Laryngo-Tracheal Tissue-Engineered Clinical Transplantation
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|ClinicalTrials.gov Identifier: NCT01997437|
Recruitment Status : Unknown
Verified January 2016 by Kuban State Medical University.
Recruitment status was: Active, not recruiting
First Posted : November 28, 2013
Results First Posted : May 22, 2015
Last Update Posted : March 7, 2016
|First Submitted Date ICMJE||November 5, 2013|
|First Posted Date ICMJE||November 28, 2013|
|Results First Submitted Date ICMJE||January 3, 2014|
|Results First Posted Date ICMJE||May 22, 2015|
|Last Update Posted Date||March 7, 2016|
|Study Start Date ICMJE||December 2013|
|Estimated Primary Completion Date||September 2016 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
|Original Primary Outcome Measures ICMJE
||Patients With Benign and Malignant Laryngo-Tracheal Diseases [ Time Frame: Within first 30 days after surgery ]
A tissue engineered tracheobronchial transplant using a bioengineered nanocomposite and autologous mononuclear cells may represent the only curative chance for terminal patients. Peripheral blood mononuclear cells are able to stimulate the migration of peripheral blood stem cells to transplanted laryngo-tracheal segments and to cause their differentiation into both respiratory epithelium and cartilaginous cells.
|Change History||Complete list of historical versions of study NCT01997437 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE||Not Provided|
|Current Other Pre-specified Outcome Measures||Not Provided|
|Original Other Pre-specified Outcome Measures||Not Provided|
|Brief Title ICMJE||Laryngo-Tracheal Tissue-Engineered Clinical Transplantation|
|Official Title ICMJE||Clinical Trial Evaluation of Stem-cell Based Bioartificial Airway Transplantation for Patients With Benign and Malignant Laryngo-tracheal Diseases|
The proposed protocol will involve the replacement of the trachea using a synthetic bioengineered scaffold seeded with autologous mononuclear cells as an intraoperative solution for patients with with benign and malignant laryngo-tracheal diseases or other terminal conditions of the trachea.
Tracheal transplant is indicated as the only therapeutic alternative in cases where instrumental, endoscopic and other evaluations show that the length of residual healthy airways (about 6 cm or longer than 50% of the airway length) and the localization and extension of the obstruction make it impossible to perform a surgical resection of the pathological segment.
In addition to tracheal surgical transplant techniques, this protocol requires knowledge and experience with autologous cell preparation as well as scaffold seeding procedures.
Before transplantation the patients will have the laboratory and instrumental evaluations.
Three days before the transplantation the patient will be underwent bone marrow aspiration. The bone marrow mononuclear cells (MNC) will be isolated from the red blood cells (RBC) in the totally enclosed FDA approved automatic system (Sepax,BioSafe America, Inc.). The final product, re-suspended with cell culture medium (DMEM+10% albumin and 10% autologous plasma) in a volume of 200 mL, will be placed in a 600 mL transfer bag. 2 mL of the product will be taken from the bag before clinical use to test sterility using culture media and immunofluorescent cytometry to characterize cell type and viability.
Two days before the transplant, the patient will begin "boosting" therapy to mobilize cells by means of systemic injections of analogous recombinants of granulocyte colony-stimulating factor (GCSF)(Granocyte, 1 M IU/kg (max. 15 M IU) and Erythropoietin, 400 IU/kg (max.6,000IU). These will be injected for the two days prior to surgery.
InBreath Bioreactor (the special bioreactor for cultivating trachea) The work in the current protocol will involve a bioreactor design previously utilized by Macchiarini P. ang colleges in a successful first-in-man implantation of a tissue-engineered large airway replacement. The device, commercialized under the name, InBreath 3D Organ Bioreactor (Harvard Bioscience, Inc.) is designed for placement within a tissue culture incubator and consists of a modular polysulphone organ chamber, motor unit and remote controller. The chamber is easily detachable from the motor unit and its polysulphone construction permits sterilization with the standard gas plasma sterilization process that is readily available in the operating room in Peoria. The motor unit provides consistent rotation to the tissue holder within the chamber, ensuring controlled application of hydrodynamic shear forces to the developing tracheal construct. A fully enclosed motor housing protects the brushless motor from the corrosive moisture within the incubator. The remote control unit is placed outside the incubator providing a means to adjust rotational speed without disturbing the incubator environment.
The seeded construct was allowed to incubate in the bioreactor for 96 hours prior to removal for implantation. Based on the five previous adult cases using the POSS-PCU (Polyhedral oligomeric silsesquioxane-poly(carbonate-urea) urethane), PET(Polyethylene terephthalate) and PET:PU (Polyurethane) synthetic scaffolds, the internal and external surfaces of the scaffold will be seeded with the freshly isolated bone marrow mononuclear cell fraction. The bioreactor will be started with an initial speed of 0.5 cycles/min for 18 hours (then stepwise increase up to 2.5 cycles/min). Incubation will be during the 48 hours preceding the transplant procedure. This incubation protocol worked very well in the previous cases using the three different synthetic nanocomposite tracheal scaffolds.
