A Trial of Cardiac Injections of iMP Cells During CABG Surgery

Study Overview
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Brief Summary
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Injury to the heart, which may occur following a heart attack or owing to the mechanical effect of high blood pressure, leads to scarring (fibrosis) of the heart muscle. Fibrosis of the muscle can cause impaired pumping of the heart, which can lead to heart failure, and the abnormal conduction of electrical signals through the heart. This may in turn lead to abnormal, potentially fatal, heart rhythms. Currently, scarring of the heart muscle cannot be reversed and is generally progressive. A previous clinical study found that participants who received injections of immunomodulatory progenitor cells (iMP cells, Heartcel) showed a reversal of heart muscle scarring when the cells were injected into heart muscle during coronary artery bypass graft (CABG) surgery. However, the previous trial was a small scale study and did not have a control group. The aim of this study is to perform a larger scale investigation with 50 participants compared to the previous trial of 11, and split the 50 participants into two groups - a test group and a control group, so that a direct comparison may be made between the two groups.

Detailed Description
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Myocardial fibrosis is a currently untreatable medical condition. A previous trial reported that when iMP cells, a cell type of mesodermal lineage which is separate from, but shares characteristics with, mesenchymal stem cells (MSCs), were injected into the myocardium during CABG surgery, there was a reduction in the degree of scarring relative to baseline observed on 4 month and 12 month Single-Photon Emission Computed Tomography (SPECT) images. The previous trial was open label with 11 participants and no control group, only historic comparisons. The proposed trial will be larger and will include a control group. The trial endpoints have been updated to take account of the findings of the first trial and late gadolinium enhanced (LGE) Magnetic Resonance Imaging (MRI) scans (LGE-CMR), which have higher resolution than SPECT scans, will be used to assess the appearance of fibrosis. iMP cells were developed by the sponsor as an allogeneic mesodermally derived cellular therapy for cardiac conditions. While iMPs are plastic adherent like MSCs, iMPs do not meet the International Society for Cellular Therapy's definition of MSCs, though like MSCs, markers indicate that iMPs are immune privileged and can therefore be employed allogeneically without inducing a significant immune response. The trial is open to participants, male and female, who require CABG surgery and have 15% or greater left ventricular scarring. Unless part of normal clinical care, participants will be required to undergo a screening LGE-MRI to assess the degree of left ventricular scarring. The MRI however, may reveal that the individual is not eligible to participate in the study. If the individual is eligible, then the LGE-MRI will be used as the baseline recording and to plan the injection sites. Each participant will be involved in the study for approximately 4.5 months. There will be two outpatient pre-operative hospital visits which will occur up to 6 weeks prior to surgery, though if a potential participant is an inpatient, the pre-operative eligibility/baseline tests can be performed over a shorter period of time as an inpatient. The CABG surgery will not differ from normal, except for the injections into the heart muscle, and participants will not miss out on any standard care. There will then be follow up visits at 1 week, 1 month and 15±2 weeks post surgery. The 1 week visit may occur as an inpatient depending on post-operative improvement. The follow up visits will not involve overnight stays. Follow up visits will mainly entail an ECG, an echocardiogram, a blood test, a urine test, health questionnaires and a discussion about the participant's health and any adverse events. Specific details are available from the chief investigator, see below. The 15±2 week visit will also involve a follow up LGE-MRI for primary endpoint assessment. After this visit, participation in the study will end and participants will receive only the normal post CABG care. As this is a quadruple blind randomised controlled trial, neither participants nor care staff will know to which group a participant is allocated. Of the 50 participants, 30 will receive injections of cells and 20 will receive control injections.

Official Title
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A Phase IIB, Randomised, Double-Blinded, Placebo-Controlled Study of the Efficacy and Safety of Intramyocardial Injection of Allogeneic Human iMP Cells in Patients Undergoing CABG Surgery.

