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The objective of this study is to determine the safety and feasibility of autologous mononuclear cells (MNS) collected from bone marrow (BM) and using an add-on intramyocardial delivery for individuals with Ebstein anomaly undergoing surgical intervention compared to the control group undergoing the same surgical procedure without cell delivery. This add-on procedure has the potential to foster a new strategy for individuals with congenital heart disease.This is an open-label study of autologous MNC derived from bone marrow with a 2-year follow-up to document 1) incidence and severity of adverse event and 2) monitor changes in cardiac structure and function.
This study is an open label Phase I trial to determine the safety and feasibility of bone marrow-derived mononuclear cells to the right ventricle of subjects with Ebstein anomaly at the time of a planned surgical Ebstein repair compared to the control group undergoing the same planned surgical intervention without the cell delivery add-on procedure. Subjects will be screened at outpatient clinic visits at Mayo Clinic and interested qualified subjects will be consented and offered participation in this trial. Subject/Family will decide to participate in cell delivery or control arm. Once informed consent has been obtained, subjects will undergo identical evaluation (other than Hematology consultation and BM harvest occurring only in the cell-treatment group),preoperative values will be established/confirmed and a selection committee will review subjects within three days prior to planned procedure to confirm inclusion and exclusion criteria.However, individuals at high-risk, primarily neonates and those with preoperative advanced right heart failure will NOT be included such that the risk of this add-on procedure may not be acceptable. Following surgical Ebstein repair for the control group and following cell-based product delivery for the treatment group, all subjects will be followed for 24-months according to a pre-determined schedule that includes imaging studies along with a questionnaire, electrophysiology and laboratory studies at 1, 6, and 24 months post procedure. All subjects will be contacted for surveillance by phone at 3, 12, and 18 month post procedure.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Treatment arm | Experimental | Individuals with Ebstein anomaly and underlying myopathic right ventricle undergoing planned surgical intervention using an add-on procedure delivering autologous bone marrow-derived mononuclear cells into the right ventricle. |
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| Control arm | Other | Individuals with Ebstein anomaly and underlying myopathic right ventricle undergoing planned surgical intervention without cell delivery. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Autologous Bone Marrow-derived Mononuclear Cells | Biological |
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| Measure | Description | Time Frame |
|---|---|---|
| Number of adverse events from time of index procedure | Safety assessment of adverse events from time of index procedure will be analyzed by counts and percents using the chi-square test and Cochran-Armitage test for trends, and the two groups compared using the Fisher exact test. A Fisher's exact test with a 0.05 two-sided significance level will have 80% power to detect a difference in a sample size of 10 in each group. Thus having reasonable power to distinguish common rates for adverse events from very rare rates. Analysis of cardiac adverse events is in terms of the yes/no information at 24 months. Subjects will be censored upon lost to follow up. If some subjects are lost to follow-up then fractions at 24 months will be described using the Kaplan-Meier method and comparison between the two groups using the log-rank test. A confidence interval for the difference between groups will be given. | 24 months post index procedure |
| Severity of adverse events from time of index procedure | Safety assessment of severity of adverse events from time of index procedure will be analyzed by counts and percents using the chi-square test and Cochran-Armitage test for trends, and the two groups compared using the Fisher exact test. A Fisher's exact test with a 0.05 two-sided significance level will have 80% power to detect a difference in a sample size of 10 in each group. Thus having reasonable power to distinguish common rates for adverse events from very rare rates. Subjects will be censored upon lost to follow up. If some subjects are lost to follow-up then fractions at 24 months will be described using the Kaplan-Meier method and comparison between the two groups using the log-rank test. A confidence interval for the difference between groups will be given. | 24 months post index procedure |
