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An adaptive randomized clinical trial in interstitial cystitis/bladder pain syndrome evaluating efficacy of ASP3652 and the relationship between disease characteristics and Hunner’s lesions

World Journal of Urology volume 39, pages 2065–2071 (2021)Cite this article

Abstract

Purpose

The primary purpose of this study was to evaluate the effect of the fatty acid amide hydrolase (FAAH) inhibitor ASP3652 on efficacy and safety in patients with Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS). The secondary purpose was to evaluate phenotyping based on Hunner’s lesions (HL).

Methods

In this randomized trial, adult female patients with moderate/severe IC/BPS received 12 weeks of treatment with an oral dose of ASP3652 (50, 150, or 300 mg twice daily) or placebo. A Bayesian model was employed using accumulating data to adjust the randomization probability and to analyze the primary efficacy variable (change from baseline to end of treatment in Mean Daily Pain [MDP; range 0–10]). Study outcomes and patient characteristics of patients with and without HL (HL+ and HL−) were compared.

Results

In total, 287 patients were randomized. The 300 mg dose group (n = 97) showed the largest effect, i.e., a mean change from baseline to end of treatment of −1.73 in MDP. However, the mean difference from placebo was 0.02. The probability that this dose was better than placebo was 13.5%. Adverse event incidence was low and similar between study groups. HL+ patients were older and had more severe symptoms than HL−. An association was suggested in HL+ patients between changes in micturition frequency and MDP (R = 0.41 [95% CI 0.18, 0.63]), which was not observed in HL− (R = 0.04 [95% CI −0.16, 0.29]).

Conclusion

ASP3652 was safe and well tolerated, but did not show efficacy in IC/BPS. The observed differences between HL+ and HL− suggest that IC/BPS diagnosis and treatment may be approached differently in these two phenotypes.

Trial registration: EudraCT number 2011-004555-39, date of registration: 2012-05-07.

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Availability of data and material

Clinical Trial data are disclosed at https://astellasclinicalstudyresults.com/study.aspx?ID=287

Data Sharing

Clinical Trial data are disclosed at https://astellasclinicalstudyresults.com/study.aspx?ID=287. Researchers may request access to anonymized participant level data, trial level data, and protocols from Astellas sponsored clinical trials at www.clinicalstudydatarequest.com. For the Astellas criteria on data sharing see https://clinicalstudydatarequest.com/Study-Sponsors/Study-Sponsors-Astellas.aspx”.

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Acknowledgements

This study was funded by Astellas Pharma Europe B.V. The authors are grateful to the following investigators and their staffs who contributed to this study (investigators received funding to conduct this study from the study sponsor Astellas Pharma): Belgium: J.J. Wyndaele and T. Roumeguere; Czech Republic: D. Ondra, M. Brodak, L. Domes, R. Pilka, and J. Klecka; Denmark: J. Nordling, A. Ryhammer, and P. Lyngdorf; Germany: M. Binder, S. Carl, S. Feyerabend, Ch. Hampel, E. Hellmis, M. Kurosch, R. Rudolph, and S.A. Wedel; Latvia: E. Vjaters, D. Litavniece, and V. Lietuvietis; The Netherlands: K. D’Hauwers, J. Bruins, G.A. van Koeveringe, J. Vis-Maters, and J.A. Nieuwenhuijzen; Poland: A. Majek, E. Narojczyk-Swiesciak, W. Nurkiewicz, P. Radziszewski, P. Szalecki, J. Tomaszewski, R. Dadej, and W. Michalik; Portugal: P. Dinis, M. Silva-Ramos, and F. Rolo; Romania: M. Orsolya, D. Georgescu, A.V. Manu-Marin, C. Pricop, I. Scarneciu, and I. Sinescu; Russia: D. Pushkar, S. Al-Shukri, O.I. Apolikhin, G. Krivoborodov, V.I. Krasnopolskiy, and V. Shirshov; Spain: D. Castro Diaz, A.M. Morales, R. Sanchez Borrego, and G. Chechile; Lithuania: A. Ulys, H. Ramonas, D. Silinis, and D. Milonas.

Funding

This study was sponsored by Astellas Pharma Europe BV

Author information

Author notes

  1. Jos Houbiers and J. W. Olivier van Till contributed equally.

Affiliations

  1. Astellas Pharma Europe B.V, Leiden, The Netherlands

    Jos G. A. Houbiers, J. W. Olivier van Till, Mathilde Kaper, Yalcin Yavuz, Reynaldo V. Martina, Dirk Cerneus, Joost Melis & Otto Stroosma

  2. Department of Urology, Queens University, Kingston, Canada

    J. Curtis Nickel

  3. Department of Urology, Stanford University, Stanford, CA, USA

    Phil M. Hanno

  4. Department of Urology, University of Copenhagen, Copenhagen, Denmark

    Jørgen Nordling

  5. Astellas Pharma Inc, Medical & Development, Medical Specialties Therapeutic Area. 2-5-1, Nihonbashi-Honcho, Chuo-ku, Tokyo, 103-8411, Japan

    J. W. Olivier van Till

Authors
  1. Jos G. A. Houbiers
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Contributions

JGAH, JWOvT, RVM, DC, JM, JCN, PH, and JN contributed to conceptualization (i.e., formulation or evolution of overarching research goals and aim) and design. JGAH, JWOvT, RVM, DC, JM, and OS are involved in trial execution and implementation. Formal analysis: MK, YY, and RVM conducted the primary statistical analysis; RVM provided statistical expertise in clinical trial design. JGAH and JWOvT are involved in writing—original draft; GAH, JWOvT, MK, YY, RVM, DC, JM, OS, JCN, PH, and JN are involved in writing—review & editing. All the authors contributed to refinement of the study protocol and approved the final manuscript.

Corresponding author

Correspondence to J. W. Olivier van Till.

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Houbiers, J.G.A., van Till, J.W.O., Kaper, M. et al. An adaptive randomized clinical trial in interstitial cystitis/bladder pain syndrome evaluating efficacy of ASP3652 and the relationship between disease characteristics and Hunner’s lesions. World J Urol 39, 2065–2071 (2021). https://doi.org/10.1007/s00345-020-03372-z

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Keywords

  • Interstitial cystitis
  • Phenotype
  • Fatty acid amide hydrolase (FAAH) inhibitor
  • Endocannabinoids
  • Hunner’s lesion
  • Patient characteristics