| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Stable coronary artery disease (CAD)/chronic coronary syndrome |
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| E.1.1.1 | Medical condition in easily understood language |
| Stable coronary artery disease (CAD) |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| 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 assess the safety and tolerability of IMB-1018972 in patients with angina and chronic coronary syndrome who have inducible myocardial ischemia. |
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| E.2.2 | Secondary objectives of the trial |
1 To further assess the safety and tolerability of IMB-1018972 in patients with angina and chronic coronary syndrome who have inducible myocardial ischemia
2 To assess the impact of IMB-1018972 on segmental (regional) MBF at rest and during adenosine stress in ischemic segments detected at baseline
3 To assess the impact of IMB-1018972 on the severity and extent of myocardial ischemia, measured with quantitative 15O-H2O PET MPI
4 To evaluate the impact of IMB-1018972 on dobutamine stress-induced regional myocardial dysfunction as a mechanical marker of myocardial ischemia evaluated at the patient level using DSE
5 To assess the impact of IMB-1018972 on the tolerance to ischemic stress and the ischemic threshold during dobutamine stress
6 To assess the impact of IMB-1018972 on resting regional LV dysfunction evaluated at the patient level
7 To measure the impact of IMB-1018972 on LV systolic function at rest
8-10 Please see the study protocol (limited characters here).
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Provide written informed consent before any screening procedures.
2.Able and willing to comply with all study procedures and requirements.
3.Male or female aged ≥35 and ≤80 years at screening
4.History of stable angina (CCS grading I-III) or anginal equivalent within 12 months prior to screening
5.Regular use of at least 1 anti-anginal medication for symptomatic treatment of angina (e.g. β-blocker or calcium channel blocker) for at least 2 weeks prior to start of dosing of study drug and likely to remain on this therapy as background anti-anginal treatment at envisaged stable doses for duration of study.
6.Patients on regular beta blockade must be able to safely abstain from beta blockers for 48 hours prior to DSE examinations in the opinion of the Investigator.
7.LVEF≥40% by any imaging modality.
8.History (e.g. within past 5 years) of obstructive CAD or stress-induced myocardial
ischemia documented by any of the following:
• CT or invasive angiography demonstrating ≥50% diameter stenosis in ≥1
major coronary artery OR in the setting of significant diffuse atheroma
• Prior percutaneous coronary intervention (PCI)
• Prior coronary artery bypass graft (CABG) surgery
• PET myocardial perfusion imaging demonstrating MBF<2.4 mL/min/g in
≥2 ischemic contiguous segments or involving ≥10.0% of the myocardium
(MBF must be <2.0 mL/min/g if it was obtained in the 3 months prior to
screening)
• Stress echo or stress CMR demonstrating ≥2 ischemic contiguous segments
• SPECT myocardial perfusion imaging demonstrating inducible perfusion
defect in ≥2 ischemic contiguous segments
9. Evaluable acoustic windows during contrast-enhanced, resting echocardiography.
10. Current 15O-H2O PET perfusion imaging demonstrating inducible ischemia defined as
hyperemic MBF<2.0 mL/min/g in ≥2 ischemic contiguous segments and/or involving
≥10% of the myocardium. Patients with a hyperemic MBF of 2.0 to 2.3 mL/min/g
may be eligible for randomization after discussion with the Sponsor taking into account other factors (e.g. anatomic extent of inducible ischemia, angina severity, known inducible ischemia, angina severity, known inducible wall motion abnormalities on DSE). |
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| E.4 | Principal exclusion criteria |
1. Clinically significant LMS or proximal LAD stenosis likely to warrant or planned for
revascularization during the study period in the opinion of the investigator.
2.For those patients planned for FDG-PET imaging, patients under 50 years old and with Type 2 diabetes mellitus requiring regular insulin or diabetes that is sub-optimally controlled (i.e. HbA1c > 8% or 64 mmol/l)
3.Patients with Type 1 insulin dependent diabetes mellitus (IDDM)
4.Known allergy/intolerance/absolute contra-indication to trimetazidine (TMZ), adenosine, dobutamine or atropine (e.g. glaucoma), echocardiography contrast agent, or excipients of the IMP.
