PASSIvation of Vulnerable Plaque With AZD5718 in AcuTe Coronary syndromE

Acute Coronary Syndrome Clinical Trial

— PASSIVATE  

Official title:

PASSIvation of Vulnerable Plaque With AZD5718 in AcuTe Coronary syndromE

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04601467
• Other study ID #: 2020/
• Status: Recruiting
• Phase: Phase 2
• Start date: July 12, 2021
• Est. completion date: September 30, 2024

Study information

• Verified date: December 2022
• Source: National University Heart Centre, Singapore
• Contact: Sock Hwee Tan
• Phone: +65 67795555
• Email: mdctshw[@]nus.edu.sg
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a multi-center study conducted at 13 sites in 3 countries (Singapore, New Zealand, and the Australia). Approximately 260 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 360
• Est. completion date: September 30, 2024
• Est. primary completion date: March 31, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 21 Years to 80 Years

Eligibility

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 =40 kg/m2

• White Blood Cell count = 7.0 X 103/uL during admission

Exclusion Criteria:

• Prior coronary artery bypass grafting (CABG)

• CABG planned within 12 months of admission

• Known history of drug or alcohol abuse within 5 years of screening

• History of QT prolongation associated with other medications that required discontinuation of that medication

• Congenital long QT syndrome

• Systolic blood pressure persistently <90 mm Hg or HR<40 beats per minute at time of enrolment

• 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)

• Any planned coronary revascularisation, valve surgery, or cardiac resynchronisation within 7 months after randomisation

• Any concomitant medications known to be associated with Torsades de Pointes or potent inducers of cytochrome P450 3A4 (CYP3A4)

• Planned treatment with zileuton, leukotriene receptor antagonists (e.g., montelukast) during trial

• Participated in another interventional clinical study with an investigational pharmaceutical product during the last 3 months

• 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

Related Conditions & MeSH terms

• Acute Coronary Syndrome
• Syndrome

Intervention

Drug:
• AZD5718
Oral dose of AZD5718 (tablet) once daily for 12 months
• Placebo
Oral dose of matching placebo (tablet) once daily for 12 months

Locations

Country	Name	City	State
Australia	Cairns Hospital	Cairns
Australia	Monash Medical Centre	Melbourne
New Zealand	North Shore Hospital	Auckland
New Zealand	Christchurch Heart Institute (CHI)	Christchurch
Singapore	Changi General Hospital (CGH)	Singapore
Singapore	Khoo Teck Puat Hospital (KTPH)	Singapore
Singapore	National Heart Centre Singapore (NHCS)	Singapore
Singapore	National University Heart Centre, Singapore (NUHCS)	Singapore
Singapore	Ng Teng Fong General Hospital (NTFGH)	Singapore
Singapore	Tan Tock Seng Hospital (TTSH)	Singapore

Sponsors (2)

Lead Sponsor	Collaborator
National University Heart Centre, Singapore	AstraZeneca

Countries where clinical trial is conducted

Australia,  New Zealand,  Singapore, 

References & Publications (2)

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. — View Citation

Pettersen D, Broddefalk J, Emtenas H, Hayes MA, Lemurell M, Swanson M, Ulander J, Whatling C, Amilon C, Ericsson H, Westin Eriksson A, Granberg K, Plowright AT, Shamovsky I, Dellsen A, Sundqvist M, Nagard 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change in low attenuation plaque burden	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	Baseline (before treatment) and after 12 months of treatment
Other	Change in levels of ex vivo stimulated plasma leukotriene B4 (LTB4)	To assess the effect of AZD5718 on LTB4 levels in ex vivo stimulated human plasma by liquid chromatography-tandem mass spectrometry	12 months
Other	Change in plasma hs-CRP concentration	To assess the changes in circulating hs-CRP concentrations from baseline (before treatment) to after 12-month of treatment	Baseline (before treatment) and after 12 months of treatment
Other	Change in plasma troponin concentration	To assess the changes in circulating troponin concentrations from baseline (before treatment) to after 12-month of treatment	Baseline (before treatment) and after 12 months of treatment
Other	Change in plasma NT-proBNP concentration	To assess the changes in circulating NT-proBNP concentrations from baseline (before treatment) to after 12-month of treatment	Baseline (before treatment) and after 12 months of treatment
Other	Echocardiographic assessment: Change in LV global longitudinal strain	Percent change in LV global longitudinal strain, as assessed by 2D echocardiography, from baseline (before treatment) to after 12-month of treatment	Baseline (before treatment) and after 12 months of treatment
Other	Echocardiographic assessment: Change in global circumferential strain	Percent change in global circumferential strain, as assessed by 2D echocardiography, from baseline (before treatment) to after 12-month of treatment	Baseline (before treatment) and after 12 months of treatment
Other	Echocardiographic assessment: Change in longitudinal early diastolic strain rate	Percent change in longitudinal early diastolic strain rate, as assessed by 2D echocardiography, from baseline (before treatment) to after 12-month of treatment	Baseline (before treatment) and after 12 months of treatment
Primary	Change in noncalcified coronary artery plaque volume (NCPV)	Percent change in NCPV (in mm3), as assessed by CT coronary angiography, from baseline (before treatment) to after 12-month of treatment	Baseline (before treatment) and after 12 months of treatment
Secondary	Change in CT pericoronary adipose tissue (PCAT)	To assess whether AZD5718 reduces coronary inflammation	Baseline (before treatment) and after 12 months of treatment
Secondary	Change in total plaque volume (mm3)	Percent change in total plaque volume (in mm3), as assessed by CT coronary angiography, from baseline (before treatment) to after 12-month of treatment	Baseline (before treatment) and after 12 months of treatment
Secondary	Echocardiographic assessment: Change in left ventricular ejection fraction (LVEF)	Percent change in LVEF (%), as assessed by 2D echocardiography, from baseline (before treatment) to after 12-month of treatment	Baseline (before treatment) and after 12 months of treatment
Secondary	Plasma concentrations of AZD5718	To assess the PK of AZD5718 after repeated oral dosing for 12 months	12 month
Secondary	Change in levels of urinary LTE4 (u-LTE4)	To assess the pharmacodynamics (PD) effect of AZD5718 by assessment of u-LTE4 in AMI patients	12 months