| Number of subjects who died | Safety assessment of all-cause mortality will be analyzed by counts and percents using the chi-square test and Cochran-Armitage test for trends, and the two groups compared using the Fisher exact test. A Fisher's exact test with a 0.05 two-sided significance level will have 80% power to detect a difference in a sample size of 10 in each group. Thus having reasonable power to distinguish common rates for adverse events from very rare rates. Subjects will be censored upon lost to follow up. If some subjects are lost to follow-up then fractions at 24 months will be described using the Kaplan-Meier method and comparison between the two groups using the log-rank test. A confidence interval for the difference between groups will be given. |
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Inclusion Criteria:
Exclusion Criteria:
Individuals requiring cavopulmonary shunt at the time of surgical Ebstein repair; planned preoperatively or required intraoperatively
Individuals with, or reasonably expected to have, complications during surgical Ebstein repair or during post-operative recovery
Individual who have not completed or will not be completing all pre-procedure work-up within 30 days of surgical Ebstein repair AND lack of pre-procedure work-up documented as a safety concern by a site investigator
Individuals who have other clinical concerns as documented by a site investigator that could reasonably increase the risk of complications during or after surgical Ebstein repair
Individuals whose cells have been determined, by the sponsor, to not be acceptable for release to the investigational site or individual whose cells have been compromised after cells released to investigational site (cell treatment group only)
Individuals who require surgery on pulmonary, mitral, or aortic valve
Individuals with pulmonary atresia or atrioventricular discordance with ventriculoarterial discordance
Individuals with history of ventricular arrhythmia or new onset ventricular arrhythmia after enrollment that requires medical management
Individuals who have undergone previous sternotomy
Individuals with preoperative ventricular arrhythmia requiring medical management
Individuals with severe chronic diseases, extensive extra-cardiac syndromes, or history of any cancer
Individuals with current IV inotrope requirements
Individuals with bleeding disorders or history of thrombosis
Subjects not eligible for MRI or CT examination due to either a medical contraindication, including acute or chronic renal failure
Individuals with a currently active infection being treated with oral antibiotics
Individuals with the following conditions within 60 days prior to Ebstein repair surgery:
Female subjects 10 years and older with positive pregnancy test or lack of effective birth control method during the 30 days prior to surgical Ebstein repair
Individuals who weigh more than 90 kg
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| Name | Affiliation | Role |
|---|---|---|
| Muhammad Y Qureshi, MBBS | Mayo Clinic | Principal Investigator |
| Timothy J Nelson, MD, PhD | Mayo Clinic | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Mayo Clinic | Rochester | Minnesota | 55905 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 34479739 | Derived | O'Leary PW, Qureshi MY, Cetta F, Nelson TJ, Holst KA, Dearani JA; Wanek Program Clinical Pipeline Group. Cone Reconstruction for Ebstein Anomaly: Ventricular Remodeling and Preliminary Impact of Stem Cell Therapy. Mayo Clin Proc. 2021 Dec;96(12):3053-3061. doi: 10.1016/j.mayocp.2021.02.015. Epub 2021 Sep 1. |
| Label | URL |
|---|---|
| Mayo Clinic Clinical Trials | View source |
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| ID | Term |
|---|---|
| D004437 | Ebstein Anomaly |
| ID | Term |
|---|---|
| D006330 | Heart Defects, Congenital |
| D018376 | Cardiovascular Abnormalities |
| D002318 | Cardiovascular Diseases |
| D006331 | Heart Diseases |
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| Insertable cardiac monitor |
| Device |
Following surgical Ebstein repair a Medtronic Reveal LINQ Insertable Cardiac Monitor (ICM) will be placed subcutaneously in the anterior chest to continuously monitor the subject's heart rhythm and to record cardiac information through automatic detection of arrhythmias. |
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| 24 months post index procedure |
| Number of subjects with sustained symptomatic cardiac arrhythmias | Safety assessment of sustained symptomatic cardiac arrhythmias will be analyzed by counts and percents using the chi-square test and Cochran-Armitage test for trends, and the two groups compared using the Fisher exact test. A Fisher's exact test with a 0.05 two-sided significance level will have 80% power to detect a difference in a sample size of 10 in each group. Thus having reasonable power to distinguish common rates for adverse events from very rare rates. Subjects will be censored upon lost to follow up. If some subjects are lost to follow-up then fractions at 24 months will be described using the Kaplan-Meier method and comparison between the two groups using the log-rank test. A confidence interval for the difference between groups will be given. | 24 months post index procedure |
