Human Penile Allotransplantation

Study Overview
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Brief Summary
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Injuries to the genitalia are of concern to the military with emphasis placed on the surgical reconstruction and psychological health of these Wounded Warriors. However, despite significant surgical advances in microvascular surgery and autologous free tissue transfer, conventional reconstructions cannot truly replace the complicated structures and functions of the penis including the urethra, erogenous sensation, and erectile corporal bodies. Conventional reconstruction poses several challenges: patients may not have sufficient donor tissue due to other injuries or previous surgery; multiple operations are often needed to restore the neophallus; the final reconstruction only approximates the penis' native form; recreating the urethra is challenging and the new urethra is prone to stricture and fistula formation; the erectile function necessary for sexual intercourse is often lacking; and insufficient protective sensation can lead to penile implant extrusion, infection, subsequent explantation or loss of the reconstruction. The investigators propose this clinical trial to determine functional outcomes and quality of life for Wounded Warriors and civilians who choose to undergo penile allotransplantation. The investigators will combine extensive experience performing total penile reconstruction in a large population affected by congenital, traumatic, and therapeutically extirpated Genitourinary deformities and expertise in reconstructive transplantation using an immunomodulatory protocol to for this study. The investigators anticipate penile transplantation can potentially replace like with like, restoring the appearance, anatomy, and function of the recipient in a manner far superior to autologous reconstruction. This project will establish the ability to perform penile allotransplantation using an immunomodulatory protocol and will compare outcomes with conventional phalloplasty patient results. Study Design: This is a non-randomized subject self-controlled clinical trial to implement a cell-based immunomodulatory protocol for penile allotransplantation. An intermediate deliverable is achieving allograft survival and functional return with reduced dosing/frequency of maintenance immunosuppression on steroid-free monotherapy (tacrolimus) immunosuppression. The long-term deliverable and goal is to demonstrate superior outcomes when compared to satisfaction and QOL in conventional phalloplasty patients 12-60 months post-transplant.

Detailed Description
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Specific Aims: 1) To assess the feasibility and function of penile allotransplantation in Wounded Warriors and civilians who have lost their penis due to battle or traumatic injury, using an immunomodulatory protocol to reduce immunosuppression; 2) To assess pre-to-post changes in QOL in patients who undergo penile allotransplantation.

Official Title
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Human Penile Allotransplantation

Conditions
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Amputation, Wounds and Injuries, Amputation, Traumatic, Urologic Surgical Procedures, Male, Amputation, Traumatic/Surgery, Penis/Transplantation, Penis/Surgery, Penis/Injuries

Intervention / Treatment
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* Biological: Monoclonal Antibody (Humanized Anti-CD52)
* Drug: Tacrolimus
* Procedure: Penile Allotransplantation


