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

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

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.

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:

1. Oral mucosa biopsy to manufacture autologous grafts of Holour.

2. 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.

Inclusion Criteria:

1. 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;
2. Male patients between 5 and 17 years old (less than 18 years old);
3. Need for urethroplasty in failed hypospadias treatment;
4. Hypospadias complications shown by clinical evaluation, uroflowmetry with post-micturition residual evaluation and/or retrograde urethrography and/or urethroscopy;
5. Uroflowmetry rate: Uroflowmetry with a plateau-shaped curve and low qmax according to paediatric uroflow normograms;
6. Absence of other contraindications to HOLOUR implantation based on investigator's judgement;
7. A cooperative attitude to follow up the study procedures (Caregivers in case of minors).

Exclusion Criteria:

1. Known or suspected intolerances against anaesthesia;

2. Bad general condition (ECOG index >2);

3. 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;

4. Severe systemic disease (i.e. uncompensated diabetes);

5. Stenosis or retraction secondary to medical conditions other than hypospadias failure (i.e. radiotherapy, lichen sclerosis, etc…);

6. 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;

7. Contraindications to the post- treatment local or systemic antibiotics and/or corticosteroids;

8. UTI or urine culture positive requiring a re-screening of patient;

9. Contraindications to undergo extensive surgical procedures;

10. 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;

11. 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;

12. Participation in another clinical trial where conventional investigational drug was received less than 1 months prior to screening visit;

13. Patients who received surgical procedure within 6 months prior to screening visit;

14. Anaesthesia or severe hypoesthesia of the area;

15. Diagnosis of local or systemic neoplastic disease.