| Number of subjects with myocardial infarction | Safety assessment of myocardial infarctions will be analyzed by counts and percents using the chi-square test and Cochran-Armitage test for trends, and the two groups compared using the Fisher exact test. A Fisher's exact test with a 0.05 two-sided significance level will have 80% power to detect a difference in a sample size of 10 in each group. Thus having reasonable power to distinguish common rates for adverse events from very rare rates. Subjects will be censored upon lost to follow up. If some subjects are lost to follow-up then fractions at 24 months will be described using the Kaplan-Meier method and comparison between the two groups using the log-rank test. A confidence interval for the difference between groups will be given. | 24 months post index procedure |
| Number of subjects with unexpected, invasive cardiovascular procedures | Safety assessment of unexpected, invasive cardiovascular procedures will be analyzed by counts and percents using the chi-square test and Cochran-Armitage test for trends, and the two groups compared using the Fisher exact test. A Fisher's exact test with a 0.05 two-sided significance level will have 80% power to detect a difference in a sample size of 10 in each group. Thus having reasonable power to distinguish common rates for adverse events from very rare rates. Subjects will be censored upon lost to follow up. If some subjects are lost to follow-up then fractions at 24 months will be described using the Kaplan-Meier method and comparison between the two groups using the log-rank test. A confidence interval for the difference between groups will be given. | 24 months post index procedure |
| Number of serious adverse events | Safety assessment of serious adverse events will be analyzed by counts and percents using the chi-square test and Cochran-Armitage test for trends, and the two groups compared using the Fisher exact test. A Fisher's exact test with a 0.05 two-sided significance level will have 80% power to detect a difference in a sample size of 10 in each group. Thus having reasonable power to distinguish common rates for adverse events from very rare rates. Subjects will be censored upon lost to follow up. If some subjects are lost to follow-up then fractions at 24 months will be described using the Kaplan-Meier method and comparison between the two groups using the log-rank test. A confidence interval for the difference between groups will be given. | 24 months post index procedure |
| Percentage of subjects in the treatment group that have cells delivered | Feasibility of the BM-MNC cell therapy will be evaluated comparing number of subjects enrolled in the treatment group to subjects in the treatment group who are accrued and have cells delivered by percentage using the binomial distribution and exact confidence limits given. | 24 months post index procedure |
| Percentage of subjects in the treatment group completing the 24 month follow-up | Feasibility of the BM-MNC cell therapy will be evaluated comparing number of subjects enrolled in the treatment group to subjects in the treatment group who are accrued and have cells delivered, who complete the 24 month follow-up visit by percentage. | 24 months post index procedure |
| Incidence of cardiac related hospitalizations from time of Ebstein repair | Efficacy will be evaluated using analysis of covariance (ANCOVA) from baseline to 24 months post-index procedure comparing outcomes between the treatment group to the control group. A sample size of 10 in each group using t-test will have 80% power to detect an effect size of 1.325 with a 0.050 two-sided significance level to identify a difference between means from the two groups. Descriptive statistics such as mean, median, SD, min, max, and 95% confidence intervals of the mean, and frequency distributions will be calculated for all variables by group. Fisher exact test will have 80% power to detect a difference in a sample size of 10 in each group having reasonable power to distinguish common rates from very rare rates. Analysis is in terms of the yes/no information at 24 months. Subjects will be censored upon lost to follow up. If a subject is lost to follow-up then fractions at 24 months will be described using the Kaplan-Meier method. | 1, 6, and 24 months post index procedure |
