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Design and rationale of FLAVOUR : A phase IIa efficacy study of the 5-lipoxygenase activating protein antagonist AZD5718 in patients with recent myocardial infarction

Prescott, Eva ; Pernow, John ; Saraste, Antti ; Åkerblom, Axel ; Angerås, Oskar ; Erlinge, David LU orcid ; Grove, Erik L. ; Hedman, Marja ; Jensen, Lisette O. and Svedlund, Sara , et al. (2020) In Contemporary Clinical Trials Communications 19.
Abstract

Patients with coronary artery disease remain at increased risk of recurrent life-threatening cardiovascular events even after adequate guideline-based treatment of conventional risk factors, including blood lipid levels. Inflammation is a critical pathway in the pathogenesis of atherosclerosis and is independently associated with risk of recurrent cardiovascular events. Leukotrienes are potent pro-inflammatory and vasoactive mediators synthesized by leukocytes in atherosclerotic lesions. AZD5718 is a novel antagonist of 5-lipoxygenase activating protein that suppresses leukotriene biosynthesis. FLAVOUR is a phase IIa efficacy and safety study of AZD5718 in patients with myocardial infarction 1–4 weeks before randomization. Stenosis of... (More)

Patients with coronary artery disease remain at increased risk of recurrent life-threatening cardiovascular events even after adequate guideline-based treatment of conventional risk factors, including blood lipid levels. Inflammation is a critical pathway in the pathogenesis of atherosclerosis and is independently associated with risk of recurrent cardiovascular events. Leukotrienes are potent pro-inflammatory and vasoactive mediators synthesized by leukocytes in atherosclerotic lesions. AZD5718 is a novel antagonist of 5-lipoxygenase activating protein that suppresses leukotriene biosynthesis. FLAVOUR is a phase IIa efficacy and safety study of AZD5718 in patients with myocardial infarction 1–4 weeks before randomization. Stenosis of the left anterior descending coronary artery after percutaneous intervention must be <50%, and Thrombolysis In Myocardial Infarction flow grade must be ≥ 2. Enrolled participants receive standard care plus oral AZD5718 200 mg, 50 mg, or placebo once daily for up to 12 weeks (extended from 4 weeks by protocol amendment). The planned sample size is 100 participants randomized to 12 weeks’ treatment. Change in urine leukotriene E4 levels is the primary efficacy outcome. FLAVOUR also aims to evaluate whether AZD5718 can improve coronary microvascular function, as measured by transthoracic colour Doppler-assisted coronary flow velocity reserve. Centrally pretrained study sonographers use standardized protocols and equipment. Additional outcomes include assessment of comprehensive echocardiographic parameters (including coronary flow, global strain, early diastolic strain rate and left ventricular ejection fraction), arterial stiffness, biomarkers, health-related quality of life, and safety. Specific anti-inflammatory therapies may represent novel promising treatments to reduce residual risk in patients with coronary artery disease. By combining primary pharmacodynamic and secondary cardiovascular surrogate efficacy outcomes, FLAVOUR aims to investigate the mechanistic basis and potential benefits of AZD5718 treatment in patients with coronary artery disease.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
5-Lipoxygenase activating protein, Coronary flow reserve, Coronary flow velocity reserve, Echocardiography, Leukotrienes, Myocardial infarction
in
Contemporary Clinical Trials Communications
volume
19
article number
100629
publisher
Elsevier
external identifiers
  • scopus:85089684422
  • pmid:32875138
ISSN
2451-8654
DOI
10.1016/j.conctc.2020.100629
language
English
LU publication?
yes
id
d1678a7d-3b08-48d7-a856-661168a81644
date added to LUP
2021-01-12 13:52:12
date last changed
2024-06-27 06:01:55
@article{d1678a7d-3b08-48d7-a856-661168a81644,
  abstract     = {{<p>Patients with coronary artery disease remain at increased risk of recurrent life-threatening cardiovascular events even after adequate guideline-based treatment of conventional risk factors, including blood lipid levels. Inflammation is a critical pathway in the pathogenesis of atherosclerosis and is independently associated with risk of recurrent cardiovascular events. Leukotrienes are potent pro-inflammatory and vasoactive mediators synthesized by leukocytes in atherosclerotic lesions. AZD5718 is a novel antagonist of 5-lipoxygenase activating protein that suppresses leukotriene biosynthesis. FLAVOUR is a phase IIa efficacy and safety study of AZD5718 in patients with myocardial infarction 1–4 weeks before randomization. Stenosis of the left anterior descending coronary artery after percutaneous intervention must be &lt;50%, and Thrombolysis In Myocardial Infarction flow grade must be ≥ 2. Enrolled participants receive standard care plus oral AZD5718 200 mg, 50 mg, or placebo once daily for up to 12 weeks (extended from 4 weeks by protocol amendment). The planned sample size is 100 participants randomized to 12 weeks’ treatment. Change in urine leukotriene E<sub>4</sub> levels is the primary efficacy outcome. FLAVOUR also aims to evaluate whether AZD5718 can improve coronary microvascular function, as measured by transthoracic colour Doppler-assisted coronary flow velocity reserve. Centrally pretrained study sonographers use standardized protocols and equipment. Additional outcomes include assessment of comprehensive echocardiographic parameters (including coronary flow, global strain, early diastolic strain rate and left ventricular ejection fraction), arterial stiffness, biomarkers, health-related quality of life, and safety. Specific anti-inflammatory therapies may represent novel promising treatments to reduce residual risk in patients with coronary artery disease. By combining primary pharmacodynamic and secondary cardiovascular surrogate efficacy outcomes, FLAVOUR aims to investigate the mechanistic basis and potential benefits of AZD5718 treatment in patients with coronary artery disease.</p>}},
  author       = {{Prescott, Eva and Pernow, John and Saraste, Antti and Åkerblom, Axel and Angerås, Oskar and Erlinge, David and Grove, Erik L. and Hedman, Marja and Jensen, Lisette O. and Svedlund, Sara and Kjaer, Magnus and Lagerström-Fermér, Maria and Gan, Li Ming}},
  issn         = {{2451-8654}},
  keywords     = {{5-Lipoxygenase activating protein; Coronary flow reserve; Coronary flow velocity reserve; Echocardiography; Leukotrienes; Myocardial infarction}},
  language     = {{eng}},
  publisher    = {{Elsevier}},
  series       = {{Contemporary Clinical Trials Communications}},
  title        = {{Design and rationale of FLAVOUR : A phase IIa efficacy study of the 5-lipoxygenase activating protein antagonist AZD5718 in patients with recent myocardial infarction}},
  url          = {{http://dx.doi.org/10.1016/j.conctc.2020.100629}},
  doi          = {{10.1016/j.conctc.2020.100629}},
  volume       = {{19}},
  year         = {{2020}},
}