Safety and Efficacy of a Unilateral Subretinal Administration of HORA-PDE6B in Patients Harboring Mutations in the PDE6B Gene Leading to a Defect in PDE6B Expression.

• Register: EUCTR
• Last refreshed on: 16 October 2017
• Main ID: EUCTR2016-001429-16-FR
• Date of registration: 12/09/2017
• Prospective Registration: No
• Primary sponsor: HORAMA SA
• Public title: Safety and Efficacy of a Unilateral Subretinal Administration of HORA-PDE6B in Patients Harboring Mutations in the PDE6B Gene Leading to a Defect in PDE6B Expression.
• Scientific title: Safety and Efficacy of a Unilateral Subretinal Administration of HORA-PDE6B in Patients Harboring Mutations in the PDE6B Gene Leading to a Defect in PDE6B Expression.
• Date of first enrolment: 28/07/2017
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-001429-16
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: no Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: yes Other specify the comparator: different doses of the same product Number of treatment arms in the trial: 3
• Phase: Human pharmacology (Phase I): yes Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

France

Contacts

• Name: Chief Medical Officer
• Affiliation: HORAMA SA

• Name: Chief Medical Officer
• Affiliation: HORAMA SA

Key inclusion & exclusion criteria

Inclusion criteria:
1. Patients with Retinitis Pigmentosa caused by defect in PDE6B gene without other syndromic manisfestations.
2. The phenotypic clinical status must be established by:
a. Disease history,
b. Presence of characteristic features of retinitis pigmentosa in fundus
c. Reduction of both rod and cone ERG responses in full field ERG, with predominance of rod involvement, and relative preservation of ERG responses of the fovea in multifocal ERG
d. Visual acuity = 0.32 for cohort 1 and = 0.63 for cohorts 2 and 3
3. Each patient will then be genotyped even if a genotyping has already been previously performed.
4. Each patient will give his/her informed consent, after having been counselled by the investigator, particularly on the high number of visits and on the requirement of hospitalization. For a minor, the investigator will explain the objectives and the course of the clinical trial in order to obtain his/her assent using understandable words appropriate to the age of the child. In total agreement with the decision of the child, the parents will be consecutively asked to sign the informed consent form.
5. Patients (male or female) with RP aged from 18 years old for the first and second cohorts
6. Patients (male or female) with RP aged from 6 years old for the third cohort.
7. Patients still having a residual central retinal function that allows ambulation.
8. For women with childbearing potential, a negative urine pregnancy test at screening (Visit 1/Day-120 to Day-7) and at visit 2 (Day -1. Women with childbearing potential (i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile) must be using a highlyan effective method of contraception (i.e. combined (estrogen and progestogen containing) hormonal/ progestogen-only hormonal contraception associated with inhibition of ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomised partner, sexual abstinence. The patient will be requested to continue the contraception for six months after surgery (Visit 9/Day 180)
9. For males of reproductive potential, agreement to use effective contraception for 6 months after administration of the IMP, for sexual activity that could lead to pregnancy.
10. Patient affiliated to a health security system

Are the trial subjects under 18? yes
Number of subjects for this age range: 6
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 6
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
Exclusion criteria related to co-morbidities
1. Patients with chronic conditions such as haematological, cardiac, renal diseases.
2. Patients with, within the past 6 months, a clinically significant cardiac disease on routine clinical examination (history, physical examination), or known congestive heart failure, myocardial infarction, clinically significant valvular heart disease, clinically significant cardiac rhythm or conduction abnormalities, uncontrolled or unstable hypertension.
3. Patients with pulmonary dysfunction or severe obstructive pulmonary disease that, in the investigator’s judgment, could interfere with the study participation and completion.
4. Patients with suspected rheumatoid arthritis or any other systemic autoimmune disease.
5. Patients with active cancer or patients currently undergoing therapy for cancer.
6. Patients with unstable endocrine disease, including unstable diabetes or thyroid disease.
7. Patients with alanine transaminase (ALAT), aspartate transaminase (ASAT), or gamma-glutamyl transferase (GGT) > 3x upper limit of normal.
8. Patients with severe anaemia (haemoglobin < 6 g/dL), leukopenia (while blood cell count <2500/mm3), thrombocytopenia (platelet count < 80.000/mm3), polycytemia (haematocrit> 54% (male) or haematocrit > 49% (female)) or clinically significant coagulopathy.
Exclusion criteria related to infections or immune-suppression
9. Patients with known history or clinical diagnosis of herpes zoster or varicella infection within 6 weeks before recruitment or chicken pox exposure within 21 days before recruitment.
10. Patients with current systemic infection.
11. Patients with active, extraocular infection requiring the prolonged or chronic use of antimicrobial agents.
12. Patients with seropositivity for human immunodeficiency virus, Ag-HBS >0, PCR-HCV >0.
13. Patients using a therapy 3 months before the recruitment that would likely affect immune responses or interfere with trial logistics (steroidal, non-steroidal anti-inflammatory, immunosuppressive and immune-modulatory drugs).
14. Patients receiving an anti-viral drug treatment 3 months before the recruitment.
15. Patients receiving a treatment based on a non-specific phosphodiesterase inhibitor 3 months before the recruitment.
16. Patients participating in another clinical trial with an investigational agent in the 30 days prior to the study participation and/or has not recovered from any reversible effects or side effects prior investigational agent.
17. Patients enrolled or being enrolled in another gene therapy clinical trial.
18. Patients with any non-ocular, medically significant co-morbid conditions that impair normal activities, require immunosuppression, or any medical condition that would likely have an impact on the participant’s ability to comply with the study schedule.
19. Recipients of a solid organ transplant.
20. Patients currently pregnant or lactating.
21. Patients with any current or history of substance abuse, psychiatric disorder or a condition that, in the opinion of the investigator, would jeopardize the safety of the subject or impact the validity of the study results.
Ophthamology-related exclusion criteria
22. Patients with “monopthalme” (monovisual capacity).
23. Patients with previous ocular surgery or thermal laser within the past 6 months.
24. Patients with previous ocular treatment for retinal disease within the past 6 months.
25. Patients with other ocular pathology, glaucoma, high myopia (> 6 diopte

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Eye Diseases [C11]

Retinitis Pigmentosa

Intervention(s)

Product Code: HORA-PDE6B (AAV2/5.hPDE6B)
Pharmaceutical Form: Solution for injection

Primary Outcome(s)

Primary end point(s): Primary endpoints will be the assessment of safety parameters : routine ophtalmologic examination, intraocular inflammation, chorioretinal tolerance, questionnaire, vital signs, laboratory measurements

Secondary Objective: Secondary objectives of this trial are to assess:
- Efficacy of a unilateral subretinal administration of HORA-PDE6B;
- Putative humoral and cellular immunological responses following a unilateral subretinal administration of HORA-PDE6b.

Main Objective: To assess the safety of a unilateral subretinal administration of HORA-PDE6B in patients harboring mutations in the pde6b gene leading to a defect in PDE6ß expression.

Timepoint(s) of evaluation of this end point: all visits

Secondary Outcome(s)

Secondary end point(s): Assessment of improvement of functional tests:
- A self evaluation of amelioration of quality of life
- Visual acuity and refraction

Assessment of improvement of morphologic tests:
• fundus autofluorescence
• immunological parameters

Exploratory endpoints: functional magnetic resonance imaging (fMRI)

Timepoint(s) of evaluation of this end point: Visit 2 and from from visit 6 to the last visit

Secondary ID(s)

HORA-PDE6B-001

Source(s) of Monetary Support

HORAMA SA