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Stratos 1 and 2 Brightling accepted pre-publication version.pdf (977.33 kB)

Tralokinumab for severe, uncontrolled asthma (STRATOS 1 and STRATOS 2): two randomised, double-blind, placebo-controlled, phase 3 clinical trials.

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posted on 2018-06-01, 08:50 authored by Reynold A. Panettieri, Ulf Sjöbring, AnnaMaria Péterffy, Peter Wessman, KKarin Bowen, Edward Piper, Gene Colice, Christopher E. Brightling
BACKGROUND: Tralokinumab is an anti-interleukin-13 human monoclonal antibody developed for the treatment of severe, uncontrolled asthma. These clinical trials aimed to assess the efficacy and safety of tralokinumab in this population. METHODS: STRATOS 1 and STRATOS 2 were randomised, double-blind, parallel-group, placebo-controlled, phase 3 clinical trials that enrolled participants aged 12-75 years with severe asthma that was inadequately controlled despite use of inhaled corticosteroids (≥500 μg per day fluticasone or equivalent) and a long-acting β2 agonist (but not oral corticosteroids). STRATOS 1 was done at 246 sites in 14 countries, and STRATOS 2 was done at 242 sites in 13 countries. In STRATOS 1, participants were randomly assigned (2:1) to receive tralokinumab 300 mg or matching placebo subcutaneously every 2 weeks or every 4 weeks for 52 weeks. In STRATOS 2, participants were randomly assigned (1:1) to receive tralokinumab 300 mg or matching placebo subcutaneously every 2 weeks for 52 weeks. STRATOS 1 attempted to identify a biomarker-positive population with enhanced tralokinumab benefit, which was then tested in STRATOS 2. The primary endpoint was the annualised asthma exacerbation rate (AAER) reduction at week 52 in the all-comers population for STRATOS 1 and in the biomarker-positive population for STRATOS 2. All efficacy analyses for both trials were done on the full analysis set by an intention-to-treat approach. The safety analysis set comprised any participant who received the investigational drug and was categorised by treatment received. These trials are registered with ClinicalTrials.gov, numbers NCT02161757 (STRATOS 1) and NCT02194699 (STRATOS 2), and with the EU Clinical Trials Register, EudraCT 2013-005614-35 (STRATOS 1) and EudraCT 2013-005615-27 (STRATOS 2). FINDINGS: STRATOS 1 was done between June 13, 2014, and Feb 28, 2017. 1207 participants were randomly assigned and 1202 treated as follows: tralokinumab every 2 weeks (n=398), tralokinumab every 4 weeks (n=404), or placebo (n=400). STRATOS 2 was done between Oct 30, 2014, and Sept 21, 2017. 856 participants were randomly assigned and 849 treated as follows: tralokinumab every 2 weeks (n=427) and placebo every 2 weeks (n=422). In the STRATOS 1 all-comers population, tralokinumab every 2 weeks did not significantly reduce AAER compared with placebo (7·0% reduction [95% CI -20·8 to 28·4]; rate ratio 0·93 [95% CI 0·72 to 1·21]; p=0·59). Baseline fractional exhaled nitric oxide (FENO) 37 ppb or greater was identified as the preferred biomarker in STRATOS 1; in FENO-high participants, tralokinumab every 2 weeks (n=97) reduced AAER by 44·0% (95% CI 6·0 to 66·0; rate ratio 0·56 [95% CI 0·34 to 0·94]; p=0·028) compared with placebo (n=102). In the STRATOS 2 FENO-high population, tralokinumab every 2 weeks (n=108) did not significantly improve AAER (15·8% reduction [95% CI -33·7 to 47·0]; rate ratio 0·84 [95% CI 0·53 to 1·34]; p=0·47) compared with placebo (n=121). The safety profile was consistent with that of previous tralokinumab trials. INTERPRETATION: Tralokinumab reduced AAER in participants with severe asthma with baseline FENO 37 ppb or higher in STRATOS 1, but not in STRATOS 2. These inconsistent effects on AAER do not support a key role for interleukin 13 in severe asthma exacerbations. FUNDING: AstraZeneca.

Funding

This trial was sponsored by AstraZeneca. We thank the health-care providers, research staff, participants, and caregivers who participated in these trials. CEB is supported by a National Institute for Health Research (NIHR) Senior Investigator Award and the Leicester NIHR Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the National Health Service (NHS), the NIHR or the Department of Health. Medical writing support was provided by Sophie Walton (QXV Comms [Macclesfield, UK], an Ashfield Company, part of UDG Healthcare plc), funded by AstraZeneca (Cambridge, UK), in accordance with Good Publication Practice (GPP3) guidelines.

History

Citation

Lancet Respiratory Medicine, 2018

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Department of Infection, Immunity and Inflammation

Version

  • AM (Accepted Manuscript)

Published in

Lancet Respiratory Medicine

Publisher

Elsevier

issn

2213-2600

eissn

2213-2619

Acceptance date

2018-04-18

Copyright date

2018

Available date

2018-11-18

Publisher version

https://www.clinicalkey.com/#!/content/playContent/1-s2.0-S221326001830184X?returnurl=https://linkinghub.elsevier.com/retrieve/pii/S221326001830184X?showall=true&referrer=

Notes

The file associated with this record is under embargo until 6 months after publication, in accordance with the publisher's self-archiving policy. The full text may be available through the publisher links provided above.

Language

en

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