Human Upper Extremity Allotransplantation
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Purpose
Background: Millions of people each year sustain injuries, have tumors surgically removed, or are born with defects that require complex reconstructive surgeries to repair the problem. In case of hand, forearm, or arm amputation, prostheses only provide less than optimal motor function and do not enable sensory feedback. However, hand and arm transplantation is a means to restore the appearance, anatomy, and function of a native hand. Although over 65 hand transplants have been performed to date and good functional results have been achieved, widespread clinical use of this treatment has been limited due to adverse effects of life-long and high-dose immunosuppression needed to prevent graft rejection. These risks include infection, cancer, and metabolic problems, all of which can greatly affect recipients' quality of life, make the procedure riskier, and jeopardize the potential benefits of hand transplantation.
Study Design: This non-randomized, Phase II clinical trial will document the use of a new immunomodulatory protocol (aka - Pittsburgh Protocol, Starzl Protocol) for establishing hand transplantation as a safe and effective reconstructive treatment for upper extremity amputations by minimizing maintenance immunosuppression therapy in unilateral and bilateral hand/forearm transplant patients. The investigators protocol combines lymphocyte depletion with donor bone marrow cell infusion and has enabled graft survival using low doses of a single immunosuppressive drug followed by weaning (and perhaps elimination) of treatment. Although initially designed for living-related solid organ donation, this regimen has been adapted for use with grafts donated by deceased donors. The investigators propose to perform 30 human hand transplants employing this novel immunomodulatory protocol.
Specific Aims: 1) To establish hand transplantation as a safe and effective reconstructive strategy for the treatment of upper extremity amputations; 2) To reduce the risk of rejection and enable allograft survival while minimizing the requirement for long-term high dose multi-drug immunosuppression.
Significance of Research: Hand transplantation could help upper extremity amputees recover functionality, self-esteem, and the capability to reintegrate into family and social life as "whole" individuals. The protocol offers the potential for minimizing the morbidity of maintenance immunosuppression, thereby beneficially shifting the risk/benefit ratio of this life-enhancing procedure and enabling widespread clinical application of hand transplantation. The significance of this research lies in combining the novel procedure of hand transplantation with the means of inducing partial tolerance to improve the safety, efficacy, and applicability of this reconstructive option.
| Condition | Intervention | Phase |
|---|---|---|
|
Amputation, Traumatic Wounds and Injuries Hand Injuries |
Procedure: Deceased donor hand transplantation Drug: Bone marrow cell-based therapy & single-drug immunosuppression. |
Phase 2 |
| Study Type: | Interventional |
| Study Design: | Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment |
| Official Title: | Human Upper Extremity Allotransplantation |
- Graft Survival [ Time Frame: Transplantation through end of study period (up to 5 years) ] [ Designated as safety issue: No ]Post-operative graft survival will be documented monthly Months 1-12 and quarterly (every 3 months) Years 2-5.
- Documentation of immunosuppression required by transplanted participants to maintain graft. [ Time Frame: Transplantation to end of study period (up to 5 years) ] [ Designated as safety issue: No ]Post-operative serum trough levels will be documented daily Days 1-28, semiweekly Weeks 5-12, weekly Weeks 13-25, biweekly Weeks 26-38, monthly Months 10-12, and quarterly (every 3 months) Years 2-5.
| Estimated Enrollment: | 30 |
| Study Start Date: | July 2011 |
| Estimated Study Completion Date: | June 2021 |
| Estimated Primary Completion Date: | June 2016 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: Treatment (Transplantation)
Hand/arm transplantation in combination with a novel donor bone marrow cell-based therapy followed by single-drug immunosuppression with potential weaning.
|
Procedure: Deceased donor hand transplantation
Deceased donor hand is surgically attached to recipient arm's stump.
Drug: Bone marrow cell-based therapy & single-drug immunosuppression.
This protocol uses a novel bone marrow cell-based therapy for composite tissue allotransplantation (CTA) rather than conventional triple-drug immunosuppression to facilitate long-term graft survival of deceased donor human upper extremities under low-dose maintenance immunosuppression. Initial T-cell depletion with alemtuzumab is followed by upper extremity transplantation and tacrolimus maintenance therapy. Donor bone marrow cells are infused on Day 10 (±4 days) post-transplantation to elicit a host alloimmune response triggering exhaustion and deletion of the respective host (anti-donor) lymphocyte clones. Subsequently, tacrolimus therapy is given for at least 6 months before spaced weaning is considered in stable recipients.
|
Eligibility| Ages Eligible for Study: | 18 Years to 69 Years |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Recent (≥6 months) or remote (i.e., several decades) unilateral or bilateral upper limb loss (below the shoulder) desiring limb transplantation.
