PASSIVATE: PASSIvation of Vulnerable Plaque With AZD5718 in AcuTe Coronary syndromE
Study Details
Study Description
Brief Summary
This is a multi-center study conducted at 13 sites in 3 countries (Singapore, New Zealand, and the United Kingdom). Approximately 360 patients with an acute myocardial infarction (AMI) will be randomized in a ratio of 1:1 ratio to receive AZD5718 125 mg or placebo for 12 months.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
PASSIVATE is a randomized, double-blind, placebo-controlled Phase IIa trial that investigates how 12 months of treatment with AZD5718 modifies coronary plaque volume. Patients with recent STEMI or NSTEMI will receive an additional oral dose of AZD5718 (or placebo) once daily to standard clinical care for 12 months. The primary hypothesis being tested in PASSIVATE is that 12 months of treatment with AZD5718 attenuates the progression of non-calcified plaque (NCP) volume on serial computed tomography coronary angiography (CTCA) studies.
Patients who gave consent (within 30 days after their index event) will undergo a CTCA scan and start treatment (AZD5718 or Placebo). The treatment duration will be 12 months. During the treatment period, patients will come to the clinic for follow-ups. At 12 months (end treatment), the patients will undergo their 2nd CTCA scan. A follow-up visit will be performed 4 weeks after the last dose in order to ensure the safety and well-being of the patients.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: AZD5718 Patients will receive once daily oral dose of AZD5718 for 12 months |
Drug: AZD5718
Oral dose of AZD5718 (tablet) once daily for 12 months
|
| Placebo Comparator: Placebo Patients will receive once daily oral dose of placebo matched to AZD5718 for 12 months |
Drug: Placebo
Oral dose of matching placebo (tablet) once daily for 12 months
|
Outcome Measures
Primary Outcome Measures
- Change in noncalcified coronary artery plaque volume (NCPV) [Baseline (before treatment) and after 12 months of treatment]
Percent change in NCPV (in mm3), as assessed by CT coronary angiography, from baseline (before treatment) to after 12-month of treatment
Secondary Outcome Measures
- Change in CT pericoronary adipose tissue (PCAT) [Baseline (before treatment) and after 12 months of treatment]
To assess whether AZD5718 reduces coronary inflammation
- Change in total plaque volume (mm3) [Baseline (before treatment) and after 12 months of treatment]
Percent change in total plaque volume (in mm3), as assessed by CT coronary angiography, from baseline (before treatment) to after 12-month of treatment
- Echocardiographic assessment: Change in left ventricular ejection fraction (LVEF) [Baseline (before treatment) and after 12 months of treatment]
Percent change in LVEF (%), as assessed by 2D echocardiography, from baseline (before treatment) to after 12-month of treatment
- Plasma concentrations of AZD5718 [12 month]
To assess the PK of AZD5718 after repeated oral dosing for 12 months
- Change in levels of urinary LTE4 (u-LTE4) [12 months]
To assess the pharmacodynamics (PD) effect of AZD5718 by assessment of u-LTE4 in AMI patients
Other Outcome Measures
- Change in low attenuation plaque burden [Baseline (before treatment) and after 12 months of treatment]
Percent change in low attenuation (<30 HU) plaque volume (mm3), as assessed by CT coronary angiography, from baseline (before treatment) to after 12-month of treatment
- Change in levels of ex vivo stimulated plasma leukotriene B4 (LTB4) [12 months]
To assess the effect of AZD5718 on LTB4 levels in ex vivo stimulated human plasma by liquid chromatography-tandem mass spectrometry
- Change in plasma hs-CRP concentration [Baseline (before treatment) and after 12 months of treatment]
To assess the changes in circulating hs-CRP concentrations from baseline (before treatment) to after 12-month of treatment
- Change in plasma troponin concentration [Baseline (before treatment) and after 12 months of treatment]
To assess the changes in circulating troponin concentrations from baseline (before treatment) to after 12-month of treatment
- Change in plasma NT-proBNP concentration [Baseline (before treatment) and after 12 months of treatment]
To assess the changes in circulating NT-proBNP concentrations from baseline (before treatment) to after 12-month of treatment
- Echocardiographic assessment: Change in LV global longitudinal strain [Baseline (before treatment) and after 12 months of treatment]
