Human Penile Tissue Allotransplantation for Devastating Penile and Concomitant Genital Trauma

Study Overview
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Brief Summary
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This is a 4-year, non-randomized, single center, patient self-controlled, clinical trial (though enrolled subjects will be followed for life as are all transplant patients) for patients seeking allotransplantation of the male external genitalia (MEG), or penile tissue, as a feasible reconstructive strategy for the treatment of devastating and irreversible injuries to the genitalia. In addition to receiving penile allotransplantation and post-operative monitoring and support, enrolled patients will receive an innovative and clinically proven immunomodulatory protocol that combines lymphocyte depletion of the recipient with donor bone marrow cell infusion. Patients will be treated with lymphocyte depleting induction therapy, donor bone marrow cell infusion and tacrolimus. After the first year, maintenance immunosuppression will be modified gradually and cautiously (tapered dose reduction or spaced frequency dosing of tacrolimus) in selected patients based on a critical evaluation of clinical and immunologic outcomes. Outcomes will include but not be limited to functional metrics (sensation, erection, voiding), psychosocial (body integrity, adaptation to transplant) and health related quality of life (HRQOL) measures.

Detailed Description
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Initial treatment with an antibody targeting recipient immune cells followed by triple-drug maintenance therapy represents the current standard in clinical VCA. Our protocol is different from the existing conventional drug treatments used in MEG allotransplantation in that it combines donor bone marrow infusion with an immunosuppression sparing protocol. The primary goal of this pilot clinical trial is to determine the feasibility of using allogeneic penile tissue to repair/replace irreversibly damaged external genitalia. Enrolled and transplanted subjects will be followed for their lifetime as a transplant patient.

Official Title
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Vascularized Composite Allotransplantation (VCA) for Devastating Penile and Concomitant Genital Trauma

Conditions
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Urologic Injuries, Genital Diseases, Male, Amputation

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For Recipients Male 18-40 years Irreversible and devastating genitalia damage not amenable to conventional reconstruction. Patent main vessels leading into the remaining penile stump, as confirmed by angiography. Adequate penile stump (> 2.5cm) to facilitate placement of a tourniquet, debridement of the distal portion and sufficient distal mobilization of the structures requiring anastomosis Eligible for long term standard of care coverage Exclusion Criteria: For Recipients Documented history of: cancer renal impairment hepatic disorders neurologic disorders (sensory or motor function deficits) severe scarring with poor host tissue bed penile resection or implant surgery diabetes hypertension hyperlipidemia coronary artery disease untreated genital cancer HIV, Hepatitis B or C, or any infectious disease erectile dysfunction Peyronie's disease urethral stricture disease balanitis xerotica obliterans pelvic embolization pelvic radiation untreated hypogonadism prior prostate surgery recurrent urinary tract infections (UTIs) nephrolithiasis connective tissue disease or collagen disease lipopolysaccharidosis or amyloidosis Use of 5-alpha-reductase inhibitors External signs, sequelae or positive serology of sexually transmitted disease (including HPV) Active UTI, stones, urethral edema and other pathology that prevents urethral anastomosis Current or past substance abuse Current or past smoker (within past 3 months) Use of any medications known to cause vasoconstriction Psychiatric illness or psychological problems, or deemed unsuitable on psychiatric evaluation Any condition that may prevent transplantation (positive cross match, high panel reactive antibody (PRA), etc.) Uncontrolled bleeding disorder, platelet count > 50,000, hemophilia or any other inherited coagulopathy or need to routinely receive blood products for bleeding disorders Concurrent participation in any other clinical investigation during the period of this investigation Inability to undergo leukapheresis Inability to participate in all necessary study activities due to physical or mental limitations Inability or unwillingness to return for all required follow-up visits. Inability or unwillingness to sign the patient informed consent document.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 35 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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: All subjects receive transplant and immunosuppression therapy
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Need for Immunosuppressive drug therapy | The amount of immunosuppressive drug therapy will be recorded. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| erectile function | This will be assessed following intracorporal injection of vaso-active agents, such as prostaglandin, phentolamine, papaverine, or some mixture of these drugs (i.e. Trimix). and through high-resolution duplex Doppler ultrasonography | 6 months | 
| Assessment of sensory return and sensory thresholds | This will be accomplished by penile biothesiometry | 6 months | 
| Determination of hemodynamic status | Dynamic infusion pharmaco-cavernosometry and cavernosography will be utilized to better understand these changes | 6 months | 
| The Reintegration to Normal Living (RNL) Index | The RNL is an 11-item questionnaire that asks how a person manages activities, roles, and relationships on a day-to-day basis. | 6 months | 
| The Situational Inventory of Body-Image Dysphoria (SIBID) | The SIBID is a multidimensional body-image survey assessment of people's negative body-image emotions in everyday situations and physical experiences. | 6 months | 
| The Function and Body Image Survey | This survey consists of six open-ended questions regarding personal thoughts, opinions, and experiences about the transplant, and the individual's current functional abilities. | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Penile Trauma, Allotransplantation, Vascularized Composite Allotransplantation, VCA, Genital Trauma, Penile Transplantation, Amputation, Penile Injury