E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Retinitis Pigmentosa |
Rétinite pigmentaire |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Eye Diseases [C11] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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 PDE6β expression. |
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E.2.2 | Secondary objectives of the trial |
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. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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
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E.4 | Principal 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 diopters), previous retinal detachment, diabetic retinopathy. 26. Patients with chronic ocular hypotony (less than 6 mmHg). 27. Patients with lens opacities or obscured ocular media upon recruitment such reliable evaluation or grading of the posterior segment cannot be performed. 28. Patients with known serious allergies to the fluorescein dye used in angiography, to the mydriatic, steroidal and non-steroidal eye drops. 29. Patients who received a vaccination during the month before recruitment and patients who will receive a vaccination within 6 months after recruitment. 30. Patients who received an anti-acneic medication containing retinoid. 31. Patients under guardianship, curatorship or legal safeguard.
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E.5 End points |
E.5.1 | 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
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | 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)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Visit 2 and from from visit 6 to the last visit |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | Yes |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
different doses of the same product |
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E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |