IK-5001 for the Prevention of Remodeling of the Ventricle and Congestive Heart Failure After Acute Myocardial Infarction

Heart failure is a significant problem, and carries substantial mortality. According to studies, left ventricular (LV) remodeling contributes independently to heart failure progression. Prevention and reversal of LV remodeling are correlated with decreased risk of death and heart failure events. IK-5001 is an implantable device to be used in subjects with recent myocardial infarction (MI). The IK-5001 device has been shown to directly halt the remodeling process that occurs following acute MI. IK-5001 replaces the damaged extracellular matrix (ECM) that has degraded during infarction, supports the damaged myocardial tissue, prevents local dyskinesis, and decreases wall stress. Because of its minimal interaction with the myocardium, its mechanism of action, its lack of specific pharmacologic activity and its elimination behavior, IK-5001 is a medical device in concurrence with the Global Harmonization Task Force's harmonized definition for medical devices.

• IK-5001 (Device), also known as Sodium Alginate Calcium Gluconate, BIOABSORBABLE CARDIAC MATRIX (BCM): 4 mL (+/- 0.2 mL) administered through intracoronary slow bolus injection over 15 to 30 seconds at least 2 days after PCI but within 5 days of onset of symptoms.
• Saline Solution (Device): 4 mL (+/- 0.2 mL) slow bolus, intracoronary injection of saline solution will be administered over 15 to 30 seconds at least 2 days after percutaneous coronary intervention (PCI) but within 5 days of onset of symptoms.

Primary outcomes

• Left Ventricular End Diastolic Volume Index [Baseline, 6 Months]: Anatomic measurement of left ventricular end diastolic volume index (LVEDVI) assessed through echocardiogram.

Secondary outcomes

• Kansas City Cardiomyopathy Questionaire [Baseline (prior to index STEMI), 1, 3, 6 and 12 month follow-up visits]: Patient reported outcomes (PROs) using The Kansas City Cardiomyopathy Questionaire (KCCQ) score - a validated disease-specific self-administered 23-item questionnaire that will be used to quantify symptoms, function, and quality of life of subjects.
• Six minute walk test [Baseline (prior to discharge STEMI), 1, 3, 6 and 12 month follow-up visits]: The six minute walk test (6MWT) is used for measuring the response to medical interventions in subjects with moderate to severe heart disease, functional status of subjects, as well as a predictor of morbidity and mortality
• New York Heart Association (NYHA) functional classification (Physician reported) [Baseline (prior to index STEMI), 1, 3, 6 and 12 month follow-up visits]: New York Heart Association (NYHA) classification assessed by physician will be categorized by Class (Class I - IV)
• Cardiovascular death, non-fatal heart failure events or cardiovascular hospitalizations [5 Years]: Time to cardiovascular death, non-fatal heart failure events or cardiovascular hospitalizations adjudicated by a Clinical Events Committee
• Re-hospitalization due to any cardiovascular event [5 Years]: Time to re-hospitalization due to any cardiovascular event

Other outcomes

• NT-pro-brain natriuretic peptide (NT-proBNP) levels [Baseline, discharge, 1, 3, and 6 month follow-up visits.]: NT-pro-brain natriuretic peptide (NT-proBNP) levels
• Short Form 12 (SF-12) Questionnaire [Baseline (prior to the index STEMI), 1, 3, 6 and 12 month follow-up visits]: The SF-12 is a validated general quality of life self-administered instrument that has been used in various disease states.
• Measurement of alginate in plasma and urine [Baseline, 5, 30 min, 1, 3, 8, 24, 48 hrs, 1, 3 month]: At selected sites, relatively intensive sampling: blood will be drawn just prior to deployment (0 hour), 5 and 30 minutes and 1, 3, 8, 24, 48 hrs post deployment or until discharge, whichever occurs first, and at 1 and 3 month follow-up visit. At selected sites, urine collection for measurements of alginate, 4 urine samples, will be collected at baseline (within 30 min prior to deployment), 0-8 hrs (from the time immediately following the device deployment through 8 hrs post deployment), 8 through 24 hours through post deployment, 24 through 48 hrs or discharge (whichever comes first). In addition, a urine sample will be taken at 1 and 3 month follow-up visits. Remaining sites: sparse sampling blood will be drawn at 1, 8 and 24 hours, 1 month and post-deployment.
• Healthcare utilization [6 and 12 month follow-up visits.]: The healthcare utilization and questionnaire consists of subject responses to questions regarding mobility, self-care, usual activities, pain, discomfort, anxiety and depression.
• Anatomic endpoints [4 to 6 hours following deployment, 1, 3 and 12 month follow-up visits]: Anatomic endpoints: ejection fraction, end systolic volume index, mitral regurgitation, diastolic function, sphericity index, wall thickness, wall motion score and left ventricular (LV) mass index derived from the echocardiogram.
• Primary Safety Evaluation [1 Year]: The following safety endpoints will be adjudicated by a Clinical Events Classification Committee: 1. Death 2. Recurrent myocardial infarction (MI) or target vessel revascularization or stent thrombosis 3. Significant arrhythmia requiring therapy 4. Myocardial rupture
• Long-term Safety Evaluation [1 year to 5 years after device deployment]: 1. Death 2. Need for devices for the management of congestive heart failure (CHF) * automated implantable cardiac defibrillator (AICD) * cardiac resynchronization therapy * left ventricular assist device (LVAD) 3. Heart transplant
• Continuous Electrocardiogram Cardiac Safety Endpoints [Baseline, prior to discharge, 1, 3 and 6 month follow-up visits]: * New ischemia by ST segment deviation * QT/QTcF (Fridericia's heart rate correction) before and 18 hours after procedure * Severe bradycardia or tachycardia, including sustained ventricular or supraventricular tachycardia, total beats in episodes of tachycardia, total pauses and newly paced beats.
• Clinical Chemistry, Hematology, and Urinalysis panel [Clinical Chemistry, Hematology: Baseline, 8 hours (± 2 hours) post-deployment, 1, 3, and 6 month follow-up visits. Urinalysis : Baseline and discharge]: Chemistry panel - levels of albumin, alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen, calcium, serum chloride, bicarbonate, direct bilirubin, creatinine, γ-GT, glucose, lactate dehydrogenase, potassium, sodium, and total bilirubin. Hematology panel - hemoglobin, hematocrit, mean corpuscular volume (MCV), red blood cell count (RBC), white blood cell (WBC) levels (with 5 part differential), and platelet count. Urinalysis - pH, specific gravity, RBC, WBC, glucose, protein in the urine, and a Human chorionic gonadotropin (HCG) pregnancy test
• Performance Goal and Study Success [Baseline to 6 months]: 5 mL/m2 change or greater in LVEDVI in IK-5001 group vs. placebo

Sex: All, ages: 18 Years to any

Inclusion criteria:

Subjects must meet all of the following inclusion criteria to participate in this trial:

1. The subject is ≥ 18 years of age.
2. The subject has given informed consent.
3. The subject has experienced a large STEMI defined by the following criteria:

   Peak cardiac enzyme value within 48 hours of symptom onset as follows:
   * Creatine kinase MB fraction (CK-MB) > 30 x the upper limit of normal OR
   * Troponin I > 200 x upper limit of normal OR
   * Troponin T > 60 x the upper limit of normal

   AND at least 1 of the following 3 criteria:
   * Delayed presentation with PCI > 6 hours from onset of symptoms
   * Significant new Q waves in ≥ 2 anterior leads or anterior ST segment elevation of at least 3 mm persistent at 24 hours after PCI
   * New onset of CHF (Killip class 3-4) or cardiogenic shock persistent at 24 hours after PCI

