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A Phase 3, Multicentre, Randomized, Double-Blind, Placebo-Controlled

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A Phase 3, Multicentre, Randomized, Double-Blind, Placebo-Controlled Menzies‑Gow et al. Respir Res (2020) 21:279 https://doi.org/10.1186/s12931‑020‑01541‑7 STUDY PROTOCOL Open Access DESTINATION: a phase 3, multicentre, randomized, double‑blind, placebo‑controlled, parallel‑group trial to evaluate the long‑term safety and tolerability of tezepelumab in adults and adolescents with severe, uncontrolled asthma Andrew Menzies‑Gow1*, Sandhia Ponnarambil2, John Downie3, Karin Bowen4, Åsa Hellqvist5 and Gene Colice6 Abstract Background: Tezepelumab is a human monoclonal antibody that blocks the activity of the epithelial cytokine thymic stromal lymphopoietin. The efcacy, safety and oral corticosteroid‑sparing potential of tezepelumab are being investigated in two ongoing, phase 3, randomized, double‑blind, placebo‑controlled studies (NAVIGATOR [NCT03347279] and SOURCE [NCT03406078]). DESTINATION (NCT03706079) is a long‑term extension (LTE) of these studies. Methods: DESTINATION is a randomized, double‑blind, placebo‑controlled LTE study in adults (18–80 years old) and adolescents (12–17 years old) with severe, uncontrolled asthma who are receiving treatment with medium‑ or high‑ dose inhaled corticosteroids plus at least one additional controller medication with or without oral corticosteroids. The study population will comprise patients who complete the 52‑ and 48‑week NAVIGATOR and SOURCE studies, respectively. Patients who were randomized to receive tezepelumab 210 mg every 4 weeks (Q4W) in either predeces‑ sor study will continue to receive this regimen for 1 year; those who were previously randomized to receive placebo will be re‑randomized (1:1) to receive either tezepelumab 210 mg Q4W or placebo for 1 year. Patients will receive their prescribed controller medications throughout DESTINATION and study physicians will have the opportunity to down‑ or up‑titrate dosage of these medications, if appropriate. The primary objective is to evaluate the long‑term safety and tolerability of tezepelumab over 104 weeks (inclusive of the treatment period of either predecessor study). The secondary objective is to assess the long‑term efect of tezepelumab on asthma exacerbations. Patients recruited from SOURCE will be followed up post‑treatment for 12 weeks. Patients recruited from NAVIGATOR who complete 100 weeks of tezepelumab treatment will be eligible for either 12 weeks of follow‑up or a 36‑week extended follow‑ up during which the clinical beneft of tezepelumab after treatment cessation will be investigated. Discussion: DESTINATION will evaluate the long‑term safety, tolerability and efcacy of tezepelumab versus pla‑ cebo with continued dosing for up to 2 years. DESTINATION will also evaluate the clinical efect of tezepelumab after *Correspondence: A.Menzies‑[email protected] 1 Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK Full list of author information is available at the end of the article © The Author(s) 2020. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Menzies‑Gow et al. Respir Res (2020) 21:279 Page 2 of 10 treatment cessation. This LTE study aims to elucidate the long‑term safety implications of receiving tezepelumab and to assess its potential long‑term treatment benefts in patients with severe, uncontrolled asthma. Trial registration: NCT03706079 (ClinicalTrials.gov). Registered 15 October 2018. Keywords: Clinical trial, Long‑term extension, Severe asthma, Tezepelumab Background Te efcacy and safety of tezepelumab are being been Biological therapies targeting type 2 (T2) infamma- evaluated in an ongoing, phase 3, randomized, double- tory cytokines, comprising anti-immunoglobulin (Ig)E blind, placebo-controlled trial (NAVIGATOR, Clini- and anti-interleukin (IL)-4/IL-13, IL-5 and IL-5R, have calTrials.gov identifer: NCT03347279), which aims to emerged as promising treatment options for patients further investigate the signifcant reduction in asthma with severe asthma [1]; however, data on the long-term exacerbations observed with tezepelumab in the PATH- safety and efcacy of these treatments are primarily WAY study. NAVIGATOR will also assess the efect derived from open-label, single-arm clinical trials [2– of tezepelumab on lung function, asthma control and 7]. Te majority