Percent change in LV global longitudinal strain, as assessed by 2D echocardiography, from baseline (before treatment) to after 12-month of treatment
- Echocardiographic assessment: Change in global circumferential strain [Baseline (before treatment) and after 12 months of treatment]
Percent change in global circumferential strain, as assessed by 2D echocardiography, from baseline (before treatment) to after 12-month of treatment
- Echocardiographic assessment: Change in longitudinal early diastolic strain rate [Baseline (before treatment) and after 12 months of treatment]
Percent change in longitudinal early diastolic strain rate, as assessed by 2D echocardiography, from baseline (before treatment) to after 12-month of treatment
Eligibility Criteria
Criteria
Inclusion Criteria:
-
hospitalised for STEMI or non-STEMI, as defined by the 4th universal definition of MI
-
underwent coronary angiography during the index hospitalisation showing at least one epicardial coronary artery with ≥50% stenosis and a 2nd epicardial coronary artery with ≥20% stenosis on the coronary angiogram
-
Body Mass Index (BMI) ≥18 to ≤35 kg/m2
-
White Blood Cell count ≥ 8.2 X 103/uL during admission
Exclusion Criteria:
-
Prior coronary artery bypass grafting (CABG)
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CABG planned within 12 months of admission
-
Known history of drug or alcohol abuse within 5 years of screening
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History of QT prolongation associated with other medications that required discontinuation of that medication
-
Congenital long QT syndrome
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Systolic blood pressure persistently <90 mm Hg or HR<40 beats per minute at time of enrolment
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ALT >2 x ULN, cirrhosis, recent hepatitis, or positive screening test for hepatitis B (hepatitis B surface antigen) or other viral hepatitis
-
Uncontrolled Type 1 or Type 2 DM defined as HbA1c >10% or 74.9 mmol/mol (by IFCC)
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Any planned coronary revascularisation, valve surgery, or cardiac resynchronisation within 7 months after randomisation
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Any concomitant medications known to be associated with Torsades de Pointes or potent inducers of cytochrome P450 3A4 (CYP3A4)
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Planned treatment with zileuton, leukotriene receptor antagonists (e.g., montelukast) during trial
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Participated in another interventional clinical study with an investigational pharmaceutical product during the last 3 months
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Known hypersensitivity to drugs with a similar chemical structure or class of study drugs or any of the excipients of the product
-
Known conditions that either increase the risk of performing the CT or make the procedure technically impractical
-
No severe asthma attack that require emergency treatment or hospitalisation in the past 6 months
-
Had severe course of COVID-19 (extracorporeal membrane oxygenation, mechanically ventilated), and/or had a confirmed case of COVID-19 within 4 weeks of Screening Visit
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- National University Heart Centre, Singapore
- AstraZeneca
Investigators
- Principal Investigator: Mark Chan, National University Heart Centre, Singapore
- Principal Investigator: Derek Hausenloy, National Heart Centre Singapore
- Study Chair: A. Mark Richards, National University Heart Centre, Singapore
Study Documents (Full-Text)
None provided.More Information
Publications
- Ericsson H, Nelander K, Lagerstrom-Fermer M, Balendran C, Bhat M, Chialda L, Gan LM, Heijer M, Kjaer M, Lambert J, Lindstedt EL, Forsberg GB, Whatling C, Skrtic S. Initial Clinical Experience with AZD5718, a Novel Once Daily Oral 5-Lipoxygenase Activating Protein Inhibitor. Clin Transl Sci. 2018 May;11(3):330-338. doi: 10.1111/cts.12546. Epub 2018 Mar 8.
- Pettersen D, Broddefalk J, Emtenäs H, Hayes MA, Lemurell M, Swanson M, Ulander J, Whatling C, Amilon C, Ericsson H, Westin Eriksson A, Granberg K, Plowright AT, Shamovsky I, Dellsèn A, Sundqvist M, Någård M, Lindstedt EL. Discovery and Early Clinical Development of an Inhibitor of 5-Lipoxygenase Activating Protein (AZD5718) for Treatment of Coronary Artery Disease. J Med Chem. 2019 May 9;62(9):4312-4324. doi: 10.1021/acs.jmedchem.8b02004. Epub 2019 Mar 26.
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