Clinical trial NCT04601467: PASSIvation of Vulnerable Plaque With AZD5718 in AcuTe Coronary syndromE
Official title: PASSIvation of Vulnerable Plaque With AZD5718 in AcuTe Coronary syndromE
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Acute Coronary Syndrome
Keywords: Acute Myocardial Infarction
Computed Tomography Coronary Angiography
Lead sponsor: National University Heart Centre, Singapore
Sponsor class: OTHER
Collaborators: name: AstraZeneca
name: University of Otago
First posted: 2020-10-23
Enrollment: 243
Sex: ALL
Minimum age (years): 21
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a multi-center study conducted at 8 sites in 2 countries (Singapore, New Zealand). Patients with an acute myocardial infarction (AMI) were randomized in a ratio of 1:1 ratio to receive AZD5718 (Atuliflapon) 125 mg or placebo for 12 months to assess the efficacy of AZD5718 to prevent coronary plaque progression as measured on serial computer tomographic coronary angiography.

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 60 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.

Eligibility 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 ≤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

Primary outcomes:
measure: Change in noncalcified coronary artery plaque volume (NCPV)
timeFrame: Baseline (before treatment) and after 12 months of treatment
Secondary outcomes:
measure: Change in CT peri vascular (coronary) adipose tissue (PVAT)
timeFrame: Baseline (before treatment) and after 12 months of treatment
measure: Change in total plaque volume (mm3)
timeFrame: Baseline (before treatment) and after 12 months of treatment
measure: Echocardiographic assessment: Change in left ventricular ejection fraction (LVEF)
timeFrame: Baseline (before treatment) and after 12 months of treatment
measure: Change in levels of urinary LTE4 (u-LTE4)
timeFrame: 12 months
Other outcomes:
measure: Change in low attenuation plaque burden
timeFrame: Baseline (before treatment) and after 12 months of treatment
measure: Change in plasma hs-CRP concentration
timeFrame: Baseline (before treatment) and after 12 months of treatment
measure: Echocardiographic assessment: Change in LV global longitudinal strain
timeFrame: Baseline (before treatment) and after 12 months of treatment
measure: Echocardiographic assessment: Change in global circumferential strain
timeFrame: Baseline (before treatment) and after 12 months of treatment
measure: Echocardiographic assessment: Change in longitudinal early diastolic strain rate
timeFrame: Baseline (before treatment) and after 12 months of treatment
Locations:
city: Auckland
country: New Zealand
facility: North Shore Hospital
city: Christchurch
country: New Zealand
facility: Christchurch Heart Institute (CHI)
city: Singapore
country: Singapore
facility: Changi General Hospital (CGH)
city: Singapore
country: Singapore
facility: Khoo Teck Puat Hospital (KTPH)
city: Singapore
country: Singapore
facility: National Heart Centre Singapore (NHCS)
city: Singapore
country: Singapore
facility: National University Heart Centre, Singapore (NUHCS)
city: Singapore
country: Singapore
facility: Ng Teng Fong General Hospital (NTFGH)
city: Singapore
country: Singapore
facility: Tan Tock Seng Hospital (TTSH)
Study officials:
affiliation: National University Heart Centre, Singapore
name: Mark Chan
role: PRINCIPAL_INVESTIGATOR
affiliation: National Heart Centre Singapore
name: Derek Hausenloy
role: PRINCIPAL_INVESTIGATOR
affiliation: National University Heart Centre, Singapore
name: A. Mark Richards
role: STUDY_CHAIR
References:
citation: 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.
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.