z o.o., Lodz, Poland. 6. Stradins Clinical University Hospital, Riga, Latvia. 7. Androgeos, Praha, Czech Republic. 8. Vilnius University Hospital "Santariskiu Klinikos" Urology Centre, Vilnius, Lithuania. 9. Glickman Urological and Kidney Institute, Cleveland Clinic Foundation, Cleveland, OH. 10. Department of Urology, Queen's University, Kingston, ON, Canada.
Abstract
OBJECTIVE: To examine the effect of a peripherally active fatty acid amide hydrolase (FAAH) inhibitor ASP3652 on safety and efficacy outcomes in chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). Inhibition of FAAH is hypothesized to reduce the excitability of urinary tract afferents including nociceptors. MATERIALS AND METHODS: In this adaptive, randomized, double-blind, placebo-controlled study, adult male patients with moderate to severe CP/CPPS were treated for 12 weeks with an oral dose of ASP3652 (25, 75, 150, or 300 mg twice daily, or 300 mg once daily), or placebo. A Bayesian model was used for adaptive prospective modeling of randomization, study continuation decisions, and analysis of the efficacy variables. RESULTS: The study was stopped for futility at preplanned interim analysis when 239 patients were randomized (226 were included in the intention-to-treat set): the 25 mg group showed the largest reduction of the primary end point National Institutes of Health Chronic Prostatitis Symptom Index total score (7.0 points), but the placebo group showed a mean reduction of 7.3 points (difference: 0.3 [95% confidence interval: -1.9, 2.6]). Micturition outcomes improved compared with placebo in all ASP3652 groups; for example, in the 300 mg twice daily group, voiding frequency decreased by -1.10 (95% CI: -2.0, -0.2) voids/24 hours vs placebo. Safety outcomes were comparable across the treatment groups. CONCLUSION:ASP3652 was generally safe and well-tolerated. It did not show efficacy on pain symptoms in patients with CP/CPPS. However, the results indicate that FAAH inhibition may attenuate lower urinary tract symptoms. Dedicated studies in patients with lower urinary tract dysfunction are needed to confirm this.
RCT Entities:
OBJECTIVE: To examine the effect of a peripherally active fatty acid amide hydrolase (FAAH) inhibitor ASP3652 on safety and efficacy outcomes in chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). Inhibition of FAAH is hypothesized to reduce the excitability of urinary tract afferents including nociceptors. MATERIALS AND METHODS: In this adaptive, randomized, double-blind, placebo-controlled study, adult male patients with moderate to severe CP/CPPS were treated for 12 weeks with an oral dose of ASP3652 (25, 75, 150, or 300 mg twice daily, or 300 mg once daily), or placebo. A Bayesian model was used for adaptive prospective modeling of randomization, study continuation decisions, and analysis of the efficacy variables. RESULTS: The study was stopped for futility at preplanned interim analysis when 239 patients were randomized (226 were included in the intention-to-treat set): the 25 mg group showed the largest reduction of the primary end point National Institutes of Health Chronic Prostatitis Symptom Index total score (7.0 points), but the placebo group showed a mean reduction of 7.3 points (difference: 0.3 [95% confidence interval: -1.9, 2.6]). Micturition outcomes improved compared with placebo in all ASP3652 groups; for example, in the 300 mg twice daily group, voiding frequency decreased by -1.10 (95% CI: -2.0, -0.2) voids/24 hours vs placebo. Safety outcomes were comparable across the treatment groups. CONCLUSION:ASP3652 was generally safe and well-tolerated. It did not show efficacy on pain symptoms in patients with CP/CPPS. However, the results indicate that FAAH inhibition may attenuate lower urinary tract symptoms. Dedicated studies in patients with lower urinary tract dysfunction are needed to confirm this.
Authors: Richard A Slivicki; Shahin A Saberi; Vishakh Iyer; V Kiran Vemuri; Alexandros Makriyannis; Andrea G Hohmann Journal: J Pharmacol Exp Ther Date: 2018-10-01 Impact factor: 4.030
Authors: Dennis J Sholler; Marilyn A Huestis; Benjamin Amendolara; Ryan Vandrey; Ziva D Cooper Journal: Pharmacol Biochem Behav Date: 2020-10-18 Impact factor: 3.533