| Incidence of cardiac arrhythmias from time of index procedure | Efficacy will be evaluated using analysis of covariance (ANCOVA) from baseline to 24 months post-index procedure comparing outcomes between the treatment group to the control group. A sample size of 10 in each group using t-test will have 80% power to detect an effect size of 1.325 with a 0.050 two-sided significance level to identify a difference between means from the two groups. Descriptive statistics such as mean, median, SD, min, max, and 95% confidence intervals of the mean, and frequency distributions will be calculated for all variables by group. Fisher exact test will have 80% power to detect a difference in a sample size of 10 in each group having reasonable power to distinguish common rates from very rare rates. Analysis is in terms of the yes/no information at 24 months. Subjects will be censored upon lost to follow up. If a subject is lost to follow-up then fractions at 24 months will be described using the Kaplan-Meier method. | 1, 6, and 24 months post index procedure |
| Change in CT derived right ventricular dimensions from time of pre-operative evaluation | Efficacy will be evaluated using analysis of covariance (ANCOVA) from baseline to 24 months post-index procedure comparing outcomes between the treatment group to the control group. End volume measurements recorded using mL and indexed to body surface area (BSA) using mL/m^2.A sample size of 10 in each group using t-test will have 80% power to detect an effect size of 1.325 with a 0.050 two-sided significance level to identify a difference between means from the two groups. Descriptive statistics such as mean, median, SD, min, max, and 95% confidence intervals of the mean, and frequency distributions will be calculated for all variables by group. Fisher exact test will be used to distinguish common rates from very rare rates. Analysis is in terms of yes/no information at 24 months.If a subject is lost to follow-up then fractions at 24 months will be described using the Kaplan-Meier method. | 6 and 24 months post index procedure |
| Change in echocardiography derived cardiac output from time of pre-operative evaluation | Efficacy will be evaluated using analysis of covariance (ANCOVA) from baseline to 24 months post-index procedure comparing outcomes between the treatment group to the control group.Volume is measured in L/min and Volume Index is L/min/m^2.Using t-test will have 80% power to identify a difference between means from the two groups. Descriptive statistics such as mean, median, SD, min, max, and 95% confidence intervals of the mean, and frequency distributions will be calculated for all variables by group. Fisher exact test will have 80% power to detect a difference in a sample size of 10 in each group to distinguish common rates from very rare rates. Analysis in terms of yes/no information at 24 months. If a subject is lost to follow-up then fractions at 24 months will be described using the Kaplan-Meier method. | 1, 6, and 24 months post index procedure |
| Change in NT-Pro-BNP derived cardiac function trend from time of pre-operative evaluation | Efficacy will be evaluated using analysis of covariance (ANCOVA) from baseline to 24 months post-index procedure comparing outcomes between the treatment group to the control group. A sample size of 10 in each group using t-test will have 80% power to detect an effect size of 1.325 with a 0.050 two-sided significance level to identify a difference between means from the two groups. Descriptive statistics such as mean, median, SD, min, max, and 95% confidence intervals of the mean, and frequency distributions will be calculated for all variables by group. Fisher exact test will have 80% power to detect a difference in a sample size of 10 in each group having reasonable power to distinguish common rates from very rare rates. Analysis is in terms of the yes/no information at 24 months. Subjects will be censored upon lost to follow up. If a subject is lost to follow-up then fractions at 24 months will be described using the Kaplan-Meier method. | During hospitalization up to 29 days, 1, 6 and 24 months post index procedure |
| Incidence of cardiac related hospitalizations in the treatment group from time of pre-operative evaluation compared to the control group | Efficacy will be evaluated using analysis of covariance (ANCOVA) from baseline to 24 months post-index procedure comparing outcomes between the treatment group to the control group. A sample size of 10 in each group using t-test will have 80% power to detect an effect size of 1.325 with a 0.050 two-sided significance level to identify a difference between means from the two groups. Descriptive statistics such as mean, median, SD, min, max, and 95% confidence intervals of the mean, and frequency distributions will be calculated for all variables by group. Fisher exact test will have 80% power to detect a difference in a sample size of 10 in each group having reasonable power to distinguish common rates from very rare rates. Analysis is in terms of the yes/no information at 24 months. Subjects will be censored upon lost to follow up. If a subject is lost to follow-up then fractions at 24 months will be described using the Kaplan-Meier method. | 1, 6, and 24 months post index procedure |