- Below-shoulder amputation.
- Male or female and of any race, color or ethnicity.
- Aged 18-69 years.
- Completes the protocol informed consent form.
- No co-existing medical condition which, in the opinion of the study team, could affect the immunomodulatory protocol, surgical procedure, or functional results (see 5.1.2 Donor and Recipient Exclusion Criteria below. If the condition is amenable to treatment, the study team must agree that said condition should not significantly enhance the surgical risks of upper extremity transplantation.)
- No co-existing psycho-social problems (i.e., alcoholism, drug abuse).
- Negative for malignancy for past 10 years.
- Negative for HIV at transplant.
- Negative crossmatch with donor.
- If female of child-bearing potential, negative serum pregnancy test.
- If female of child-bearing potential, consent to use reliable contraception for at least one year following transplantation.
- Consents to cell collection, storage, and bone marrow infusion as part of the treatment regime.
- USA citizen or equivalent.
- Patient agrees to comply with the protocol and states a dedication to the immunomodulatory treatment regime.
Exclusion Criteria:
Positive for any of the following conditions:
- Untreated sepsis.
- HIV (active or seropositive).
- Active tuberculosis.
- Hepatitis B or C.
- Viral encephalitis.
- Toxoplasmosis.
- Malignancy (within past 10 years).
- Current/recent (within 3 months of donation/screening consent) IV drug abuse.
- Paralysis of ischemic or traumatic origin.
- Inherited peripheral neuropathy.
- Infectious, post infectious, or inflammatory (axonal or demyelinating) neuropathy.
- Toxic neuropathy (i.e. heavy metal poisoning, drug toxicity, industrial agent exposure).
- Mixed connective tissue disease.
- Severe deforming rheumatoid or osteoarthritis in the limb.
- Conditions that, in the opinion of the study team, may impact the immunomodulatory protocol potentially exposing the recipient to an unacceptable risk under immunosuppressive treatment.
- Sensitized recipients with high levels (50%) of panel-reactive HLA antibodies.
- Conditions that may impact the success of the surgical procedure or increase the risk of postoperative complications including inherited coagulopathies like Hemophilia, Von-Willebrand's disease, Protein C and S deficiency, Thrombocythemias, Thallassemias, Sickle Cell disease, etc.
- Mixed connective tissue diseases and collagen diseases can result in poor wound healing after surgery.
- Conditions that may impact functional outcomes including Lipopolysaccharidosis and amyloidosis (may impact nerve regeneration) or rare disorders of bone healing like osteopetrosis.
- Patients considered unsuitable per the consulted Psychiatrists appraisal.
Contacts and Locations| Contact: Cynthia Cohen, DNP,RN,CRNP | 410-502-3895 | ccohen3@jhmi.edu |
| United States, Maryland | |
| Johns Hopkins University School of Medicine | Recruiting |
| Baltimore, Maryland, United States, 21287 | |
| Contact: Carisa M Cooney, MPH, CCRP 443-287-4629 ccooney3@jhmi.edu | |
| Principal Investigator: W. P. Andrew Lee, MD | |
| Sub-Investigator: Gerald Brandacher, MD | |
| Sub-Investigator: Stefan Schneeberger, MD | |
| Sub-Investigator: Damon S Cooney, MD, PhD | |
| Sub-Investigator: Justin Sacks, MD | |
| Principal Investigator: | W. P. Andrew Lee, MD | Johns Hopkins University |
More Information
No publications provided
| Responsible Party: | W. P. Andrew Lee, M.D., Professor and Chairman, Department of Plastic and Reconstructive Surgery, Johns Hopkins University |
| ClinicalTrials.gov Identifier: | NCT01459107 History of Changes |
| Other Study ID Numbers: | NA_00046418 |
| Study First Received: | September 29, 2011 |
| Last Updated: | October 24, 2011 |
| Health Authority: | United States: Institutional Review Board |
Keywords provided by Johns Hopkins University:
|
Hand Transplant CTA VCA Composite Tissue |
Amputation Upper limb Immunosuppression |
Additional relevant MeSH terms:
|
Amputation, Traumatic Hand Injuries Wounds and Injuries |
ClinicalTrials.gov processed this record on May 19, 2013