Participation Criteria
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Eligibility Criteria
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Donor Inclusion Criteria: Males aged 16 - 65 years. Brain dead meeting the criteria for Determination of Death. Family consent for penile graft donation. Stable donor (i.e., does not require excessive vasopressors to maintain blood pressure). Same blood type as recipient. Negative lymphocytotoxic crossmatch. Accurately matched for skin tone Recipient Inclusion Criteria: Males of any race, color or ethnicity; aged 18-69 years. Recent (≥6 months) or remote (i.e., several decades) penile injury resulting in the loss of ≥75% of the phallus. Penectomy secondary to penile cancer Penile Cancer Survivors > 5 years Micropenis associated with congenital/birth defect and severely ambiguous male genitalia Must have completed a clinic appointment with one of the study surgeons to discuss all penile reconstructive options. Completes the protocol informed consent form(s). No co-existing medical condition which, in the opinion of the study team, could affect the immunomodulatory protocol, surgical procedure, or functional results (If the condition is amenable to treatment, the study team must agree that said condition should not significantly enhance the surgical risks of penile transplantation.). No co-existing psycho-social problems (i.e., alcoholism, drug abuse). Negative for malignancy for past 5 years. Negative for HIV at transplant. Negative crossmatch with donor. Consents to sample (i.e., skin biopsy) collection and storage and bone marrow infusion as part of the treatment regimen. USA citizen or equivalent. Patient agrees to comply with the protocol and states a dedication to the immunomodulatory treatment regimen. Recipient and Donor Exclusion Criteria: Untreated sepsis. HIV (active or seropositive). Active tuberculosis. Active Hepatitis B infection. Hepatitis C. Viral encephalitis. Toxoplasmosis. Malignancy (within past 5 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. Donor Only Exclusion Criteria: Evidence of active herpes simplex virus-2 (HSV-2) infection. Tattoos: non-professional tattoo within the last 6 months, or personally identifiable tattoo (i.e., donor name) on potential transplant. Recipient Only Exclusion Criteria: 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 human leukocyte antigen (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, Thalassemias, Sickle Cell disease, etc. Conditions that may impact functional outcomes including Lipopolysaccharidosis and amyloidosis (may impact nerve regeneration). Patients considered psychologically/psychiatrically unsuitable.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 69 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment: Transplantation<br>Penile transplantation with an immunomodulatory protocol consisting of monoclonal antibody induction therapy of humanized anti CD52 followed by donor bone marrow infusion and tacrolimus monotherapy. | Biological: Monoclonal Antibody (Humanized Anti-CD52)<br> <br> Drug: Tacrolimus<br> <br> Procedure: Penile Allotransplantation<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Allograft Survival | use an immunomodulatory protocol to reduce immunosuppression. Post-operative allograft survival will be assessed by various clinical measures including: physical assessments, imaging assessments (ultrasound, CT angiography, magnetic resonance (MR) Neurography and MRI) immune monitoring (screen patient sera for donor specific antibodies), hematologic and metabolic tests, viral tests, chimerism tests, and skin biopsies | Transplantation through end of study period (up to 5 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quality of Life (QOL) as assessed by Brief Symptom Inventory | Brief Symptom Inventory questionnaire evaluates psychological distress and psychiatric disorders. It consists of 53-item self-report inventory in which participants rate the extent to which they have been bothered. 5-point rating scale, 0 indicating not at all bothered to 4 extremely bothered. | Transplantation through end of study period ( 5 years) | 
| QOL as assessed by Affect Balance Scale (ABS) | ABS is a 10-item questionnaire that assess positive and negative affect as indicators of life satisfaction and/or well-being. Score range from 0-4. 0 indicating the feeling never affected to 4, where the feeling is affected always. | Transplantation through end of study period (up to 5 years) | 
| QOL as assessed by NEO Five-Factor Inventory Scale (NEO-FFI) | NEO-FFI is used to examine personality traits. Questions consists of 60 items. Items are scored from Strongly disagree to Strongly agreed | Transplantation through end of study period (up to 5 years) | 
| QOL as assessed by the International Index of Erectile Function (IIEF) | A score of 0-5 is awarded to each of the 15 questions that examine the 4 main domains of male sexual function: erectile function, orgasmic function, sexual desire and intercourse satisfaction. | Transplantation through end of study period (up to 5 years) | 
| Psychosexual Measures assessed by Self-Esteem and Relationship (SEAR) questionnaire | 14 item questionnaire where responses are scored from 1-5. Response of 1 indicating almost never/never to 5 indicating almost always/always | Transplantation through end of study period ( 5 years) | 
| T0 asses Erection Hardness Score (EHS) | EHS rates the hardness of erection on a scale of one to four, with four being the maximal score. | Transplantation through end of study period ( 5 years) | 
| Modified Sexual Life Quality Questionnaire-Quality of Life (mSLQQ- QoL) | Used to validate as a tool for evaluating sexual QoL. mSLQQ is measured from score of 0 to 8. 0 indicates a low score compare to 8, indicating high. A score of 4 indicates, nothing has been changed. | Transplantation through end of study period ( 5 years) | 
| Psychological Measures by Satisfaction with Life Scale (SWLS) | SWLS is a measure of life satisfaction. Uses scale to rate from 1-7, Where 1 indicates Strongly disagree to 7 indicating strongly agree. | Transplantation through end of study period ( 5 years) | 
| Brief Pain Inventory (Short Form) ) (BPISF) | BPISF assesses the severity of pain and its impact on functioning. It is scored from 0 to 10, 0 indicating no pain, does not interfere to 10 indicating pain as bad as you can imagine, completely interferes. | Transplantation through end of study period ( 5 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Penile Transplant, Vascularized Composite Allotransplantation (VCA), Composite Tissue Allotransplantation (CTA), Penis, Amputation, Immunosuppression, Composite Tissue, Male, Humans, Allotransplantation, Micropenis, Severely Aambiguous Male Genitalia, congenital/birth defect