Study protocol of the global Effisayil 1 Phase II, multicentre, randomised, double-blind, placebo-controlled trial of spesolimab in patients with generalized pustular psoriasis presenting with an acute flare

Abstract

Introduction: Generalized pustular psoriasis (GPP) is a rare, potentially life-threatening disease characterised by recurrent flares of widespread neutrophilic aseptic skin pustular eruption. Despite the availability of approved biologics for GPP in Japan, Taiwan and Thailand, associated evidence is largely based on uncontrolled studies in which acute flares were not directly assessed. Therefore, there is a high unmet need to investigate new rapid-acting effective treatments that resolve symptoms associated with acute GPP flares. A prior Phase I proof-of-concept study showed rapid improvements in skin and pustule clearance with a single intravenous dose of spesolimab, a novel anti-interleukin-36 receptor antibody, in patients presenting with an acute GPP flare. Here, we present the design and rationale of Effisayil 1, a global, Phase II, placebo-controlled study to evaluate the efficacy, safety and tolerability of spesolimab in patients presenting with an acute GPP flare.

Methods and analysis: At least 51 patients with an acute GPP flare will be randomised 2:1 to receive a single 900 mg intravenous dose of spesolimab or placebo and followed for up to 28 weeks. The primary endpoint is a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) pustulation subscore of 0 (pustule clearance) at Week 1. The key secondary endpoint is a GPPGA score of 0 or 1 (clear or almost clear) at Week 1. Safety will be assessed over the study duration by the occurrence of treatment-emergent adverse events. Blood and skin biopsies will be collected to assess biomarkers. Superiority of spesolimab over placebo in the proportion of patients achieving the primary and key secondary endpoints will be evaluated.

Ethics and dissemination: The study complies with the ethical principles of the Declaration of Helsinki, the International Council for Harmonisation's Good Clinical Practice and local regulations. Ethics committee approvals have been obtained for each centre from all participating countries and are listed in online supplementary file 1. Primary results will be published in a peer-reviewed journal.

Trial registration details: ClinicalTrials.gov identifier: NCT03782792; Pre-results.

Keywords: clinical trials; dermatopathology; psoriasis.