   AND at least 1 of the following 2 criteria:
   * MI ≥ 20% by Single Photon Emission Computed Tomography scan (SPECT) or cardiac Magnetic Resonance Imaging (MRI) with defect in the appropriate distribution
   * Ejection fraction ≤ 35% with wall motion abnormality in the appropriate distribution at baseline imaging assessment
4. The subject has had successful PCI with stent within 48 hours of symptom onset, and residual stenosis less than 20% in the infarct related artery and greater than or equal to thrombolysis in myocardial infarction (TIMI) 2 flow. Subjects undergoing rescue PCI after thrombolysis or delayed presentation with ongoing ischemia may be enrolled.
5. For Germany only: Patients determined to have Killip class 4 at time of device deployment are not eligible for randomization.
6. For Germany only: If SPECT is used for determination of MI size in order to meet inclusion criteria, the SPECT must have been previously performed as part of standard clinical care. SPECT is not to be performed solely to qualify a patient for this study in Germany.

Exclusion criteria:

Subjects will be excluded from participating in this trial if ANY of the following exclusion criteria are met:

1. Any subject with cardiogenic shock requiring mechanical ventilation or mechanical support at the time of deployment. Subject must be off mechanical support prior to deployment.
2. Need for urgent coronary artery bypass graft (CABG)
3. Clinically significant valvular heart disease with planned surgical correction or transcatheter aortic valve implantation (TAVI)
4. Uncontrolled ventricular arrhythmias
5. Renal insufficiency with a calculated creatinine clearance of less than 30 mL/ minute. See Appendix A for determining estimated creatinine clearance.
6. Clinically significant hepatic insufficiency
7. Inadequate imaging windows (defined as the inability to visualize the endocardial border of at least 16 of the 17 segments in both the apical four chambers and apical two chamber views without foreshortening) or arrhythmia that would preclude adequate 3D imaging on transthoracic echocardiography at the local baseline echo assessment
8. Non-ambulatory prior to the index MI
9. The subject has participated in another trial of an investigational agent within 30 days prior to randomization.
10. Subject has received resorbable stent as part of PCI.
11. The subject is pregnant or breastfeeding. Women of child-bearing potential will have a negative urine pregnancy test prior to randomization.
12. Any other concurrent condition that, in the opinion of the investigator, would prevent completion of the clinical trial, including inability to comply with follow up requirements.
13. For Germany only: In the investigator's opinion, the patient is not expected to survive ≥12 months.
14. For Germany only: 24 hours prior to device deployment, the patient has a serum calcium level greater than the upper limit of normal as determined by the local laboratory.

• Results publication: Wei X, Chen S, Xie T, Chen H, Jin X, Yang J, Sahar S, Huang H, Zhu S, Liu N, Yu C, Zhu P, Wang W, Zhang W. An MMP-degradable and conductive hydrogel to stabilize HIF-1alpha for recovering cardiac functions. Theranostics. 2022 Jan 1;12(1):127-142. doi: 10.7150/thno.63481. eCollection 2022. PMID 34987638
• Results publication: Rao SV, Zeymer U, Douglas PS, Al-Khalidi H, White JA, Liu J, Levy H, Guetta V, Gibson CM, Tanguay JF, Vermeersch P, Roncalli J, Kasprzak JD, Henry TD, Frey N, Kracoff O, Traverse JH, Chew DP, Lopez-Sendon J, Heyrman R, Krucoff MW. Bioabsorbable Intracoronary Matrix for Prevention of Ventricular Remodeling After Myocardial Infarction. J Am Coll Cardiol. 2016 Aug 16;68(7):715-23. doi: 10.1016/j.jacc.2016.05.053. PMID 27515331
• Results publication: Frey N, Linke A, Suselbeck T, Muller-Ehmsen J, Vermeersch P, Schoors D, Rosenberg M, Bea F, Tuvia S, Leor J. Intracoronary delivery of injectable bioabsorbable scaffold (IK-5001) to treat left ventricular remodeling after ST-elevation myocardial infarction: a first-in-man study. Circ Cardiovasc Interv. 2014 Dec;7(6):806-12. doi: 10.1161/CIRCINTERVENTIONS.114.001478. Epub 2014 Oct 28. PMID 25351198

• Ashika Ahmed, MD, Study director, Bellerophon Therapeutics