Clinical Trial to Assess the Safety and Efficacy of Investigational Product in Patients Due to Hypospadias Treatment Failure

Study Overview
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Brief Summary
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The purpose of this trial is to assess the safety and efficacy of Holour in patients suffering from hypospadias treatment failure. Holour is intended for urethral replacement and is made from ex vivo expanded autologous oral mucosal cells including stem cells.

Detailed Description
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Holour is a prospective, open-label, uncontrolled pilot clinical trial phase i/ii. The aim of this clinical trial is to perform a tissue engineering therapy to assess the safety (at 3 and 12 months) and efficacy (at 12 months) of the autologous treatment. Patients will be screened according to the study inclusion and exclusion criteria and will be candidate for the treatment if all eligibility criteria are met. Up to 8 patients will be treated by means of autologous cultured oral mucosa grafts containing oral mucosa stem cells. Holour is produced by ex vivo expansion of cells obtained from oral mucosa biopsy collected from patient. The biopsy will be processed in a laboratory of a regenerative medicine manufacturing site where the epithelial cells will be isolated, expanded and prepared as final graft to be implanted. Holour administration will be planned according to the procedures and the need of the patient. The entire procedure envisages the following steps: Oral mucosa biopsy to manufacture autologous grafts of Holour. Penile urethroplasty in two stages: First stage: application of holour on the wound bed prepared according to standard surgery. Second stage: penis reconstruction according to standard surgical procedure. The surgical procedures may be followed by a post-implantation treatment (if necessary) with corticosteroids and antibiotics. The treatment includes a single administration of Holour; in case of failure of the first procedure eligible patients can undergo to a second implantation. Three months after the transplantation, primary endpoint will be evaluated by the investigator. The study completion will be reached when 1 year (secondary endpoint) of follow-up after the last transplant in the last patient will be accomplished. The end of the trial is defined as the last visit of the last patient after the last treatment if any.

Official Title
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Prospective, Open-label, Uncontrolled Pilot Clinical Trial to Assess the Safety and Efficacy of Autologous Cultured Oral Mucosa Grafts for Urethral Reconstruction in Patients Due to Hypospadias Treatment Failure

Conditions
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Hypospadias

Intervention / Treatment
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* Drug: Ex vivo expanded autologous human oral epithelium containing stem cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed and dated informed consent prior to any study-related procedures (Caregivers); Patients whose parents/legal representatives have been thoroughly informed of the aim of the study procedures and provided signed and dated written informed consent; Male patients between 5 and 17 years old (less than 18 years old); Need for urethroplasty in failed hypospadias treatment; Hypospadias complications shown by clinical evaluation, uroflowmetry with post-micturition residual evaluation and/or retrograde urethrography and/or urethroscopy; Uroflowmetry rate: Uroflowmetry with a plateau-shaped curve and low qmax according to paediatric uroflow normograms; Absence of other contraindications to HOLOUR implantation based on investigator's judgement; A cooperative attitude to follow up the study procedures (Caregivers in case of minors). Exclusion Criteria: Known or suspected intolerances against anaesthesia; Bad general condition (ECOG index >2); Clinical and/or laboratory signs of acute systemic infections and/or severe inflammation at the time of screening. Patient can be re-screened after appropriate treatment; Severe systemic disease (i.e. uncompensated diabetes); Stenosis or retraction secondary to medical conditions other than hypospadias failure (i.e. radiotherapy, lichen sclerosis, etc…); Allergy, sensitivity or intolerance to drugs or excipients (hypersensitivity to any of the excipients listed in Investigator's brochure or in this protocol): Transport medium (Dulbecco's Modified Eagles Medium supplemented with L-glutamine) Fibrin support; Contraindications to the post- treatment local or systemic antibiotics and/or corticosteroids; UTI or urine culture positive requiring a re-screening of patient; Contraindications to undergo extensive surgical procedures; Clinically significant or unstable concurrent disease or other clinical contraindications to stem cell implantation based on investigator's judegment or other concomitant medical conditions affecting grafting procedure; Patients and parents/tutor unlikely to comply with the study protocol or unable to understand the nature and scope of the study or the possible benefits or unwanted effects of the study procedures and treatments; Participation in another clinical trial where conventional investigational drug was received less than 1 months prior to screening visit; Patients who received surgical procedure within 6 months prior to screening visit; Anaesthesia or severe hypoesthesia of the area; Diagnosis of local or systemic neoplastic disease.

