E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Acute Myocardial Infarction |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10064345 |
E.1.2 | Term | ST segment elevation myocardial infarction |
E.1.2 | System Organ Class | 100000004849 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To investigate the effects of the CXCR4 antagonist POL6326 on cardiac function and infarct size in patients with large reperfused STEMI. |
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E.2.2 | Secondary objectives of the trial |
• To determine the safety and tolerability of POL6326 following 2-hour IV infusions in patients with large reperfused STEMI.
• To determine the pharmacokinetic profile of POL6326 in plasma following 2-hour IV infusions in patients with large reperfused STEMI. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patients must present with symptoms suggestive of an acute MI with ST-segment elevation ≥1 mm in at least 2 contiguous leads or new left bundle-branch block. It is possible that the ECGs of STEMI patients presenting late within the 48 hour time window may no longer show any ST-segment elevations. Instead, they may have already developed other ECG patterns (e.g., new Q-waves with T-wave inversion). These patients can also be included in the trial as long as they meet the following criteria: • They must have a high-grade stenosis or total occlusion on angiography, associated with abnormalities in regional wall motion AND • A rise and/or fall in cardiac necrosis biomarkers upon serial measurements with at least one value above the 99th percentile of the upper reference limit (preferably, troponin).
2. Patients must be scheduled to undergo coronary angiography for the purposes of primary PCI culminating in successful stent implantation as determined by Thrombolysis in Myocardial Infarction (TIMI) grade 2 or 3 preferably within 24 hours, but up to 48 hours after the onset of their symptoms. Use of a bare-metal stent or drug-eluting stent will be at the discretion of the interventional cardiologist. Patients who have had previous PCI for medical reasons other than STEMI or NSTEMI are eligible as long as they meet the other eligibility criteria.
3. Patients will be males or females ≥18 and ≤80 years of age, inclusive. • Male patients with a female partner of childbearing potential and female patients of childbearing potential must be willing to use a condom, diaphragm or cervical vault cap in conjunction with spermicidal foam, gel, film, cream, or suppository from the time of first dose until 3 months after the last dose of IMP. Female patients will also be requested to use an additional highly effective form of contraception (e.g., placement of an effective hormonal intra-uterine device i.e. Mirena® coil; use of oral injected or implanted hormonal methods of contraception) from the time of first dose until 3 months after the last dose of IMP. • Female patients of non-childbearing potential must be postmenopausal or permanently sterile following hysterectomy, bilateral salpingectomy or confirmed tubal occlusion (not tubal ligation). Postmenopausal is defined as no menses for at least 1 year, or a follicle stimulating hormone (FSH) level >40 IU/L, unless the patient is taking hormone replacement therapy.
4. Patients must have an LVEF ≤45% as determined by Investigator assessment of baseline cardiac MRI.
5. Patients must not have had any previous occurrence of MI as assessed by clinical history and baseline cardiac MRI.
6. Patients must have an estimated glomerular filtration rate (eGFR) ≥40 mL/minute prior to MRI, as determined by the Cockroft-Gault formula: [(140 – age) * (weight in kg) * (0.85 if female)] / [72 * serum creatinine in mg/dL]
7. Patients will have given their written informed consent to participate in the study. |
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E.4 | Principal exclusion criteria |
1. If there is, in the physician’s opinion, evidence of multi-vessel coronary artery disease likely to require repeat PCI or coronary artery bypass grafting within 4 months after randomisation.
2. Patients with pulmonary oedema or cardiogenic shock requiring intubation or mechanical support at the time of the planned baseline MRI.
3. Fitted with a non-MRI-compatible cardiac pacemaker or implantable cardioverter defibrillator, or expected to require such a device within 4 months after randomisation.
4. Terminal illness or malignant disease.
5. Advanced hepatic disease as determined by the following laboratory values: • Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3x upper limit of normal (ULN) and total bilirubin >2x ULN or international normalised ratio >1.5 or, • ALT or AST >3x ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash or eosinophilia.
6. Renal disease whereby eGFR is <40 mL/minute, as determined by the Cockroft-Gault formula (see Inclusion Criterion 6).
7. Diagnosis of severe obesity which precludes MRI assessments.
8. Suffering from claustrophobia.
9. Acute systemic infection or fever.
10. Anaemia (where haemoglobin levels are <10 g/dL), thrombocytopaenia (platelet count <100000/μL) or coagulopathy.
11. Patients with a history of multiple drug allergies or with a known allergy to the drug class of CXCR4 antagonists.
12. Pregnancy or females of childbearing potential who are not using double contraception.
13. Known history of human immunodeficiency virus (HIV) infection, chronic hepatitis B or hepatitis C infection or significant active chronic inflammatory disease that requires immunosuppressive medication or regular systemic corticosteroids.
14. Patients who have participated in any investigational drug or device trial within 30 days prior to signing informed consent.
15. Patients who are unwilling or unable to abide by the study requirements. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is:
• Group mean difference of intra-individual changes in global LVEF from baseline to 4 months, as determined by cardiac MRI. The baseline MRI is conducted at screening on Day 2 or Day 3 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary endpoint is assessed at 4 months. |
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E.5.2 | Secondary end point(s) |
Secondary endpoints: • Change in infarct size assessed using late enhancement MRI. • Change in LVEDV index assessed using MRI. • Change in LVESV index assessed using MRI. • Change in regional LV function assessed using MRI.
Exploratory endpoint: • Evaluation of N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, high-sensitive troponin T, and growth differentiation factor-15 at predose and at 4 months after baseline. Additional exploratory biomarkers may be analysed.
Single and combined clinical endpoints: • All-cause mortality. • Heart failure hospitalisations. • Non-fatal MI. • All-cause mortality + heart failure hospitalisations. • All-cause mortality + heart failure hospitalisations + non-fatal MI. • Safety laboratory assessments. • Physical examination. • Concomitant medications will also be recorded.
Follow-up assessment at 12 months: • Via telephone/letter contact to assess the patient’s health status.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Secondary and exploratory (biomarker) endpoints are assessed at 4 months.
• Single and combined clinical endpoints are assessed at 6 weeks and 4 months
• Follow-up assessment at 12 months
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 17 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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Completion of the 4-month visit for the last patient |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | 11 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 2 |
E.8.9.2 | In all countries concerned by the trial days | 2 |