Then, the patients in the 60C150?mg dose group will continue to receive 12 weeks of consecutive multiple doses (MAD) once every 2 weeks. in accordance with the Declaration of Rabbit polyclonal to PITPNM2 Helsinki, and the ethics approvals of the protocol have been obtained from the ethics committees of all participating centres, including Peking University Peoples Hospital, Chinese PLA General Hospital, The First Affiliated Hospital, College of Medicine, Zhejiang University and the Second Xiangya Hospital of Central South University. The findings of MLN1117 (Serabelisib) the study will be presented in published journals or at scientific conferences or meetings. Trial registration number ChiCTR1800017956. strong class=”kwd-title” Keywords: clinical pharmacology, psoriasis, clinical trials Strengths and limitations of this study In this study, we will use the combination design of phase I/II dose escalation and expansion, an innovative study design, which is intended to accelerate the development of new drugs from bench to bedside by seamlessly proceeding from the initial determination of a potentially effective dose in subject cohorts using the phase b trial approach. Choosing no observed adverse effect level as the method of determining the starting dose may lead to the inability to account for the effect of pharmacological pathways on dose selection. The inclusion of seriously ill patients or those with concomitant diseases and medications as study subjects may bring potential risks. Introduction Psoriasis is a common life-long immune-mediated genetic disease characterised by raised areas of abnormal skin and/or joint symptoms, with a prevalence of 2%C4%.1 2 Plaque psoriasis is the most common type of psoriasis, accounting for approximately 90% of all psoriasis cases.1 Patients with psoriasis report a tremendous economic and psychosocial burden, with tens of thousands of dollars being spent annually on the disease MLN1117 (Serabelisib) and a significant reduction in physical activity, cognitive MLN1117 (Serabelisib) function and quality of life.3 4 Psoriasis results from a T-cell-mediated immune inflammatory response, which is mainly driven by the TNF- pathway and interleukin-23 (IL-23)/Th17/IL-17 axis pathway. In the IL-23/Th17/IL-17 axis pathway, progression of psoriasis leads to an increase in the level of IL-23, which then drives the differentiation of Th17 cells. Activated Th17 cells produce several mediators such as IL-17A, which induces keratinocyte proliferation and other hallmark features of psoriasis.5C8 IL-17A is a proinflammatory cytokine mainly produced by activated T cells. Many studies have shown that IL-17A plays an important role in the pathogenesis of various inflammatory diseases: plaque psoriasis, ankylosing spondylitis and rheumatoid arthritis.9 10 Currently, the available treatments for patients with psoriasis include phototherapy, traditional systemic therapy and targeted biologics.11 The management of plaque psoriasis has been revolutionised in the past decades with the advent of biologic agents owing to their high efficacy and tolerability.12 Anti-IL-17 agents are one of the most efficacious biologic agents available for psoriasis. Currently, there are three anti-IL-17 agents on the market: secukinumab, ixekizumab and brodalumab. GR1501, a fully human IgG4 monoclonal antibody, is a new product targeted at IL-17A with high affinity and selectivity for IL-17A; it is to be administered subcutaneously. The objective of this study is to evaluate the safety, tolerability, pharmacokinetics (PK), immunogenicity and preliminary efficacy of GR1501 via a phase I/II dose escalation and expansion clinical trial of GR1501 in patients with moderate to severe plaque psoriasis. The study will provide baseline data for the MLN1117 (Serabelisib) next phase of clinical trials. The study protocol consists of two stages: the dose-escalation stage and the expansion cohort stage. In the dose-escalation stage, the primary outcome is the safety and tolerability of GR1501. The secondary outcome includes the PK characteristics, immunogenicity and efficacy of GR1501 after single or multiple subcutaneous injections. The expansion cohort will MLN1117 (Serabelisib) help obtain more reliable outcomes for safety and tolerability as well as toxicity estimates and efficacy outcomes in a larger population. Methods and analysis Study design This is a randomised, double-blind, multicentre, phase I/II dose escalation and expansion trial in China, aiming to evaluate the safety, tolerability, immunogenicity, PK and efficacy of GR1501 in patients with moderate to severe plaque psoriasis. In the phase I/II trial, 46 patients will be enrolled in the dose escalation cohorts who will receive dose from 10 to 200?mg with single-ascending dosing (SAD) and multiple ascending dosing (MAD). The study will also have 180 patients enrolled in the expansion.