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Safety and Efficacy Evaluation of Intracoronary Infusion of Allogeneic Human Cardiac Stem Cells in Patients With AMI (CAREMI)

Primary Purpose

Acute Myocardial Infarction

Status
Completed
Phase
Phase 1
Locations
Spain
Study Type
Interventional
Intervention
Allogeneic human cardiac stem cells (CSCs)
Human Serum Albumin-HSA 5%
Sponsored by
Coretherapix
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Myocardial Infarction

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Adult patients ≥ 18 years of age and ≤ 80 years.
  • Patients presenting a ST-segment-elevation myocardial infarction (STEMI) according to the universally accepted definition found in the STEMI management guide of the European Society of Cardiology
  • Killip ≤ 2 on admission
  • Successful primary coronary revascularization by Percutaneous Coronary Intervention- PCI - (Thrombolysis In Myocardial Infarction [TIMI] = 3) within 12h after the onset of infarct symptoms
  • Bare-metal or drug-eluting stents (DES) of second generation (including new second generation stents, e.g. biolimus, novolimus and bioreabsorbable stents) at coronary revascularization by PCI
  • Ejection Fraction (EF) ≤45% by magnetic resonance imaging (MRI). This MRI will be done between day 3 and day 5 after infarction and will be used as inclusion MRI
  • Infarct size in left ventricle (LV) tested in the screening MRI ≥25% The presence of microvascular obstruction at inclusion MRI is permitted
  • The affected coronary artery is adequate for cells infusion at the administration time. The administration procedure is technically feasible on day 4-7 after coronary revascularization by PCI
  • The patient is stable and in adequate clinical condition to undergo the procedure.

Exclusion Criteria:

  • Participation in another clinical trial in the last 30 days
  • Previous allogeneic transplant (blood transfusions are allowed) or treated with cell or gene therapy
  • Previous Q-wave infarction
  • Significant valve disease, relapsing pericarditis, history of cardiac tamponade, cardiomyopathies
  • Severe stenotic lesions (>90%) in a coronary vessel with size >2.75 mm not treated by PCI at least 24 hours before the baseline MRI study
  • Previous EF≤45%, NYHA > 2 (New York Heart Association Functional Classification) or hospital admission for heart failure before STEMI
  • Sustained VT that does not revert with treatment or requires >6 hours to be controlled in the 48 hours prior to the product administration procedure
  • Complete atrioventricular blockade, or acute left bundle branch block in the 48 hours prior to the product administration procedure
  • History of cardioembolic disease
  • Platelets <100,000 and/or Hb<8.5g/dL
  • Acute or chronic renal failure with creatinine ≥2.5 mg/dl or creatinine clearance ≤30 mL/min
  • Infection with systemic involvement
  • Cancer disease, except that eradicated at least 5 years before inclusion, and without receiving radiotherapy on chest. It is permitted coetaneous non-melanoma neoplasms completely eliminated (at any time) and that do not require subsequent chemotherapy or radiotherapy on chest.
  • Child-Pugh's C stage chronic liver disease
  • Baseline respiratory failure requiring oxygen at home
  • Uncontrolled hypertension at screening despite treatment (systolic blood pressure [BP] ≥180 and/or diastolic BP ≥110)
  • Very poorly controlled diabetes (Hb1Ac ≥8.5 g/dL) or with serious target organ lesion (peripheral vascular disease requiring revascularization or non revascularize)
  • History of autoimmune disease
  • Primary or acquired immune deficiency or immunosuppressant treatment (including treatments with immunosuppressants in the previous three months, or foreseeable need for those treatments during the course of the study).
  • Women who are pregnant or breastfeeding or women of childbearing potential who do not agree to use contraceptives during the study period
  • Life expectancy of less than 2 years for any reason.
  • Allergy to aminoglycoside antibiotics or HSA hypersensitivity
  • Contraindications preventing the use of Magnetic Resonance Imaging: Pacemaker, Implantable cardioverter-defibrillator (ICD), known reaction to gadolinium, claustrophobia, cochlear implants

Sites / Locations

  • Coretherapix (Tigenix Group)

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Allogeneic human cardiac stem cells

Placebo: Human Serum Albumin-HSA 5%

Arm Description

After randomization, subjects will received a suspension of allogeneic human cardiac stem cells (35 millions of CSCs - cell medicine) infused into the coronary artery responsible for the ischemic event.

After randomization, subjects will received placebo (which is also the cell medicine diluent). The placebo consists of a final administered volume of human serum albumin 5% in saline solution equivalent to the reconstituted cell medicine (18 mL). The placebo to be used is a marketed product (HSA 5%).

Outcomes

Primary Outcome Measures

Safety measured as the number of deaths and number of Major Adverse Cardiac Events (MACE)
The primary objective is to demonstrate the safety of the intra-coronary infusion of allogeneic cardiac stem cells in patients with a 7 days evolution first myocardial infarction and left ventricle dysfunction. Safety will be assessed a) evaluating the number of deaths from any cause within 30 days after cell medicine administration; b) evaluating the number of Major Adverse Cardiac Events (MACE) during the first 30 days (composite endpoint), defined as death from any cause, new Acute Myocardial Infarction (AMI), hospitalization due to Heart Failure (HF), sustained Ventricular Tachycardia (VT), Ventricular Fibrillation (VF), and stroke within 12 months after cell medicine administration.

Secondary Outcome Measures

Efficacy measured by MRI as the infarct size change
Change of the Infarct Size as percentage (%) of LV mass analysed by MRI at 6 and 12 months after treatment administration versus screening MRI and 1 month MRI.
Efficacy measured by MRI as the evolution of biomechanical parameters
Percentage of change of the End Systolic Volume (ESV) and End Diastolic Volume (EDV), of the Wall Motion score as segmental contraction score, of the Sphericity Index, of the Systolic thickening by segment and of the Absolute change of Ejection Fraction (EF) analysed by MRI at 6 and 12 months after treatment administration versus screening MRI and 1 month MRI.
Efficacy measured by MRI as the evolution of edema
Percentage of change in the edema volume analysed by MRI at 1 month after treatment administration versus screening MRI.

Full Information

First Posted
April 27, 2015
Last Updated
November 13, 2017
Sponsor
Coretherapix
Collaborators
European Commission, Universitaire Ziekenhuizen KU Leuven, Saint-Louis Hospital, Paris, France, Hospital General Universitario Gregorio Marañon, Complejo Hospitalario de Navarra, Hospital Clínico Universitario de Valladolid, Hospital Donostia, Hospital Clínico Universitario de Valencia, University of Salamanca, Hospital Universitario Virgen de la Victoria
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1. Study Identification

Unique Protocol Identification Number
NCT02439398
Brief Title
Safety and Efficacy Evaluation of Intracoronary Infusion of Allogeneic Human Cardiac Stem Cells in Patients With AMI
Acronym
CAREMI
Official Title
First-in-human, Double Blind, Randomized With Placebo, Open for the 6 First Patients (Dose Ranging) to Evaluate the Safety and Efficacy of Intracoronary Infusion of Allogeneic Human CSCs in Patients With AMI and Left Ventricular Dysfunction
Study Type
Interventional

2. Study Status

Record Verification Date
November 2017
Overall Recruitment Status
Completed
Study Start Date
June 2014 (Actual)
Primary Completion Date
December 2015 (Actual)
Study Completion Date
November 14, 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Coretherapix
Collaborators
European Commission, Universitaire Ziekenhuizen KU Leuven, Saint-Louis Hospital, Paris, France, Hospital General Universitario Gregorio Marañon, Complejo Hospitalario de Navarra, Hospital Clínico Universitario de Valladolid, Hospital Donostia, Hospital Clínico Universitario de Valencia, University of Salamanca, Hospital Universitario Virgen de la Victoria

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Development of myocardial reparative therapy for the treatment of acute ischemic cardiac disease, based on the intracoronary administration of allogeneic Cardiac Stem Cells (CSCs) to ameliorate myocardial cell death and promote cardio-regeneration. The study comprises two phases: Initial dose-escalation open-label safety phase comprising 6 patients. Escalation will start with the Maximum Recommended Safe Dose (MRSD) calculated from Non-Observed Adverse Events Level (NOAEL) and it is expected to finish with the target dose (TD). There will be no placebo group for this initial phase. Randomized double-blind placebo-controlled safety and efficacy phase in which the TD will be injected if the dose-escalation phase is completed successfully.
Detailed Description
This is a "First in Patient" Clinical Trial to obtain safety and efficacy results about the intracoronary administration of a suspension of allogeneic cardiac stem cells (CSCs) for the treatment of ST elevation Myocardial Infarction (STEMI). This clinical trial will have a first dose-escalation phase in which the safety of 10, 20 and 35 million CSCs administration will be evaluated in 6 patients. A second double-blind randomized and placebo controlled phase will be initiated, if no major safety effects are observed during the first week after cell administration. The 35 million cells dose is the one expected to be used during the randomized phase. Patients with EF<45% and with infarct sizes > 25% will be selected by magnetic resonance image (MRI). 49 patients will be included in the randomized phase with the aim of having 38 patients for efficacy analysis at the end of the follow up period (12 months). In this phase, patients will be randomly allocated for receiving CSCs or placebo in a 2:1 scheme. Three bioequivalent cellular batches obtained from different donors will be indistinctly used during the assay. CSCs or placebo treatment will be infused into the coronary artery responsible for the ischemic event. Placebo will be a commercial preparation of human serum albumin 5% in saline solution that will also be used for cell product reconstitution. After treatment, patients will be monitored overnight in a coronary care unit for any toxicity and discharged from hospital 24h after treatment if no adverse events are observed. Subsequent safety follow-up will be done first at day 7 after treatment and then monthly or quarterly thereafter for 12 months. In addition, efficacy evaluations will be performed by MRI and clinical parameters at 1, 6 and 12 months after treatment. Finally, cellular and humoral immunological response (screening for anti-HLA (Human Leukocyte Antigen) class I and class II antibodies, HLA typing, cross-matching between cells and treated patient and cytokine profiling in blood samples) will be analysed during the clinical trial.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Myocardial Infarction

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
55 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Allogeneic human cardiac stem cells
Arm Type
Experimental
Arm Description
After randomization, subjects will received a suspension of allogeneic human cardiac stem cells (35 millions of CSCs - cell medicine) infused into the coronary artery responsible for the ischemic event.
Arm Title
Placebo: Human Serum Albumin-HSA 5%
Arm Type
Placebo Comparator
Arm Description
After randomization, subjects will received placebo (which is also the cell medicine diluent). The placebo consists of a final administered volume of human serum albumin 5% in saline solution equivalent to the reconstituted cell medicine (18 mL). The placebo to be used is a marketed product (HSA 5%).
Intervention Type
Biological
Intervention Name(s)
Allogeneic human cardiac stem cells (CSCs)
Other Intervention Name(s)
AlloCSC-01
Intervention Description
Allogeneic human CSCs is a new cell medicine based on cells isolated from human heart biological samples (right atrium appendage of donors) and expanded in vitro.
Intervention Type
Other
Intervention Name(s)
Human Serum Albumin-HSA 5%
Intervention Description
Human Serum Albumin (HSA) is a well-known physiologic protein widely used in clinical practice and without known toxicity after parenteral administration.
Primary Outcome Measure Information:
Title
Safety measured as the number of deaths and number of Major Adverse Cardiac Events (MACE)
Description
The primary objective is to demonstrate the safety of the intra-coronary infusion of allogeneic cardiac stem cells in patients with a 7 days evolution first myocardial infarction and left ventricle dysfunction. Safety will be assessed a) evaluating the number of deaths from any cause within 30 days after cell medicine administration; b) evaluating the number of Major Adverse Cardiac Events (MACE) during the first 30 days (composite endpoint), defined as death from any cause, new Acute Myocardial Infarction (AMI), hospitalization due to Heart Failure (HF), sustained Ventricular Tachycardia (VT), Ventricular Fibrillation (VF), and stroke within 12 months after cell medicine administration.
Time Frame
12 months
Secondary Outcome Measure Information:
Title
Efficacy measured by MRI as the infarct size change
Description
Change of the Infarct Size as percentage (%) of LV mass analysed by MRI at 6 and 12 months after treatment administration versus screening MRI and 1 month MRI.
Time Frame
6 and 12 months
Title
Efficacy measured by MRI as the evolution of biomechanical parameters
Description
Percentage of change of the End Systolic Volume (ESV) and End Diastolic Volume (EDV), of the Wall Motion score as segmental contraction score, of the Sphericity Index, of the Systolic thickening by segment and of the Absolute change of Ejection Fraction (EF) analysed by MRI at 6 and 12 months after treatment administration versus screening MRI and 1 month MRI.
Time Frame
6 and 12 months
Title
Efficacy measured by MRI as the evolution of edema
Description
Percentage of change in the edema volume analysed by MRI at 1 month after treatment administration versus screening MRI.
Time Frame
1 month

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Adult patients ≥ 18 years of age and ≤ 80 years. Patients presenting a ST-segment-elevation myocardial infarction (STEMI) according to the universally accepted definition found in the STEMI management guide of the European Society of Cardiology Killip ≤ 2 on admission Successful primary coronary revascularization by Percutaneous Coronary Intervention- PCI - (Thrombolysis In Myocardial Infarction [TIMI] = 3) within 12h after the onset of infarct symptoms Bare-metal or drug-eluting stents (DES) of second generation (including new second generation stents, e.g. biolimus, novolimus and bioreabsorbable stents) at coronary revascularization by PCI Ejection Fraction (EF) ≤45% by magnetic resonance imaging (MRI). This MRI will be done between day 3 and day 5 after infarction and will be used as inclusion MRI Infarct size in left ventricle (LV) tested in the screening MRI ≥25% The presence of microvascular obstruction at inclusion MRI is permitted The affected coronary artery is adequate for cells infusion at the administration time. The administration procedure is technically feasible on day 4-7 after coronary revascularization by PCI The patient is stable and in adequate clinical condition to undergo the procedure. Exclusion Criteria: Participation in another clinical trial in the last 30 days Previous allogeneic transplant (blood transfusions are allowed) or treated with cell or gene therapy Previous Q-wave infarction Significant valve disease, relapsing pericarditis, history of cardiac tamponade, cardiomyopathies Severe stenotic lesions (>90%) in a coronary vessel with size >2.75 mm not treated by PCI at least 24 hours before the baseline MRI study Previous EF≤45%, NYHA > 2 (New York Heart Association Functional Classification) or hospital admission for heart failure before STEMI Sustained VT that does not revert with treatment or requires >6 hours to be controlled in the 48 hours prior to the product administration procedure Complete atrioventricular blockade, or acute left bundle branch block in the 48 hours prior to the product administration procedure History of cardioembolic disease Platelets <100,000 and/or Hb<8.5g/dL Acute or chronic renal failure with creatinine ≥2.5 mg/dl or creatinine clearance ≤30 mL/min Infection with systemic involvement Cancer disease, except that eradicated at least 5 years before inclusion, and without receiving radiotherapy on chest. It is permitted coetaneous non-melanoma neoplasms completely eliminated (at any time) and that do not require subsequent chemotherapy or radiotherapy on chest. Child-Pugh's C stage chronic liver disease Baseline respiratory failure requiring oxygen at home Uncontrolled hypertension at screening despite treatment (systolic blood pressure [BP] ≥180 and/or diastolic BP ≥110) Very poorly controlled diabetes (Hb1Ac ≥8.5 g/dL) or with serious target organ lesion (peripheral vascular disease requiring revascularization or non revascularize) History of autoimmune disease Primary or acquired immune deficiency or immunosuppressant treatment (including treatments with immunosuppressants in the previous three months, or foreseeable need for those treatments during the course of the study). Women who are pregnant or breastfeeding or women of childbearing potential who do not agree to use contraceptives during the study period Life expectancy of less than 2 years for any reason. Allergy to aminoglycoside antibiotics or HSA hypersensitivity Contraindications preventing the use of Magnetic Resonance Imaging: Pacemaker, Implantable cardioverter-defibrillator (ICD), known reaction to gadolinium, claustrophobia, cochlear implants
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Marie Paule Richard, MD
Organizational Affiliation
Coretherapix (Tigenix Group)
Official's Role
Study Director
Facility Information:
Facility Name
Coretherapix (Tigenix Group)
City
Tres Cantos
State/Province
Madrid
ZIP/Postal Code
28760
Country
Spain

12. IPD Sharing Statement

Citations:
PubMed Identifier
25213554
Citation
Boukouaci W, Lauden L, Siewiera J, Dam N, Hocine HR, Khaznadar Z, Tamouza R, Borlado LR, Charron D, Jabrane-Ferrat N, Al-Daccak R. Natural killer cell crosstalk with allogeneic human cardiac-derived stem/progenitor cells controls persistence. Cardiovasc Res. 2014 Nov 1;104(2):290-302. doi: 10.1093/cvr/cvu208. Epub 2014 Sep 11.
Results Reference
background
PubMed Identifier
23243206
Citation
Lauden L, Boukouaci W, Borlado LR, Lopez IP, Sepulveda P, Tamouza R, Charron D, Al-Daccak R. Allogenicity of human cardiac stem/progenitor cells orchestrated by programmed death ligand 1. Circ Res. 2013 Feb 1;112(3):451-64. doi: 10.1161/CIRCRESAHA.112.276501. Epub 2012 Dec 12.
Results Reference
background
PubMed Identifier
31151405
Citation
Crisostomo V, Baez C, Abad JL, Sanchez B, Alvarez V, Rosado R, Gomez-Mauricio G, Gheysens O, Blanco-Blazquez V, Blazquez R, Toran JL, Casado JG, Aguilar S, Janssens S, Sanchez-Margallo FM, Rodriguez-Borlado L, Bernad A, Palacios I. Dose-dependent improvement of cardiac function in a swine model of acute myocardial infarction after intracoronary administration of allogeneic heart-derived cells. Stem Cell Res Ther. 2019 May 31;10(1):152. doi: 10.1186/s13287-019-1237-6.
Results Reference
derived
PubMed Identifier
29921651
Citation
Fernandez-Aviles F, Sanz-Ruiz R, Bogaert J, Casado Plasencia A, Gilaberte I, Belmans A, Fernandez-Santos ME, Charron D, Mulet M, Yotti R, Palacios I, Luque M, Sadaba R, San Roman JA, Larman M, Sanchez PL, Sanchis J, Jimenez MF, Claus P, Al-Daccak R, Lombardo E, Abad JL, DelaRosa O, Corcostegui L, Bermejo J, Janssens S. Safety and Efficacy of Intracoronary Infusion of Allogeneic Human Cardiac Stem Cells in Patients With ST-Segment Elevation Myocardial Infarction and Left Ventricular Dysfunction. Circ Res. 2018 Aug 17;123(5):579-589. doi: 10.1161/CIRCRESAHA.118.312823.
Results Reference
derived
PubMed Identifier
28533209
Citation
Sanz-Ruiz R, Casado Plasencia A, Borlado LR, Fernandez-Santos ME, Al-Daccak R, Claus P, Palacios I, Sadaba R, Charron D, Bogaert J, Mulet M, Yotti R, Gilaberte I, Bernad A, Bermejo J, Janssens S, Fernandez-Aviles F. Rationale and Design of a Clinical Trial to Evaluate the Safety and Efficacy of Intracoronary Infusion of Allogeneic Human Cardiac Stem Cells in Patients With Acute Myocardial Infarction and Left Ventricular Dysfunction: The Randomized Multicenter Double-Blind Controlled CAREMI Trial (Cardiac Stem Cells in Patients With Acute Myocardial Infarction). Circ Res. 2017 Jun 23;121(1):71-80. doi: 10.1161/CIRCRESAHA.117.310651. Epub 2017 May 22.
Results Reference
derived
Links:
URL
http://www.ncbi.nlm.nih.gov/pubmed/25213554
Description
Natural killer cell crosstalk with allogeneic human cardiac-derived stem/progenitor cells controls persistence.
URL
http://www.ncbi.nlm.nih.gov/pubmed/23243206
Description
Allogenicity of human cardiac stem/progenitor cells orchestrated by programmed death ligand
URL
http://www.tigenix.com/
Description
Sponsor web page
URL
https://www.clinicaltrialsregister.eu/ctr-search/search?query=Coretherapix
Description
European Clinical Trial Data Base

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Safety and Efficacy Evaluation of Intracoronary Infusion of Allogeneic Human Cardiac Stem Cells in Patients With AMI

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