Safety Study of Autologous Umbilical Cord Blood Cells for Treatment of Hypoplastic Left Heart Syndrome

• ClinicalTrials.gov Identifier: NCT01883076
• Recruitment Status: Active, not recruiting
• First Posted: June 21, 2013
• Last Update Posted: October 5, 2020
• Sponsor: Timothy J Nelson, MD, PhD
• Collaborators: University of Oklahoma; Children's Hospital of Philadelphia; Children's Hospitals and Clinics of Minnesota; Children's Hospital Los Angeles; Children's Hospital Colorado; Mayo Clinic
• Information provided by (Responsible Party): Timothy J Nelson, MD, PhD, ReGen Theranostics, Inc.

Tracking Information

• First Submitted Date: June 11, 2013
• First Posted Date: June 21, 2013
• Last Update Posted Date: October 5, 2020
• Actual Study Start Date: May 15, 2013
• Estimated Primary Completion Date: November 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 25, 2016)

• Incidence of all-cause mortality [ Time Frame: Within 2 years following cell therapy treatment ]
• Incidence of new and worsening adverse cardiac events [ Time Frame: Within 2 years following cell therapy treatment ]
  The adverse cardiac events would include sustained/symptomatic ventricular arrhythmias, heart failure, myocardial infarction, cardiac infections, and unexpected cardiovascular surgery.
• Percentage of subjects whose cells meet all cell release criteria [ Time Frame: Up to 2 years ]
• Percentage of subjects enrolled who undergo cell therapy treatment [ Time Frame: Up to 2 years ]

Original Primary Outcome Measures (submitted: June 20, 2013)

• Number of patients completing consent, collection of umbilical cord blood, and intramyocardial delivery of autologous stem cells [ Time Frame: 1 week post Glenn procedure ]
  The percentage of patients consented for the study that have successfully undergone umbilical cord blood collection, completed GMP-processing to meet release criteria, and achieved uncomplicated intramyocardial cell delivery will determine the feasibility of this approach.
• Number of patients with cardiac-related adverse events [ Time Frame: up to 6 months follow-up post Glenn procedure ]
  Upon intramyocardial cell delivery at the time of planned Glenn procedure, signs of cardiac toxicity will be measured according to worsening of ejection fraction by more than 10%, any new cardiac arrhythmias that could be attributed to stem cell therapy based on follow-up electrocardiograms and 24-hr Holter monitoring, and abnormal routine blood chemistry to monitor for evidence of organ failure.

Current Secondary Outcome Measures (submitted: October 25, 2016)

• Change in right ventricular ejection fraction at one month according to cardiac imaging with echocardiography [ Time Frame: baseline, 1 month ]
• Change in right ventricular ejection fraction at 3 months according to cardiac imaging with echocardiography [ Time Frame: baseline, 3 months ]
• Change in right ventricular ejection fraction at 6 months according to cardiac imaging with echocardiography [ Time Frame: baseline, 6 months ]
• Change in right ventricle tricuspid annular plane systolic excursion (TAPSE) at one month according to cardiac imaging with echocardiography [ Time Frame: baseline, 1 month ]
• Change in right ventricle TAPSE at 3 months according to cardiac imaging with echocardiography [ Time Frame: baseline, 3 months ]
• Change in right ventricle TAPSE at 6 months according to cardiac imaging with echocardiography [ Time Frame: baseline, 6 months ]
• Change in right ventricle fractional area change at one month according to cardiac imaging with echocardiography [ Time Frame: baseline, 1 month ]
• Change in right ventricle fractional area change at 3 months according to cardiac imaging with echocardiography [ Time Frame: baseline, 3 months ]
• Change in right ventricle fractional area change at 6 months according to cardiac imaging with echocardiography [ Time Frame: baseline, 6 months ]

Original Secondary Outcome Measures (submitted: June 20, 2013)

Change in right ventricular ejection fraction according to cardiac imaging with echocardiography [ Time Frame: 6 months follow-up post Glenn procedure ]

The secondary analysis is focused on the potential benefit of intramyocardial delivery of the manufactured cell-based product in pediatric hearts at the time of planned surgical palliation for HLHS. The change from baseline to 1, 3, and 6-month follow-up in right ventricular ejection fraction is the primary variable along with secondary variables of change in right ventricle TAPSE and fractional area change.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Safety Study of Autologous Umbilical Cord Blood Cells for Treatment of Hypoplastic Left Heart Syndrome
• Official Title: Phase I Safety Study of Autologous Umbilical Cord Blood Derived Mononuclear Cells During Surgical Stage II Palliation of Hypoplastic Left Heart Syndrome

Brief Summary

This is a Phase I study to determine the safety and feasibility of injections of autologous umbilical cord blood (UCB) cells into the right ventricle of Hypoplastic Left Heart Syndrome (HLHS) children undergoing a scheduled Glenn surgical procedure.

The investigators are doing this research study to find out if autologous stem cells from the individual's own umbilical cord blood can be used to strengthen the muscle of the right side of their heart. This will help determine the safety and feasibility of using cell-based regenerative therapy as an additional treatment for the management of HLHS.