| Incidence of cardiac arrhythmias in the treatment group from time of pre-operative evaluation compared to the control group | Efficacy will be evaluated using analysis of covariance (ANCOVA) from baseline to 24 months post-index procedure comparing outcomes between the treatment group to the control group. A sample size of 10 in each group using t-test will have 80% power to detect an effect size of 1.325 with a 0.050 two-sided significance level to identify a difference between means from the two groups. Descriptive statistics such as mean, median, SD, min, max, and 95% confidence intervals of the mean, and frequency distributions will be calculated for all variables by group. Fisher exact test will have 80% power to detect a difference in a sample size of 10 in each group having reasonable power to distinguish common rates from very rare rates. Analysis is in terms of the yes/no information at 24 months. Subjects will be censored upon lost to follow up. If a subject is lost to follow-up then fractions at 24 months will be described using the Kaplan-Meier method. | 1, 6, and 24 months post index procedure |
| Change in MRI derived cardiac output in the treatment group from time of pre-operative evaluation compared to the control group | Efficacy will be evaluated using analysis of covariance (ANCOVA) from baseline to 24 months post-index procedure comparing outcomes between the treatment group to the control group.Volume is measured in L/min and Volume Index is L/min/m^2.Using t-test will have 80% power to identify a difference between means from the two groups. Descriptive statistics such as mean, median, SD, min, max, and 95% confidence intervals of the mean, and frequency distributions will be calculated for all variables by group. Fisher exact test will have 80% power to detect a difference in a sample size of 10 in each group to distinguish common rates from very rare rates. Analysis in terms of yes/no information at 24 months.If a subject is lost to follow-up then fractions at 24 months will be described using the Kaplan-Meier method. | 6 and 24 months post index procedure |
| Change in echocardiography derived right ventricular dimensions from time of pre-operative evaluation | Efficacy will be evaluated using analysis of covariance (ANCOVA) from baseline to 24 months post-index procedure comparing outcomes between the treatment group to the control group. End volume measurements recorded using mL and indexed to body surface area (BSA) using mL/m^2,diameter as cm.A sample size of 10 in each group using t-test will have 80% power to detect an effect size of 1.325 with a 0.050 two-sided significance level to identify a difference between means from the two groups. Descriptive statistics such as mean, median, SD, min, max, and 95% confidence intervals of the mean, and frequency distributions will be calculated for all variables by group. Fisher exact test will be used to distinguish common rates from very rare rates. Analysis is in terms of yes/no information at 24 months.If a subject is lost to follow-up then fractions at 24 months will be described using the Kaplan-Meier method. | 1, 6, and 24 months post index procedure |
| Change in NT-Pro-BNP derived cardiac function trend in the treatment group from time of pre-operative evaluation compared to the control group | Efficacy will be evaluated using analysis of covariance (ANCOVA) from baseline to 24 months post-index procedure comparing outcomes between the treatment group to the control group. A sample size of 10 in each group using t-test will have 80% power to detect an effect size of 1.325 with a 0.050 two-sided significance level to identify a difference between means from the two groups. Descriptive statistics such as mean, median, SD, min, max, and 95% confidence intervals of the mean, and frequency distributions will be calculated for all variables by group. Fisher exact test will have 80% power to detect a difference in a sample size of 10 in each group having reasonable power to distinguish common rates from very rare rates. Analysis is in terms of the yes/no information at 24 months. Subjects will be censored upon lost to follow up. If a subject is lost to follow-up then fractions at 24 months will be described using the Kaplan-Meier method. | During hospitalization up to 29 days, 1, 6, and 24 month post index procedure |
| Number of serious adverse events from time of enrollment | Safety assessment of the number of serious adverse events from time of enrollment will be analyzed by counts and percents using the chi-square test and Cochran-Armitage test for trends, and the two groups compared using the Fisher exact test. A Fisher's exact test with a 0.05 two-sided significance level will have 80% power to detect a difference in a sample size of 10 in each group. Thus having reasonable power to distinguish common rates for adverse events from very rare rates. Subjects will be censored upon lost to follow up. If some subjects are lost to follow-up then fractions at 24 months will be described using the Kaplan-Meier method and comparison between the two groups using the log-rank test. A confidence interval for the difference between groups will be given. | index procedure |