of these trials are limited by the lack health-related quality of life in adults (18–80 years old) of inclusion of a placebo group with which to compare and adolescents (12–17 years old) with severe, uncon- the efects of biologic treatment and to support inter- trolled asthma, irrespective of their disease phenotype. pretation of the fndings. Te inclusion of a control Te oral corticosteroid- (OCS-) sparing potential of group would also have provided further contextualiza- tezepelumab is being evaluated in an ongoing, phase 3, tion of pharmacologically unexpected adverse events randomized, double-blind, placebo-controlled trial in [8]. Although double-blind extension studies of biolog- adults with OCS-dependent asthma (SOURCE, Clinical- ics for the treatment of severe asthma have been con- Trials.gov identifer: NCT03406078), for which the pri- ducted, these have been limited to extended treatment mary endpoint is a reduction in the prescribed daily OCS periods of less than 1 year [9, 10]. Data on the efect of maintenance dose. Secondary objectives in the SOURCE treatment cessation beyond the typical 12-week safety study include assessing the efect of tezepelumab on follow-up period in clinical trials are also generally exacerbation rate, lung function and patient-reported lacking for available biologics. outcomes, while reducing the OCS dose. Tymic stromal lymphopoietin (TSLP) is an epithelial- Patients who complete either the NAVIGATOR or derived cytokine produced in response to environmental SOURCE studies are eligible to enrol in DESTINATION and infammatory stimuli (including allergens, viruses (ClinicalTrials.gov identifer: NCT03706079), a long- and other airborne particles) that is implicated in the ini- term extension (LTE) study that is evaluating the long- tiation and maintenance of airway infammation [11–13]. term safety and tolerability of tezepelumab compared TSLP acts upstream of T2 infammatory cytokines and with placebo, with continued dosing for approximately regulates multiple downstream infammatory cascades 1 year. During DESTINATION, study physicians have the [11]. It also has efects on airway structural cells [14–18] opportunity to down- or up-titrate patients’ background and may contribute to neutrophilic infammation [19, medication, if appropriate. Tis LTE study also aims 20]. Te expression of TSLP is elevated in the airways of to evaluate the efect of treatment cessation after up to patients with asthma and correlates with disease severity 2 years of tezepelumab therapy in an exploratory analysis [21, 22]. of patients recruited from NAVIGATOR who complete Tezepelumab is a human monoclonal antibody (IgG2λ) tezepelumab dosing during DESTINATION. Tis article that binds specifcally to TSLP, blocking it from inter- describes the design and objectives of the phase 3 DES- acting with its heterodimeric receptor, thereby inhibit- TINATION study in adults and adolescents with severe, ing the production of multiple infammatory cytokines uncontrolled asthma. and activation of multiple cell types [23, 24] (Fig. 1). In the PATHWAY phase 2b study (ClinicalTrials.gov iden- Methods tifer: NCT02054130), treatment with tezepelumab sig- Study design nifcantly reduced asthma exacerbations by up to 71% DESTINATION is an ongoing phase 3, multicentre, compared with placebo in patients with severe, uncon- randomized, double-blind, placebo-controlled, parallel- trolled asthma, irrespective of baseline infammation sta- group LTE study aiming to evaluate the long-term safety tus. Improvements in lung function, asthma control and and tolerability of tezepelumab 210 mg administered patient health-related quality of life were also observed subcutaneously (SC) every 4 weeks (Q4W) in adults [24, 25]. (18–80 years old) and adolescents (12–17 years old) Menzies‑Gow et al. Respir Res (2020) 21:279 Page 3 of 10 Fig. 1 Mechanism of action by which tezepelumab improves clinical outcomes in patients with severe asthma. TSLP is released from the airway epithelium in response to insults such as viruses, allergens and pollutants, triggering multiple infammatory cascades. Tezepelumab specifcally blocks TSLP from binding to its heterodimeric receptor, thereby inhibiting the production of various infammatory cytokines and cell types. Treatment with tezepelumab has thus far been shown to reduce blood eosinophil count, IgE, IL‑5,
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