• Detailed Description: This study is a Phase I trial to determine the safety of autologous mononuclear cells (MNC) derived from umbilical cord blood for intramyocardial delivery into the right ventricle during a planned and non-emergent Stage II surgical palliation in subjects with HLHS. This is the first critical step towards applying autologous MNC therapy as an add-on regenerative intervention for congenital heart disease management. The choice of HLHS as the target disease for regenerative therapies in congenital heart disease management is multi-factorial and includes the following considerations: 1) Severity of of this incurable disease, 2) palliative nature and burden of long-term outcomes with a single right ventricular system, 3) three stages of planned surgical procedures that provide time points to adjunctively intervene, and 4) prenatal diagnosis enabling planned collection of UCB. An emerging goal for cardiac regeneration includes the application of cell-based technology to congenital heart disease, which is a favorable substrate due to the lack of fibrotic scaring, and the presence of a microenvironment that is expected to support ongoing cardiac proliferation and growth for functional remuscularization. This Phase I safety study will determine the feasibility of collection, processing, and delivery of autologous cells as used in adult cardiac regenerative protocols in the setting of HLHS surgical management.
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Hypoplastic Left Heart Syndrome

Intervention

Biological: autologous cell-based delivery

autologous cells (derived from "self")

Other Name: umbilical cord blood derived mononuclear cells

Study Arms

Experimental: autologous cell-based delivery

autologous cell-based delivery a target dose of 3 million cells / kg of body weight will be delivered into the right heart muscle at the time of surgery. Cells are derived from autologous (self) umbilical cord blood.

Intervention: Biological: autologous cell-based delivery

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: March 8, 2019): 30
• Original Estimated Enrollment (submitted: June 20, 2013): 10
• Estimated Study Completion Date: May 2021
• Estimated Primary Completion Date: November 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria

1. Individuals with autologous cord blood product that met all cell release criteria (listed on the certificate of analysis from Mayo Clinic Human Cell Therapy Lab) as follows:

   1. No aerobic or anaerobic bacterial growth after 14 days
   2. Greater than 70% cell viability pre-freeze
   3. Total Nucleated Cells (TNC) concentration of 30-42 x 106 cells/mL (pre-freeze)
   4. Minimum of one (1) vial of cells
   5. Mononuclear cell percentage of greater than 50%
   6. Endotoxin result of less than 16 Endotoxin Units (EU)/mL.
2. Mother's serology test results are negative for HIV, Hepatitis B, and Hepatitis C.
3. Individuals with HLHS having undergone Stage I surgical palliation and undergoing planned Stage II palliative Glenn surgery.
4. Ages up to 18 months are eligible if written informed consent can be obtained from both parents (unless one parent is not reasonably available) and/or legal guardians.

Exclusion Criteria

1. Child who's UCB does not meet the specified cell release criteria in Inclusion Criterion #1.
2. History of dimethyl sulfoxide (DMSO) reaction for either the child or mother.
3. Parent(s)/child unwilling to participate.
4. Child with severe chronic diseases, extensive extra-cardiac syndromic features, or history of cancer.
5. Child not completing all pre-procedure work-up within 10 days of the Stage II Glenn surgery as listed in section 6 of this protocol AND lack of pre-procedure work-up documented as a safety concern by a site investigator.
6. Child who's cells have been compromised after meeting cell release criteria (as defined in Inclusion Criterion #1).

7. Child with the following complications of their congenital heart disease:

   1. Any condition requiring urgent, or unplanned procedure within 15 days prior to Stage II surgical repair
   2. Severe pulmonary hypertension (reported in the medical record as >70% systemic pressure)
   3. Other clinical concerns as documented by a site investigator that would predict (more likely to happen than not to happen) a risk of severe complications or very poor outcome during or after Stage II surgical repair.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: up to 18 Months (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01883076
• Other Study ID Numbers: 12-008521
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Timothy J Nelson, MD, PhD, ReGen Theranostics, Inc.
• Study Sponsor: Timothy J Nelson, MD, PhD

Collaborators

• University of Oklahoma
• Children's Hospital of Philadelphia
• Children's Hospitals and Clinics of Minnesota
• Children's Hospital Los Angeles
• Children's Hospital Colorado
• Mayo Clinic

Investigators

• Study Director: Timothy J Nelson, M.D., Ph.D.; Mayo Clinic
• Principal Investigator: Muhammad Y Qureshi, MBBS; Mayo Clinic
• Principal Investigator: Harold M Burkhart, M.D.; Oklahoma University Children's Hospital
• Principal Investigator: Joseph W Rossano, M.D.; Children's Hospital of Philadelphia
• Principal Investigator: David M Overman, M.D.; Children's Hospital of Minnesota
• Principal Investigator: Ram Kumar Subramanyan, M.D., Ph.D.; Children's Hospital Los Angeles
• Principal Investigator: James Jaggers, M.D.; Children's Hospital Colorado

• PRS Account: ReGen Theranostics, Inc.
• Verification Date: October 2020