Stable coronary artery disease (CAD) /Chronic coronary syndrome
Conditions
Interventions
Product Code: IMB-1018972
Pharmaceutical Form: Tablet
INN or Proposed INN: Ninerafaxstat
Current Sponsor code: IMB-1018972
Other descriptive name: IMB-1018972 trihydrochloride monohydrate
Concentratio
Sponsors
Imbria Pharmaceuticals, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
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 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. ß-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=65 years) yes F.1.3.1 Number of subjects for this age range 10
Exclusion criteria
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 or 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 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 of or other 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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To assess the safety and tolerability of IMB-1018972 in patients with angina and chronic coronary syndrome who have inducible myocardial ischemia. ;Secondary Objective: •To further assess the safety and tolerability of IMB 1018972 in patients with angina and chronic coronary syndrome who have inducible myocardal ischemia •To assess the impact of IMB-1018972 on segmental (regional) MBF, at rest and during adenosine stress in ischemic segments detected at baseline •To assess the impact of IMB-1018972 on the severity and extent of myocardial ischemia, measured with quantitative 15O-H2O PET MPI 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 • To assess the impact of IMB-1018972 on the tolerance to ischemic stress and the ischemic threshold during dobutamine stress • To assess the impact of IMB-1018972 on resting regional LV dysfunction at the patient level • To measure the impact of IMB-1018972 on LV systolic function at rest See CSP for further secondary objectives. ;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 ;Timepoint(s) of evaluation of this end point: Safety and tolerability will be assessed throughout the study | — |
Secondary
| Measure | Time frame |
|---|---|
| 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 2.3 mL/g/min 3c.Change in inducible perfusion defect, from baseline to EOT, expressed as % of myocardium 4a.Change in the mean ?WMSI 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 | — |
Countries
Denmark, Finland, Sweden
Contacts
Public ContactKaren Jauregi
Imbria Pharmaceuticals, Inc
Outcome results
None listed