Conditions
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Myocardial Fibrosis

Intervention / Treatment
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* Biological: iMP cells
* Other: Control injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Greater than or equal to 15% LV scar volume measured by LGE-CMR. LVEF ≤50%. Ischaemic heart disease where CABG is the recommended revascularisation strategy. Age range: 18 years of age and over with no history of congenital cardiac anomalies (men and women). Able to provide written informed consent (including willingness to have two CMRs). New York Heart Association (NYHA) class >=2 and/or Canadian Cardiovascular Society (CCS) class angina >=2. For women of child bearing potential (WOCBP): Negative (non-pregnant) beta-human chorionic gonadotropin (beta-hCG) blood test. Exclusion Criteria: Previous cardiac surgery Requirement for additional cardiac surgery including concomitant valve replacement surgery. Estimated GFR of <30mL/min Contraindication to performance of CMR Clinical history of malignancy within 5 years Comorbidities likely to influence the safety of performing the protocol Liver disease including ALT 3 times or more the upper limit of normal Low platelet count (<100,000) platelets per microliter of blood Evidence of coagulopathy - International Normalised Ratio (INR) >2. Note: Elevated INR due solely to warfarin (or similar medication) is NOT an exclusion criterion. Increased mortality risk over a 12-month period due to comorbidity

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: iMP cell injection<br>iMP cells injected in to the epicardial surface of the heart during coronary artery bypass graft surgery. | Biological: iMP cells<br>* Immunomodulatory progenitor cells<br>* Other names: Heartcel;|
| Placebo Comparator: Control injection<br>Control (cell suspension solution) injected in to the epicardial surface of the heart during coronary artery bypass graft surgery. | Other: Control injection<br>* Cell suspension solution<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| LGE-CMR | Change in left ventricular LGE-CMR imaging (e.g. scar/fibrosis volume reduction), iMP group compared to control group. | Baseline and 15±2 weeks post surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| LGE-CMR | Difference in Left Ventricular Ejection Fraction (LVEF), Left Ventricular End-Diastolic Volume Index (LVEDVi), Left Ventricular End-Systolic Volume Index (LVESVi), LV late gadolinium enhancement pattern, myocardial perfusion and myocardial strain. | Baseline and 15±2 weeks post surgery | 
| Major Adverse Cardiac Events (MACE) | Comparison of MACE rates between the two groups - Cardiovascular death, non fatal MI, non fatal stroke and unplanned cardiovascular hospitalisation. | Recorded 1 month and 15±2 weeks post surgery | 
| Major arrhythmic events | Comparison of rates between the two groups. | Recorded 1 month and 15±2 weeks post surgery | 
| All cause mortality | Comparison of rates between the two groups. | Recorded 1 month and 15±2 weeks post surgery | 
| New York Heart Association (NYHA) Class | Assessment of difference in NYHA class between groups. | Baseline and 15±2 weeks post surgery | 
| Quality of life questionnaires | Kansas City Cardiomyopathy Questionnaire (KCCQ), the Minnesota Living with Heart Failure (MLHF) questionnaire and the EQ5D questionnaire - compared between the two groups. | Baseline and 15±2 weeks post surgery | 
| Length of stay in intensive care/high dependency unit and time to discharge | Comparison of length of stay in intensive care/high dependency unit and time to discharge - compared between the two groups. | Operation date until discharge from hospital date, assessed up to 30 days post surgery. | 
| Blood biomarkers (routine and exploratory) | Blood biomarkers related to cardiac function. Routine - Urea and electrolytes, liver function tests and full blood count. Exploratory - Uric acid, lipid profile, high sensitivity C reactive protein, high sensitivity troponin, N terminal pro brain natriuretic peptide. Levels compared between the two groups. | Baseline, 4 times during the post operative recovery period (12h, 24h, 48h and 72h) and at 1 week, 30 days and 15±2 weeks post surgery. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Heart, CABG, Injection, Scar, Fibrosis, Cell, Progenitor, Immunomodulatory, MRI, Randomized