5.If any of the following have occurred:
• Any prior treatment with trimetazidine (TMZ)
• In the 4 months prior to screening:
i. NYHA functional class 3 or 4 HF
ii. CABG
• In the 2 months prior to screening:
i. acute coronary syndrome
ii. PCI
iii. stroke/TIA
• In the 1 month prior to screening, use of:
i. perhexiline
ii. meldonium
6.Ongoing treatment with heparin or heparin derivatives
7.SGLT2 inhibitor and/or GLP-1 agonist therapy change (initiated or dose changed) within 2 months prior to Visit 1
8.Presence of pacemaker, cardiac resynchronization therapy and/or implantable cardioverter defibrillator
9. Severe valvular heart disease
10. Severe renal impairment defined as eGFR < 30 ml/min/1.73 m2 (calculated by CKD-EPI).
11.ALT /AST and/or bilirubin > 2 x ULN at baseline
12.History of Parkinson’s disease, Parkinsonian symptoms, or clinically significant restless legs syndrome.
13. Exacerbating reversible medical cause for angina (e.g. severe anemia, sustained hypertension defined as persistent BP > 160/90 mmHg, despite medical therapy, uncontrolled hyperthyroidism).
14. Long QT duration at screening (QTcF duration >470 ms for males, and >480 ms for females), or previously diagnosed long QT syndrome, or first degree relative with diagnosed long QT syndrome.
15. Permanent atrial fibrillation (AF).
16. Left bundle branch block (LBBB).
17. BMI ≤18 or >40 kg/m2, or body mass >180 kg that precludes imaging procedures.
18.History of alcohol or drug abuse within the prior 2 years
19.Female patients who are pregnant, of child-bearing potential or who are currently breast-feeding.
20.Male patients with partners who are currently breast-feeding or women of child-bearing potential unable or unwilling to use condoms as a method of birth control for the duration of the study and until 90 days after the last dose of study drug
21. Any malignancy currently under active treatment (e.g. chemotherapy, radiation).
Patients with a history or concurrent malignancy may be discussed on a case by case
basis with the Sponsor.
22. Currently participating in or have participated in any other investigational drug or
implantable medical device trial within 3 months prior to entry into this study.
23.Any major surgical procedure planned during the study period
24.Evidence of clinically significant renal, hepatic, hematological, gastrointestinal, pulmonary, metabolic-endocrine, neurological, urogenital or psychiatric disease that may constitute a health risk for the patient and/or would interfere with the evaluation of the results or any other reasons that, in the opinion of the investigator, make the patient unsuitable for enrollment. Specifically, site specific requirements for COVID must be followed. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Incidence and severity of treatment emergent AEs (including AEs leading to study drug discontinuation and AEs leading to death)
Incidence of treatment emergent SAEs
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Safety and tolerability will be assessed throughout the study |
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| E.5.2 | Secondary end point(s) |
1a.Changes in vital signs, physical examination, clinical laboratory findings and 12 lead electrocardiogram (ECG) findings.
1b.Rate of death from cardiovascular causes, nonfatal MI, and urgent revascularization
1c.Number of hospitalizations for cardiac reasons
1d.Frequency of cardiac ischemia-driven hospitalization and/or revascularization while on study
1e.Frequency of treatment interruptions or discontinuations
2a.Change in hyperemic (stress) MBF in the segments that were ischemic at baseline
2b.Change in resting segmental MBF from baseline to end-of-treatment (EOT) in the segments that were ischemic at baseline
2c.Change in MFR (myocardial flo reserve) in ischemic segments detected at baseline
2d. MFR defined as the ration of stress MBF to rest MBF.