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 17 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: Urethral reduced functionality and/or lesions due to previous hypospadias treatment failure<br>The first step consists in a small oral mucosa biopsy collection by surgeon under general anaesthesia. The biopsy will be processed in a laboratory of a regenerative medicine manufacturing site where the epithelial cells will be isolated, expanded and prepared as final graft to be implanted. The treatment for urethra reconstruction required a two stage urethroplasty: First stage: application of Holour on the wound bed prepared according to standard surgery The penis will be immobilized for some days after this operation. Second stage: surgical procedure for urethral tubularization and penile reconstruction according to standard surgical procedure. The surgical procedures may be followed by a post-implantation treatment (if necessary) with corticosteroids and antibiotics. | Drug: Ex vivo expanded autologous human oral epithelium containing stem cells<br>* The treatment includes a single administration of investigational product through a dedicated surgical procedure of penis wound bed preparation, epithelial surface adaption and product application followed by urethra tubularization and penis reconstruction.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number and percentage of patients experiencing AESI | To demonstrate the safety of Holour in terms of AESI (persistent fever, infections) | 3 months after treatment | 
| Number and percentage of patients experiencing ADRs | To demonstrate the safety of Holour in terms of ADRs | 3 months after treatment | 
| Number and percentage of patients experiencing SAEs | To demonstrate the safety of Holour in terms of SAEs | 3 months after treatment | 
| Number and percentage of patients experiencing Serious ADRs | To demonstrate the safety of Holour in terms of Serious ADRs | 3 months after treatment | 
| Number and percentage of patients experiencing AESI | To demonstrate the safety of Holour in terms of AESI (persistent fever, infections) | 12 months after treatment | 
| Number and percentage of patients experiencing ADRs | To demonstrate the safety of Holour in terms of AESI ADRs | 12 months after treatment | 
| Number and percentage of patients experiencing SAEs | To demonstrate the safety of Holour in terms of SAEs | 12 months after treatment | 
| Number and percentage of patients experiencing Serious ADRs | To demonstrate the safety of Holour in terms of Serious ADRs | 12 months after treatment | 
| Number of patients with implantation success | Implantation success is defined on the basis of the degree of clinical (no lesions, no significant retractions) epithelial stability on the transplanted area. The degree of epithelial stability will be evaluated by visual inspection, cistouretrography, uretroscophy and checked for evaluating reepithelialization, erosions, infection, etc. and documented with photos with measures. | 12 months after treatment | 
| percentage of patients with implantation success | Implantation success is defined on the basis of the degree of clinical (no lesions, no significant retractions) epithelial stability on the transplanted area. The degree of epithelial stability will be evaluated by visual inspection, cistouretrography, uretroscophy and checked for evaluating reepithelialization, erosions, infection, etc. and documented with photos with measures. | 12 months after treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with the treatment efficacy after Holour implantation and surgical reconstruction | Regeneration of a clinically normal appearing urethra epithelium with absence of detectable erosions/retractions and Clinical functionality (uroflowmetry) after the second step (urethral reconstruction) of transplant. | up to 1 year after implantation | 
| Evaluation of the percentage of re-epithelialization | Evaluation of the percentage of re-epithelialization | up to 1 year after implantation | 
| Evaluation of the clinical epithelial stability on the transplanted area by visual inspections | Evaluation of the regeneration of a clinically normal appearing epithelium with absence of detectable erosions/retractions | up to 1 year after implantation | 
| Evaluation of scar retraction presence | Evaluation of the penile retraction due to presence/absence of scars | up to 1 year after implantation | 
| Evaluation of uroflowmetry rate | Evaluation of the change of uroflowmetry compared to the baseline value with change of the curve shape and significant increase of the qmax flow rate; | From 3 to 12 months after the treatment | 
| Evaluation of the post-void residual volume through uroflowmetry | Evaluation of the change of the post-void residual compared to the baseline | From 3 to 12 months after the treatment | 
| Evaluation of the presence and severity of surgical complications | Presence and severity of surgical complications using the Clavien Dindo scale with the classification into 5 grades (I, II, III, IV and V from no need for clinical intervention to the death of the patient) | up to 1 year after implantation | 
| Evaluation of the adeverse events in terms of SAEs, AESI, ADR Serious ADRs, | Evaluation of the adeverse events in terms of SAEs, AESI, ADR Serious ADRs, | up to 1 year after implantation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hypospadias treatment failure, Urethral reconstruction, Cell therapy, Stem cells