SOURCE: a phase 3, multicentre, randomized, double-blind, placebo-controlled, parallel group trial to evaluate the efficacy and safety of tezepelumab in reducing oral corticosteroid use in adults with oral corticosteroid dependent asthma

Michael E Wechsler,Åsa Hellqvist,Karin Bowen,Primal Kaur,Tor Skärby,Gun Almqvist,Janet M Griffiths,Gene Colice,May Mo,Esther Garcia Gil,Teresa Piechowiak

doi:10.1186/s12931-020-01503-z

Abstract

BackgroundMany patients with severe asthma continue to experience asthma symptoms and exacerbations despite standard-of-care treatment. A substantial proportion of these patients require long-term treatment with oral corticosteroids (OCS), often at high doses, which are associated with considerable multiorgan adverse effects, including metabolic disorders, osteoporosis and adrenal insufficiency. Tezepelumab is a human monoclonal antibody that blocks the activity of the epithelial cytokine thymic stromal lymphopoietin. In the PATHWAY phase 2b study (NCT02054130), tezepelumab significantly reduced exacerbations by up to 71% in adults with severe, uncontrolled asthma. Several ongoing phase 3 trials (SOURCE, NCT03406078; NAVIGATOR, NCT03347279; DESTINATION, NCT03706079) are assessing the efficacy and safety of tezepelumab in patients with severe, uncontrolled asthma. Here, we describe the design and objectives of SOURCE, a phase 3 OCS-sparing study.MethodsSOURCE is an ongoing phase 3, multicentre, randomized, double-blind, placebo-controlled study to evaluate the effect of tezepelumab 210 mg administered subcutaneously every 4 weeks on OCS dose reduction in adults with OCS-dependent asthma. The study comprises a 2-week screening and enrolment period, followed by an OCS optimization phase of up to 8 weeks and a 48-week treatment period, which consists of a 4-week induction phase, followed by a 36-week OCS reduction phase and an 8-week maintenance phase. The primary objective is to assess the effect of tezepelumab compared with placebo in reducing the prescribed OCS maintenance dose. The key secondary objective is to assess the effect of tezepelumab on asthma exacerbation rates. Other secondary objectives include the proportion of patients with a reduction in OCS dose (100% or 50% reduction or those receiving < 5 mg) and the effect of tezepelumab on lung function and patient-reported outcomes.ConclusionsSOURCE is evaluating the OCS-sparing potential of tezepelumab in patients with OCS-dependent asthma. SOURCE also aims to demonstrate that treatment with tezepelumab in patients with severe asthma is associated with reductions in exacerbation rates and improvements in lung function, asthma control and health-related quality of life, while reducing OCS dose.Trial registrationNCT03406078 (ClinicalTrials.gov). Registered 23 January 2018. https://clinicaltrials.gov/ct2/show/NCT03406078

Highlights

Many patients with severe asthma continue to experience asthma symptoms and exacerbations despite standard-of-care treatment
SOURCE aims to demonstrate that treatment with tezepelumab in patients with severe asthma is associated with reductions in exacerbation rates and improvements in lung function, asthma control and healthrelated quality of life, while reducing oral corticosteroids (OCS) dose
Study design SOURCE is an ongoing phase 3, multicentre, randomized, double-blind, placebo-controlled, parallel-group study that aims to evaluate the effect of tezepelumab 210 mg administered subcutaneously every 4 weeks (Q4W) on OCS dose reduction in adults with OCSdependent asthma

Summary

Introduction

Many patients with severe asthma continue to experience asthma symptoms and exacerbations despite standard-of-care treatment. A substantial proportion of these patients require long-term treatment with oral corticosteroids (OCS), often at high doses, which are associated with considerable multiorgan adverse effects, including metabolic disorders, osteoporosis and adrenal insufficiency. Current biologic treatments (e.g. benralizumab, dupilumab and mepolizumab) may be viable alternative therapies to OCS, and can assist in tapering and discontinuing OCS therapy [9,10,11] These treatments precisely target factors contributing to asthma pathogenesis and severity, such as inflammationpromoting cytokines and interleukins [9, 10, 12], and are indicated for the treatment of patients with specific severe asthma phenotypes (e.g. eosinophilic or allergic asthma) [13,14,15]. Targeting an upstream mediator of inflammatory pathways may have a broader effect on airway inflammation, and may provide more effective asthma control in a broader patient population than currently available biologic treatments

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