The tracheal reseeding procedure will be done in our aseptic culture GMP (Good Manufacturing Practice) facility that was established and fully functional.
Day of transplantation:
Intra-operative Surgical Procedure The morning of the transplant the graft will be tested for cell growth (MTT test and for sterility by gram stain and analysis of interim culture results). Once the graft is deemed ready for implantation, the patient will be placed under general endotracheal anesthesia.
Thoracic and abdominal procedures Having performed the resection of the airway's damaged segment, the airway construct will be seeded intraoperatively with the respiratory cell biopsies on the internal surface. The graft will be then injected (conditioned) with growth factors including 10 ng/mL of recombinant human transforming growth factor-β 3, 10 nmol/L recombinant parathyroid hormone-related peptide, 100 nmol/L dexamethasone, and 10 µg/mL insulin, GCSF (10 µg/kg) and Erythropoietin (40,000 UI) (to stimulate the mobilization of the peripheral hematopoietic cells). The implant will be then anastomosed proximally and distally so as to reconstruct the airway defect using sutures. It will be then covered and wrapped by an omentum major flap (adipose vascularized tissue detached from the large bend of the stomach, harvested on the right or left gastroepiploic artery and then carried over to the mediastinum trans-diaphragmatically or sub-sternally), to guarantee long-term protection of the graft and of the anastomosis and obtain indirect graft's neovascularisation.
To boost the regenerative process, the patient (current weight about 13 Kg) will be treated pharmacologically in the post-op period by systemic injections of:
Both factors will be administered in suitable concentrations to stimulate the mobilization/recruitment of hematopoietic cells, in "regenerative" doses which have not been associated with any side-effects. Every second day the plasma Erythropoietin level and the blood count (including haemoglobin and white blood cell counts) will be monitored. Haemoglobin levels greater than 15 g/dl will raise concerns for hyper-viscosity and prompt removal of 10-20 cc/kg of blood and may prompt the addition of a continuous infusion of heparin to keep the Activated Partial Thromboplastin Time (APTT) levels between 40-60 seconds. White blood cell levels above 50-60,000/μl will be considered "toxic" and will result in a reduction/suspension of the GCSF therapy until numbers fall below 30,000. Treatment with GCSF and Erythropoietin will be carried out every other day for 2 weeks following the transplant according to the following table:
The follow-up will be carried out at the Cardiothoracic Surgery Department of the Krasnodar Regional Hospital, and will include:
|Study Type ICMJE||Interventional|
|Study Phase ICMJE||Not Applicable|
|Study Design ICMJE||Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Condition ICMJE||Tracheal Diseases|
|Intervention ICMJE||Device: Stem-cell seeded bioartificial tracheal scaffold
Seeding the synthetic scaffold with autologous stem cells; scaffold' cultivation within 48-72 hours in bioreactor, injection of growth factors into scaffold in the first and last stages of the cultivation, replacement of the damaged trachea by generated tissue-engineered organ
|Study Arms ICMJE||Tissue-engineered airway transplantation
Stem-cell seeded bioartificial tracheal scaffold
Intervention: Device: Stem-cell seeded bioartificial tracheal scaffold
|Publications *||Jungebluth, P, Alici, E, Baiguera S, et al. Tracheobronchial transplantation with a stem-cell-seeded bioartificial nanocomposite: a proof-of-concept study. Lancet 2011 Dec 10; 378 (9808):1997-2004; Macchiarini P, Jungebluth P, Go T, et al. Clinical transplantation of a tissue-engineered airway. Lancet 2008; 372, 2023-3030; Acocella F, Brizzola S, et al. Prefabricated tracheal prosthesis with partial biodegradable materials: a surgical and tissue engineering evaluation in vivo. Journal of Biomaterials Science; Polymer Edition 2007; 18(5):579-594; Bader A, Macchiarini P. Moving towards in situ tracheal regeneration: the bionic tissue engineered transplantation approach. J Cell Mol Med 2010; 14(7):1877-89; Jungebluth P, Moll G, Baiguera S, Macchiarini P. Tissue engineered airway: a regenerative solution. Clin Pharm Ther 2012; 91:81-93;|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Unknown status|
|Actual Enrollment ICMJE
|Original Estimated Enrollment ICMJE
|Estimated Study Completion Date ICMJE||December 2016|
|Estimated Primary Completion Date||September 2016 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
|Ages ICMJE||Child, Adult, Older Adult|
|Accepts Healthy Volunteers ICMJE||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||Russian Federation|
|Removed Location Countries|
|NCT Number ICMJE||NCT01997437|
|Other Study ID Numbers ICMJE||11.G34.31.0065|
|Has Data Monitoring Committee||Yes|
|U.S. FDA-regulated Product||Not Provided|
|IPD Sharing Statement ICMJE||Not Provided|
|Responsible Party||Kuban State Medical University|
|Study Sponsor ICMJE||Kuban State Medical University|
|Collaborators ICMJE||Not Provided|
|PRS Account||Kuban State Medical University|
|Verification Date||January 2016|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP