Two-Year Study of the Safety and Efficacy of the Second-Generation Tissue Engineered Vascular Grafts (TEVG-2)

Prospective, Open-labeled, Single-arm Clinical Trial to Evaluate the Safety and Efficacy of the Second-generation Tissue Engineered Vascular Graft as Vascular Conduits for Extracardiac Total Cavopulmonary Connection.

A single arm clinical trial evaluating the safety and efficacy of the second generation TEVG as vascular conduits for extracardiac total cavopulmonary connection.

Study Overview

• Status: Recruiting
• Conditions: Heart Diseases; Cardiovascular Diseases; Heart Defects, Congenital; Cardiovascular Abnormalities; HLH - Hypoplastic Left Heart Syndrome; DORV; DILV - Double Inlet Left Ventricle; Mitral Atresia; Tricuspid Atresia; Unbalanced AV Canal; Single-ventricle
• Intervention / Treatment: Combination product: Tissue Engineered Vascular Grafts

Detailed Description

This investigation is a prospective, open-labeled clinical trial determining the safety of the use of tissue engineered vascular grafts as conduits for EC TCPC. Patients will be monitored for adverse events (AE) and serious adverse events (SAE). Special attention will be paid to the incidence of stenosis. We will determine graft-related morbidity and mortality for the second generation TEVGs which will include any post-operative complication such as any aneurismal dilation, stenosis, thromboembolic or infectious event that requires treatment and is thought to be caused by the graft as determined by the investigators and confirmed by the data safety monitoring board. The graft related complication rates will be compared between the first and second generation TEVGs. An interim analysis will be performed to assess the incidence of early (<6 month) graft-related complications in the first 6 enrolled patients. Safety and tolerability will be assessed through serial imaging, to determine the effect of growth and remodeling on graft performance through echocardiography and 4-dimensional MRI. All appropriate patients requiring EC TCPC who meet study inclusion/exclusion criteria will be evaluated for enrollment in the clinical trial. All enrolled subjects will be required to have follow-up visits at Nationwide Children's Hospital for a minimum of 2 years following implant. After obtaining informed consent for the patient's parents, patients with single ventricle cardiac anomalies will undergo EC TCPC using a tissue engineered conduit. Post-operative care and monitoring will follow an established, standardized, clinical algorithm in which the patient's clinical status including complications and measurements of graft function will be serially evaluated and recorded over a two year period using physical examination, echocardiography, and MRI.

• Study Type: Interventional
• Enrollment (Estimated): 24
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Samantha Fichtner, BSN, RN; Phone Number: 614-355-5764; Email: samantha.fichtner@nationwidechildrens.org
• Study Contact Backup: Name: Joanne Chisolm, MSN, RN; Email: joanne.chisolm@nationwidechildrens.org

Study Locations

• United States
  • Ohio
    • Columbus, Ohio, United States, 43215
      • Recruiting
      • Nationwide Children's Hospital
      • Contact: Samantha Fichtner, BSN, RN; Phone Number: 614-355-5764; Email: samantha.fichtner@nationwidechildrens.org
      • Contact: Joanne Chisolm, MSN, RN; Email: joanne.chisolm@nationwidechildrens.org
      • Principal Investigator: Mark Galantowicz, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients will be eligible for inclusion in the study if they meet all of the following criteria.

  1. Patient must be a candidate to undergo an extracardiac total cavopulmonary connection.
  2. Patient and/or legal guardian must voluntarily provide informed consent/assent for participation in the study.

Exclusion Criteria:

• Patients will be excluded from participation in the study if they meet any of the following criteria.

  1. Patient has an urgent/emergent operative status.
  2. Patient has acute renal failure or renal insufficiency in the opinion of the investigator
  3. Patient requires a graft less than 12 mm or greater than 24 mm in diameter.
  4. Patient has a pacemaker.
  5. Patient has pulmonary vascular resistance greater than 4 um2 (u=Wood's units)
  6. Patient has abnormal venous drainage (interrupted inferior vena cava [IVC]).
  7. Patient presents with significant atrio-ventricular valve regurgitation that in the opinion of the investigator, makes them ineligible.
  8. Patient has a history of another condition or significant medical problem that, in the opinion of the investigator, precludes compliance with protocol-specified procedures.
  9. Patients taking any medications that in the opinion of the Investigator could interfere with the TEVG, including bisphosphonates (i.e. Clodronate or Zoledronate).
  10. Patient or parent/legal guardian is, in the opinion of the investigator, unable to comply with protocol evaluations.
  11. Preoperative hemoglobin <11.0 mg/dL at time of patient's pre-admission testing.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tissue Engineered Vascular Grafts	Combination product: Tissue Engineered Vascular Grafts; Patients will undergo EC TCPC interposition grafting with a tissue engineered vascular graft and serial magnetic resonance imaging (MRI)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and Tolerability of TEVG	Assessed through graft related complications as determined by serial echocardiogram	2 years
Safety and Tolerability of TEVG	Assessed through graft related complications as determined by serial MRI	2 years
Safety and Tolerability of TEVG	Assessed through adverse events	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy of TEVG	Evaluate graft performance based on MRI	2 years
Efficacy of TEVG	Measured graft volume(mL) as determined by MRI	2 years
Efficacy of TEVG	Measured graft length (mm) as determined by MRI	2 years

Collaborators and Investigators

• Sponsor: Nationwide Children's Hospital
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); National Institutes of Health (NIH); Gunze Limited
• Investigators: Study Chair: Christopher Breuer, MD, Nationwide Children's Hospital; Study Chair: Toshiharu Shinoka, MD/PhD, Nationwide Children's Hospital; Principal Investigator: Mark Galantowicz, MD, Nationwide Children's Hospital