3a.Change in number of ischemic segments during hyperemia (ischemia defined as absolute MBF ≤2.3 ml/kg/min)
3b.Change in total ischemia burden measured as ischemia score summed across all segments, from baseline to EOT. Ischemia score defined on the basis of absolute hyperemic MBF as: (1) MBF 2.0-2.3 ml/g/min (mild ischemia); (2) 1.7 to < 2.0 ml/g/min (moderate ischemia); (3) MBF <1.7 ml/g/min (severe ischemia) NB: normal hyperemic MBF defined as > 2.3 mL/g/min
3c.Change in inducible perfusion defect, from baseline to EOT, expressed as % of myocardium
4a.Change in the mean ΔWMSI deviation above normal from baseline DSE to EOT DSE study, termed "mean WMSI".
4b.WMSI evaluates both the extent and severity of-treatment abnormal segments, with mean WMSI for a patient representing an average of the patient's WMSI profile over the course of the DSE study from rest and through all DSE stages evaluated
□ Assessed in evaluable patients defined as those with any abnormal stress response to DSE (i.e. readout of anti-ischemic efficacy applicable to all categories of abnormal dobutamine stress response including any of classical ischemic, viability [meaning those dysfunctional at rest but improving with dobutamine], biphasic or fixed patterns) – this DSE readout is designed to be applicable to the broadest number of patients
□In addition, a specific evaluation will be made of all patients with any pattern of inducible ischemia, defined as those with either classical ischemic or biphasic responses to dobutamine
□Patients who have normal wall motion response at the baseline DSE examination (i.e. WMSI = 1 at rest and at all DSE stages evaluated) will not be evaluable for the mean WMSI endpoint
□Patients who reach different peak DSE stages between baseline and EOT imaging will have the mean WMSI deviation above normal analysis limited up to the highest common DSE stage reached in both studies. Change in mean Wall Motion Score (WMS) deviation above normal from baseline DSE to EOT DSE study in segments that were abnormal at baseline DSE, termed 'mean WMS of abnormal segments'
□For this endpoint, instead of averaging over 16 segments to obtain WMSI, the mean WMS is taken over the number of segments that exhibited abnormal responses at baseline (i.e. excluding all segments with normal WMS = 1 throughout DSE)
□Assessed in evaluable patients defined as those with any abnormal stress response to DSE (i.e. including any of classical ischemic, viability, biphasic or fixed patterns)
□Change in the maximal WMSI from baseline (pre-study drug) to the EOT, termed 'ΔΔWMSI'
□Assessed in evaluable patients with inducible ischemia defined as those with ΔWMSI > 0 at the baseline DSE study, i.e. those patients with evidence of either a classical ischemic response pattern or biphasic response pattern to dobutamine stress
□Patients who exhibit viability, normal or fixed patterns of responses to DSE at baseline study will not be evaluable for the ΔΔWMSI endpoint
□Maximal ΔWMSI is defined as the maximum increase in WMSI during the DSE protocol: for those with a classical ischemic pattern of response to dobutamine stress, maximal ΔWMSI is defined as the maximum increase in WMSI from rest to peak stress (the latter may be at any stage of the DSE protocol, i.e. 20, 30 or 40 μg/kg/min dose levels of infused dobutamine)
o for those with a biphasic pattern of response to dobutamine stress (where only at higher doses of dobutamine is there evidence ofinducible ischemia, i.e. an increase in WMSI), maximal ΔWMSI is defined at baseline as the maximum increase in WMSI from the dose at which WMSI is lowest to peak stress (maximum level of dobutamine reached after the WMSI nadir). At follow-up maximal ΔWMSI is the maximum increase in WMSI during the DSE protocol.Analyses will be undertaken grouping both classical and biphasic responses together (i.e. representing all patients with inducible ischemia by DSE), as well as individually.
Please see the study protocol Table 2-2 for further endpoints (character limitation here).
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
a.Safety and tolerability will be assessed throughout the study
b.Changes from baseline to end of treatment |
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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 | No |
| 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 | No |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 4 |
| 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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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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