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

Abstract

Background: Tezepelumab is a human monoclonal antibody that blocks the activity of the epithelial cytokine thymic stromal lymphopoietin. The efficacy, 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 predecessor 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 effect 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 benefit of tezepelumab after treatment cessation will be investigated.

Discussion: DESTINATION will evaluate the long-term safety, tolerability and efficacy of tezepelumab versus placebo with continued dosing for up to 2 years. DESTINATION will also evaluate the clinical effect of tezepelumab after treatment cessation. This LTE study aims to elucidate the long-term safety implications of receiving tezepelumab and to assess its potential long-term treatment benefits in patients with severe, uncontrolled asthma.

Trial registration: NCT03706079 (ClinicalTrials.gov). Registered 15 October 2018.

Keywords: Clinical trial; Long-term extension; Severe asthma; Tezepelumab.

Conflict of interest statement

AMG has attended advisory boards for AstraZeneca, GlaxoSmithKline, Novartis, Sanofi and Teva. He has received speaker fees from AstraZeneca, Novartis, Roche and Teva. He has participated in research with AstraZeneca for which his institution has been remunerated and has attended international conferences with Teva. He has had consultancy agreements with AstraZeneca, Sanofi and Vectura. GC, SP, KB and ÅH are employees of AstraZeneca. JD is an employee of Amgen Inc.

Figures

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 inflammatory cascades. Tezepelumab specifically blocks TSLP from binding to its heterodimeric receptor, thereby inhibiting the production of various inflammatory cytokines and cell types. Treatment with tezepelumab has thus far been shown to reduce blood eosinophil count, IgE, IL-5, IL-13 and FeNO. FeNO fractional exhaled nitric oxide, IgE immunoglobulin E, IL interleukin, ILC2 type 2 innate lymphoid cell, Th T‑helper, TSLP thymic stromal lymphopoietin

Fig. 2

Study design. aIn light of the COVID-19 pandemic, the protocol was amended. Patients aiming to enrol in the DESTINATION study who are not able to attend an onsite end of treatment visit in either predecessor study will continue to participate in the 12-week safety follow-up period of either NAVIGATOR (up to week 64) or SOURCE (up to week 60) until on-site randomization and administration of the first dose of study treatment in the DESTINATION study can be conducted. bOnly patients from the NAVIGATOR predecessor study were eligible for a 36-week extended follow-up. EOT end of treatment, LTE long-term extension, Q4W every 4 weeks, R randomization, SC subcutaneously

Fig. 3

Step-down of asthma background medication. aAdditional controller medications can be changed or their doses can be up-titrated or down-titrated at the discretion of the investigator. bIf the patient is not taking a combination of ICS/LABA and is taking a separate ICS and additional controller medication(s), reduce only the dose of ICS and maintain the same dose of the additional controller medication(s). ICS inhaled corticosteroid, LABA long-acting β2-agonist, OCS oral corticosteroid, PRN prescribed-as-needed, SABA short-acting β2-agonist

Fig. 4

Treatment groupings across the predecessor (NAVIGATOR or SOURCE) studies and the DESTINATION LTE study. LTE long-term extension