Conflict of interest statement

Competing interests: SR is an employee of Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, Connecticut, USA. HD is an employee of Boehringer Ingelheim Investment Co Ltd, Shanghai, China. KT is an employee of Boehringer Ingelheim GmbH, Ingelheim, Germany. CT is an employee of Boehringer Ingelheim International GmbH, Biberach, Germany. SEC declares paid activities as advisor, speaker or consultant for AbbVie, Boehringer Ingelheim, Eli Lilly, Janssen, Leo Pharma, MSD, Novartis, Pfizer, Sanofi and UCB. MGL declares paid consulting activities for Aditum Bio, Allergan, Almirall, Arcutis, Inc, Avotres Therapeutics, BirchBioMed Inc, BMD skincare, Boehringer Ingelheim, Bristol Myers Squibb, Cara Therapeutics, Castle Biosciences, Corrona, Dermavant Sciences, Evelo, Facilitate International Dermatologic Education, Foundation for Research and Education in Dermatology, Inozyme Pharma, Kyowa Kirin, LEO Pharma, Meiji Seika Pharma, Menlo, Mitsubishi, NeuroDerm, Pfizer, Promius (Dr Reddy’s Laboratories Ltd), Serono, Theravance and Verrica, and research funds from AbbVie, Amgen, Arcutis, Boehringer Ingelheim, Dermavant, Eli Lilly, Incyte, Janssen Research & Development, LLC, LEO Pharma, Ortho Dermatologics, Pfizer and UCB. SM and HT declare paid consulting activities for Boehringer Ingelheim. ADB declares paid consulting activities for AbbVie, Almirall, Boehringer Ingelheim, Celgene, Janssen, LEO Pharma, Lilly, Novartis and UCB. TFT declares conducting clinical trials or paid consulting activities for AbbVie, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Galderma, GlaxoSmithKline, Janssen-Cilag, LEO Pharma, Merck Sharp & Dohme, Novartis International, Pfizer and UCB Pharma. AM declares receiving research grants, consulting fees and/or speaker’s fees from AbbVie, Boehringer Ingelheim, Celgene, Eli Lilly, Eisai, Janssen, Kyowa Hakko Kirin, LEO Pharma, Maruho, Mitsubishi Tanabe, Nichi-Iko, Nippon Kayaku, Novartis, Sun Pharmaceutical Industries, Taiho Pharmaceutical and Torii Pharmaceutical and Ushio. AAN declares being a consultant and advisor and/or receiving speaking fees and/or grants and/or served as an investigator in clinical trials for AbbVie, Almirall, Amgen, BMS, Boehringer Ingelheim, Celgene, Eli Lilly, Galderma, GSK, LEO Pharma, Janssen-Cilag, MSD, Novartis, Pfizer, Sandoz, Sanofi, Serono and UCB. MZ declares receiving grants, consulting fees, and/or speaker’s fees from AbbVie, Boehringer Ingelheim, Janssen-Cilag, LEO Pharma China, Novartis, Pfizer Inc and Xian-Janssen. JX declares receiving grants, consulting fees, and/or speaker’s fees from AbbVie, Boehringer Ingelheim, Novartis, Pfizer Inc and Sanofi. HB declares paid consulting activities for AbbVie, Almirall, BIOCAD, Boehringer Ingelheim, Celgene, Janssen, Kyowa-Kirin, LEO Pharma, Lilly, Mylan, Novartis and UCB, and grant support from Boehringer Ingelheim, Janssen, LEO Pharma, Novartis and Pfizer.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Study design. *Day 1: 51 screened patients with GPP with an acute flare defined as GPPGA≥3 and GPPGA pustulation subscore of ≥2 will be randomised 2:1 to a single intravenous dose of 900 mg spesolimab or intravenous placebo. †Day 2–7: Escape treatment (SoC) may be offered in case of disease worsening, defined as worsening of clinical status or GPP skin and/or systemic symptoms as defined by the investigator. ‡Day 8: Patients with a GPPGA≥2 and pustular component of GPPGA≥2 will qualify for treatment with OL spesolimab. §After Day 8–Week 12: Only one rescue dose with OL spesolimab is permitted if a patient who has previously achieved clinical response (GPPGA 0/1) to initial treatment, either with spesolimab or placebo at Day 1, or escape medication or OL spesolimab at Day 8, experiences a recurrence of a GPP flare (≥2-point increase in the GPPGA score and the pustular component of GPPGA≥2). Subsequent flares will be treated with SoC per physician’s choice. ¶Patients who do not require rescue treatment with OL spesolimab are to be followed until Week 12 (EoS) prior to entering into OLE trial. Patients who receive rescue treatment with OL spesolimab between Week 2 and Week 6 are to be followed until Week 12 (EoS) prior to entering the OLE trial. If at Week 12 they qualify to enter the OLE trial, then the EoS will be considered for these patients. If not, patients will have an additional 10 weeks’ follow-up and have an EoS at Week 16–28. Patients who receive rescue treatment with OL spesolimab between Weeks 7 and 12 are to be followed for an additional 6 weeks and have a response evaluation at Week 13–18; these patients will not have a visit at Week 12. If at Week 13–18 patients qualify to enter the OLE trial, the EoS will be considered for these patients. If not, patients will have an additional 10 weeks follow-up and have an EoS at Week 16–28. Patients who do not qualify to enter the OLE trial are to be followed for 16 weeks (EoS/Week 16–28) after the last dose of trial medication, which is the latest time point of trial medication given during the study (eg, Day 1, Day 8 if OL spesolimab is given, rescue with OL spesolimab if given). The white arrow head indicates a single dose of intravenous spesolimab or placebo at Day 1 or spesolimab at/after Day 8. EoS, end of study; GPP, generalized pustular psoriasis; GPPGA, Generalized Pustular Psoriasis Physician Global Assessment; IV, intravenous; OL, open label, OLE, open-label extension; R, randomisation; SoC, standard of care.