A Trial of Cardiac Injections of iMP Cells During CABG Surgery

• Sponsor: Cell Therapy Ltd.
• Collaborator: Royal Brompton & Harefield NHS Foundation Trust
• Information provided by (Responsible Party): Cell Therapy Ltd.

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Myocardial Fibrosis	Biological: iMP cells; Other: Control injection	Phase 2

Detailed Description:

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, 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 13.5 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, and participants will not miss out on any standard care. There will then be follow up visits at 1 week, 1 month, 6 months and 12 months 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 6 month visit will also involve a follow up LGE-MRI for primary endpoint assessment. After 12 months, 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.

Study Design

Layout table for study information

Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	50 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Treatment
Official Title:	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.
Estimated Study Start Date :	April 2019
Estimated Primary Completion Date :	February 2020
Estimated Study Completion Date :	August 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: iMP cell injection; iMP cells injected in to the epicardial surface of the heart during coronary artery bypass graft surgery.	Biological: iMP cells; Immunomodulatory progenitor cells; Other Name: "Heartcel"
Placebo Comparator: Control injection; Control (cell suspension solution) injected in to the epicardial surface of the heart during coronary artery bypass graft surgery.	Other: Control injection; Cell suspension solution

Outcome Measures

Primary Outcome Measures :

1. LGE-MRI [ Time Frame: Baseline and 6 months post surgery ]
   Change in left ventricular LGE-MRI imaging (e.g. scar/fibrosis reduction), iMP group compared to control group.

Secondary Outcome Measures :

1. LGE-MRI [ Time Frame: Baseline and 6 months post surgery ]
   Difference in Left Ventricular End-Diastolic Volume Index (LVEDVi), Left Ventricular End-Systolic Volume Index (LVESVi), Left Ventricular Ejection Fraction (LVEF), Late Gadolinium pattern, extent of fibrosis and strain analysis (wall motion and thickness) between groups.
2. Major Adverse Cardiac Events (MACE) [ Time Frame: Recorded 30 days, 3 months, 6 months and 12 months post surgery ]
   Comparison of MACE rates between the two groups.
3. New York Heart Association (NYHA) Class [ Time Frame: Baseline and 6 months post surgery ]
   Assessment of difference in NYHA class between groups
4. Quality of life questionnaires [ Time Frame: Baseline and 6 months post surgery ]
   Kansas City Cardiomyopathy Questionnaire and the Minnesota Living with Heart Failure questionnaire - compared between the two groups.
5. Quality of life questionnaires [ Time Frame: Baseline and 12 months post surgery ]
   Kansas City Cardiomyopathy Questionnaire and the Minnesota Living with Heart Failure questionnaire - compared between the two groups.
6. Length of stay in intensive care/high dependency unit and time to discharge [ Time Frame: Operation date until discharge from hospital date, assessed up to 30 days post surgery. ]
   Comparison of length of stay in intensive care/high dependency unit and time to discharge - compared between the two groups.
7. Blood biomarkers (routine and exploratory) [ Time Frame: Baseline, 4 times during the post operative recovery period (72 hours) and at 1 week, 30 days, 6 months and 12 months post surgery. ]
   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.
8. Blood test - Assessment of immunogenicity [ Time Frame: Baseline and 30 days post surgery. ]
   Humoral response assay to assess immunogenicity: Tests for immunoglobulins (Ig) - IgG1-4, IgM, IgA and IgE. Levels compared between the two groups.

Eligibility Criteria

Layout table for eligibility information

Ages Eligible for Study:	55 Years to 80 Years (Adult, Older Adult)
Sexes Eligible for Study:	All
Gender Based Eligibility:	Yes
Gender Eligibility Description:	Female participants must not be pregnant or of child bearing potential (post menopausal for at least 2 years) and must not be lactating.
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

1. > or equal to 15% left ventricular scar defined by Late Gadolinium Enhanced (LGE)-MRI
2. Moderately reduced ejection fraction of <50%
3. Ischaemic heart disease referred for CABG following discussion with a multidisciplinary heart team
4. Age range: 55-80 years (men and women),
5. Female participants only: Post menopausal (no menses for 2 years without an alternative medical cause)

Exclusion Criteria:

1. Previous cardiac surgery (PCI is allowed providing MRIs are still possible)
2. Requirement for additional cardiac surgery
3. Estimated Glomerular Filtration Rate (GFR) of <30mL/min by calculation
4. Contra-indication to performance of Cardiac MRI
5. Clinical history of malignancy within 5 years
6. Comorbidities likely to influence the safety of performing the protocol
7. Individuals with liver disease including Alanine Transaminase (ALT) 3 times or more the upper limit of normal
8. Individuals with a low platelet count (<100,000) platelets per microliter of blood
9. Individuals with evidence of coagulopathy - International Normalised Ratio (INR) >2. Note: Elevated INR due solely to warfarin (or similar medication) is NOT an exclusion criterion.
10. Individuals with any condition likely to interfere with CABG surgery over a 12-month period.
11. Female participants only: A woman of child bearing potential, a pregnant or lactating woman.

Contacts and Locations

Contacts

Layout table for location contacts

Contact: Ali Vazir, MBBS, PhD	+44 (0)20 7352 8121	a.vazir@imperial.ac.uk

Sponsors and Collaborators

Cell Therapy Ltd.

Royal Brompton & Harefield NHS Foundation Trust

Investigators

Layout table for investigator information

Study Director:	Nigel Scott, MB BChir PhD	Cell Therapy Ltd.

More Information

Publications:

Anastasiadis K, Antonitsis P, Westaby S, Reginald A, Sultan S, Doumas A, Efthimiadis G, Evans MJ. Implantation of a Novel Allogeneic Mesenchymal Precursor Cell Type in Patients with Ischemic Cardiomyopathy Undergoing Coronary Artery Bypass Grafting: an Open Label Phase IIa Trial. J Cardiovasc Transl Res. 2016 Jun;9(3):202-13. doi: 10.1007/s12265-016-9686-0. Epub 2016 Apr 1.

Layout table for additonal information

Responsible Party:	Cell Therapy Ltd.
ClinicalTrials.gov Identifier:	NCT03515291 History of Changes
Other Study ID Numbers:	CLX003-IMP-2-170121
First Posted:	May 3, 2018
Last Update Posted:	January 31, 2019
Last Verified:	May 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

Layout table for additional information

Studies a U.S. FDA-regulated Drug Product:		Yes
Studies a U.S. FDA-regulated Device Product:		No

Keywords provided by Cell Therapy Ltd.:

Heart; CABG; Injection; Scar; Fibrosis	Cell; Progenitor; Immunomodulatory; MRI; Randomized

Additional relevant MeSH terms:

Layout table for MeSH terms

Fibrosis; Pathologic Processes