Publications and helpful links

General Publications

• Drews JD, Pepper VK, Best CA, Szafron JM, Cheatham JP, Yates AR, Hor KN, Zbinden JC, Chang YC, Mirhaidari GJM, Ramachandra AB, Miyamoto S, Blum KM, Onwuka EA, Zakko J, Kelly J, Cheatham SL, King N, Reinhardt JW, Sugiura T, Miyachi H, Matsuzaki Y, Breuer J, Heuer ED, West TA, Shoji T, Berman D, Boe BA, Asnes J, Galantowicz M, Matsumura G, Hibino N, Marsden AL, Pober JS, Humphrey JD, Shinoka T, Breuer CK. Spontaneous reversal of stenosis in tissue-engineered vascular grafts. Sci Transl Med. 2020 Apr 1;12(537):eaax6919. doi: 10.1126/scitranslmed.aax6919.
• Ruiz-Rosado JD, Lee YU, Mahler N, Yi T, Robledo-Avila F, Martinez-Saucedo D, Lee AY, Shoji T, Heuer E, Yates AR, Pober JS, Shinoka T, Partida-Sanchez S, Breuer CK. Angiotensin II receptor I blockade prevents stenosis of tissue engineered vascular grafts. FASEB J. 2018 Jun 15;32(12):fj201800458. doi: 10.1096/fj.201800458. Online ahead of print.
• Lee YU, Mahler N, Best CA, Tara S, Sugiura T, Lee AY, Yi T, Hibino N, Shinoka T, Breuer C. Rational design of an improved tissue-engineered vascular graft: determining the optimal cell dose and incubation time. Regen Med. 2016 Mar;11(2):159-67. doi: 10.2217/rme.15.85. Epub 2016 Feb 29.
• Kurobe H, Tara S, Maxfield MW, Rocco KA, Bagi PS, Yi T, Udelsman BV, Dean EW, Khosravi R, Powell HM, Shinoka T, Breuer CK. Comparison of the biological equivalence of two methods for isolating bone marrow mononuclear cells for fabricating tissue-engineered vascular grafts. Tissue Eng Part C Methods. 2015 Jun;21(6):597-604. doi: 10.1089/ten.TEC.2014.0442. Epub 2014 Dec 29.
• Kurobe H, Maxfield MW, Naito Y, Cleary M, Stacy MR, Solomon D, Rocco KA, Tara S, Lee AY, Sinusas AJ, Snyder EL, Shinoka T, Breuer CK. Comparison of a closed system to a standard open technique for preparing tissue-engineered vascular grafts. Tissue Eng Part C Methods. 2015 Jan;21(1):88-93. doi: 10.1089/ten.TEC.2014.0160.
• Hibino N, McGillicuddy E, Matsumura G, Ichihara Y, Naito Y, Breuer C, Shinoka T. Late-term results of tissue-engineered vascular grafts in humans. J Thorac Cardiovasc Surg. 2010 Feb;139(2):431-6, 436.e1-2. doi: 10.1016/j.jtcvs.2009.09.057.

Study record dates

Study Major Dates

• Study Start (Actual): July 15, 2020
• Primary Completion (Estimated): August 1, 2025
• Study Completion (Estimated): August 1, 2027

Study Registration Dates

• First Submitted: June 30, 2020
• First Submitted That Met QC Criteria: July 8, 2020
• First Posted (Actual): July 13, 2020

Study Record Updates

• Last Update Posted (Actual): August 3, 2023
• Last Update Submitted That Met QC Criteria: August 1, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: Fontan; TEVG; Tissue Engineered Vascular Graft
• Additional Relevant MeSH Terms: Heart Diseases; Heart Valve Diseases; Cardiovascular Diseases; Congenital Abnormalities; Heart Defects, Congenital; Univentricular Heart; Hypoplastic Left Heart Syndrome; Cardiovascular Abnormalities; Tricuspid Atresia
• Other Study ID Numbers: IDE18703; 1UG3HL148693 (U.S. NIH Grant/Contract); 1UH3HL148693 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Biological Samples: We plan to make available representative samples of the bone marrow-derived mononuclear cells and seeded scaffold to a NIH-designated entity (RM Innovation Catalyst) for in depth and independent characterization. Specifically, for each TEVG manufactured, 1 ml of bone marrow-derived mononuclear cells and a 5mm x 5mm section of the seeded scaffold will be sampled, packed, and transported to the RM Innovation Catalyst per their instructions. In addition, copies of the batch record and completed certificate of analysis will be forwarded to the NIH-designated laboratory.
• IPD Sharing Time Frame: Prior to study initiation, the US FDA will have a comprehensive description of the processes followed to assure the accuracy, reliability, integrity, availability, and authenticity of required records and signatures supporting the data reported in the CSR will be provided to the Agency for confirmation that it will support a regulatory filing for TEVG. Every 6 months throughout the study, data will be shared with RM Innovation Catalyst, with a final locked data set no later than six months prior to the end of the award. Data from our long-term follow up policy will be made available on an annual basis if requested by the RM Innovation Catalyst or the NIH.
• IPD Sharing Access Criteria: De-identified data will be provided to RM Innovation Catalyst. A Clinical Study Report will be submitted to the US FDA following the International Conference on Harmonization E3 Guideline for Industry: Structure and Content of Clinical Study Reports. Summary results of the trial will be submitted to ClinicalTrial.gov within one year of the primary completion date (per regulation and NIH policy). Results of screening tests and subjects participation in the study and ongoing test results will be shared with their primary care physician and/or primary cardiologist if cardiac care is being provided outside of Nationwide Children's Hospital.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No