| Percentage of subjects in the treatment group whose cells meet all release criteria | Feasibility of the BM-MNC cell therapy will be evaluated comparing number of subjects enrolled in the treatment group to subjects in the treatment group with collected bone marrow and the bone marrow cells have met all product release criteria to any products that did not meet release criteria by percentage. | 24 months post index procedure |
| Change in CT derived cardiac output from time of pre-operative evaluation | Efficacy will be evaluated using analysis of covariance (ANCOVA) from baseline to 24 months post-index procedure comparing outcomes between the treatment group to the control group.Volume is measured in L/min and Volume Index is L/min/m^2.Using t-test will have 80% power to identify a difference between means from the two groups. Descriptive statistics such as mean, median, SD, min, max, and 95% confidence intervals of the mean, and frequency distributions will be calculated for all variables by group. Fisher exact test will have 80% power to detect a difference in a sample size of 10 in each group to distinguish common rates from very rare rates. Analysis in terms of yes/no information at 24 months. If a subject is lost to follow-up then fractions at 24 months will be described using the Kaplan-Meier method. | 6 and 24 months post index procedure |
| Change in MRI derived right ventricle ejection fraction in the treatment group from time of pre-operative evaluation compared to the control group | Efficacy will be evaluated using analysis of covariance (ANCOVA) from baseline to 24 months post-index procedure comparing outcomes between the treatment group to the control group measured in %.Using t-test will have 80% power to detect an effect size of 1.325 with a 0.050 two-sided significance level to identify a difference between means from the two groups. Descriptive statistics such as mean, median, SD, min, max, and 95% confidence intervals of the mean, and frequency distributions will be calculated for all variables by group. Fisher exact test will have 80% power to detect a difference in a sample size of 10 in each group having reasonable power to distinguish common rates from very rare rates. Analysis is in terms of the yes/no information at 24 months. Subjects will be censored upon lost to follow up. If a subject is lost to follow-up then fractions at 24 months will be described using the Kaplan-Meier method. | 6 and 24 months post index procedure |
| Change in MRI derived right ventricular dimensions in the treatment group from time of pre-operative evaluation compared to the control group | Efficacy will be evaluated using analysis of covariance (ANCOVA) from baseline to 24 months post-index procedure comparing outcomes between the treatment group to the control group. End volume measurements recorded using mL and indexed to body surface area (BSA) using mL/m^2.A sample size of 10 in each group using t-test will have 80% power to detect an effect size of 1.325 with a 0.050 two-sided significance level to identify a difference between means from the two groups. Descriptive statistics such as mean, median, SD, min, max, and 95% confidence intervals of the mean, and frequency distributions will be calculated for all variables by group. Fisher exact test will be used to distinguish common rates from very rare rates. Analysis is in terms of yes/no information at 24 months.If a subject is lost to follow-up then fractions at 24 months will be described using the Kaplan-Meier method. | 6 and 24 months post index procedure |
| Change in CT derived right ventricle ejection fraction from time of pre-operative evaluation | Efficacy will be evaluated using analysis of covariance (ANCOVA) from baseline to 24 months post-index procedure comparing outcomes between the treatment group to the control group measured in %.Using t-test will have 80% power to detect an effect size of 1.325 with a 0.050 two-sided significance level to identify a difference between means from the two groups. Descriptive statistics such as mean, median, SD, min, max, and 95% confidence intervals of the mean, and frequency distributions will be calculated for all variables by group. Fisher exact test will have 80% power to detect a difference in a sample size of 10 in each group having reasonable power to distinguish common rates from very rare rates. Analysis is in terms of the yes/no information at 24 months. Subjects will be censored upon lost to follow up. If a subject is lost to follow-up then fractions at 24 months will be described using the Kaplan-Meier method. | 6 and 24 months post index procedure |
| D000013 | Congenital Abnormalities |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |