Clinical trial NCT05043610: MSCs for Prevention of MI-induced HF
Official title: Transplantation of Mesenchymal Stem Cells for Prevention of Acute Myocardial Infarction Induced Heart Failure: a Phase III Randomized Clinical Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Myocardial Infarction, Acute
Myocardial Infarction First
Myocardial Infarction, Anterior Wall
Cardiac Remodeling, Ventricular
STEMI
Regenerative Medicine
Heart Failure
Keywords: WJ-MSCs
Myocardial infarction
Heart failure
Regenerative medicine
Tissue therapy
Stem cell therapy
Lead sponsor: Shiraz University of Medical Sciences
Sponsor class: OTHER
Collaborators: name: National Institute of Medical Research Development (NIMAD), Iran
First posted: 2021-09-14
Enrollment: 420
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A single-blinded, randomized, multicenter trial.
Primary purpose: TREATMENT

Brief summary: Results from recent clinical trials on bone marrow mononuclear cell (BM-MNC) transplantation show that this intervention can help reduce the incidence of heart failure (HF) after acute myocardial infarction (AMI). However, no study has evaluated the effect of the transplantation of mesenchymal stem cells (MSCs) on a clinical endpoint such as HF.

This single-blinded, randomized, multicenter trial aims to establish whether the intracoronary infusion of umbilical cord-derived Wharton's jelly MSCs (WJ-MSCs) helps prevent HF development after AMI. The study will enroll 240 patients 3 to 7 days following an AMI treated with primary percutaneous coronary intervention (PPCI). Only patients aged below 65 years with impaired LV function (LVEF \< 40%) will be included. Patients will be randomized to receive either a single intracoronary infusion of WJ-MSCs or standard care. The primary outcome of this study is the assessment of HF development during long-term follow-up (three years). Since the efficacy of MSCs is higher than BM-MNCs after AMI in the improvement of LVEF, it would be probable that these cells may have a better clinical effect as well. However, no study has evaluated the impact of the transplantation of MSCs on a clinical endpoint such as HF. This study will help determine whether or not the infusion of intracoronary WJ-MSCs in AMI patients with impaired LVEF would prevent HF development and future adverse events.

Detailed description: A randomized, multicenter, single-blinded phase III trial will be conducted to assess whether the intracoronary infusion of umbilical cord WJ-MSCs demonstrates a superior effect in reducing HF incidence following AMIs compared to standard treatment.

The sample size was determined with a 5% error, 80% power, a one-year HF incidence rate of 1.3-4%, and division between two groups in a 2:1 ratio (control:intervention), and a three-year follow-up period.

A total of 360 patients with a history of an anterior ST-elevation MI (STEMI) successfully reperfused within standard golden time within 3-7 days after AMI will be enrolled.

Randomization will be done via permuted block randomization through a web-based service. A block size of 4 will be considered. Two groups of equal proportion will be formed, where only one will receive an intracoronary infusion of WJ-MSCs besides the conventional therapy provided to both groups. Those who assess the study outcomes will remain unaware of the allocation (single-blind).

This study will use cGMP-certified clinical-grade human WJ-MSCs. In the intervention group, all 120 patients will receive a single intracoronary infusion of 10\^7 WJ-MSCs alongside the conventional treatment that will be provided to the same number of patients in the control group. Patients in the intervention group will be taken to the cardiac catheterization lab, where the infusion of 10\^7 WJ-MSCs will be done through the intracoronary route.

Before statistical analysis, adjudication of all measurements will be done by an experienced cardiology department member excluded from the research group. The adjudicator will assess the quality of each measurement and will exclude patients with inadequate quality from the analysis, where participants will be regarded as missing. An independent, blinded safety committee will evaluate potential major adverse cardiac events (MACEs). Once the adjudication process is complete, the finalized database will be unblinded.

Data will be kept anonymous until analysis, which is to be performed by an independent statistician external to the research group. Treatment efficacy will be assessed according to the decrement in HF with the help of Cox regression analysis. The investigators will consider the EF to have improved significantly if a minimum increment of 3% is achieved after six months. The analysis will follow the intention-to-treat approach. The baseline characteristics of the two study groups will also be compared. Continuous variables will be summarized using the mean and standard deviation, while frequencies and percentages will be given for categorical data. The EF, as the primary outcome, will be compared between the study groups using the independent t-test and one-way analysis of variance (ANOVA). The therapeutic effect will be estimated with a 95% CI. Two-sided P-values will be used. Safety will be compared between the two groups according to the occurrence of MACEs (death, recurrent AMI, ICD insertion, non-target vessel revascularization, etc.) and serious adverse events (SAEs). These events will be followed over time with Kaplan-Meier curves, which will allow us to understand their patterns. With the help of the Cox proportional hazards model, The investigators will assess the statistical significance and 95% CI.

Data will be kept anonymous until analysis, which is to be performed by an independent statistician external to the research group. Treatment efficacy will be assessed according to the decrement in HF with the help of Cox regression analysis. The investigators will consider the EF to have improved significantly if a minimum increment of 3% is achieved after six months. The analysis will follow the intention-to-treat approach. The baseline characteristics of the two study groups will also be compared. Continuous variables will be summarized using the mean and standard deviation, while frequencies and percentages will be given for categorical data. The EF, as the primary outcome, will be compared between the study groups using the independent t-test and one-way analysis of variance (ANOVA). The therapeutic effect will be estimated with a 95% CI. Two-sided P-values will be used. Safety will be compared between the two groups according to the occurrence of MACEs (death, recurrent AMI, ICD insertion, non-target vessel revascularization, etc.) and serious adverse events (SAEs). These events will be followed over time with Kaplan-Meier curves, which will allow us to understand their patterns. With the help of the Cox proportional hazards model, The investigators will assess the statistical significance and 95% CI.

Adverse events will be reported by the study's executive committee to an independent Data and Safety and Monitoring Board (DSMB). The DSMB will have the authority to stop the trial early if patient safety is compromised or if the primary research objective is met. All safety issues (unanticipated SAEs, mortality, intracoronary infusion complications, and severe arrhythmias, etc.) will be monitored by the DSMB, and the DSMB statistician will report the occurrence of safety issues in each study group quarterly. All deaths will be reported.

The investigators have discussed all ethical issues with the Institutional Review Board of Shiraz University of Medical Sciences, which ultimately approved the study protocol (IR.SUMS.REC.1400.409). Informed consent will be obtained once patients are clinically stable and sedatives or strong analgesics do not alter their consciousness. Importantly, the use of low balloon inflation pressure and divided (three-part) infusions will prevent complications related to intracoronary cell infusion. The principles of the Declaration of Helsinki will be upheld throughout this study.

Eligibility criteria: Inclusion Criteria:

* Age 18-65 years
* Either gender
* First myocardial infarction in the preceding 3 to 7 days
* Post-acute myocardial infarction left ventricular ejection fraction \< 40%
* Negative pregnancy test (for women of reproductive age)
* Written informed consent

Exclusion Criteria:

* A history of any prior cardiac conditions (valvular, ischemic, or congenital disorders)
* Regional wall motion abnormalities outside the region of the infarction
* LV dysfunction due to other etiologies like non-ischemic cardiomyopathy, anthracycline use, or ethanol abuse (\> 6 oz./day regularly)
* Poor echocardiography window
* Active infection, malignancy, or autoimmune disease

Primary outcomes:
measure: Incidence of Heart Failure
timeFrame: Checked at three years
Secondary outcomes:
measure: Change in Left Ventricular Function from base line
timeFrame: At baseline and after six months
measure: Cardiovascular Death
timeFrame: Checked at three years
measure: Composite outcome of cardiovascular death and heart failure incidence
timeFrame: Checked at three years
Other outcomes:
Locations:
city: Shiraz
country: Iran, Islamic Republic of
facility: Al-Zahra Heart Hospital, Shiraz University of Medical Sciences
state: Fars
city: Shiraz
country: Iran, Islamic Republic of
facility: Faghihi Hospital
state: Fars
city: Shiraz
country: Iran, Islamic Republic of
facility: Namazee Hospital
state: Fars
Study officials:
affiliation: Department of Cardiovascular Medicine, TAHA clinical trial group, Shiraz University of Medical Sciences, Shiraz, Iran
name: Armin Attar, MD
role: STUDY_DIRECTOR
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