|E.1 Medical condition or disease under investigation
|Medical condition(s) being investigated
|X-Linked Retinitis Pigmentosa caused by mutations in the RPGR gene
|Medical condition in easily understood language
|Progressive reduction in vision, starting with night blindness and progressing to visual field constriction, caused by mutations on Chromosome X (RPGR gene).
|Diseases [C] - Eye Diseases [C11]
|E.1.2 Medical condition or disease under investigation
|System Organ Class
|10010331 - Congenital, familial and genetic disorders
|Condition being studied is a rare disease
|E.2 Objective of the trial
|Main objective of the trial
|The primary research objective is to assess the safety of AAV2/5-hRKp.RPGR, for RGPR-ORF15 gene replacement in the retina of patients with RPGR XLRP.
Safety is defined as the absence of an ATIMP-related reduction in visual acuity by 15 ETDRS letters or more, severe unresponsive inflammation, infective endophthalmitis, ocular malignancy and grade III or above non-ocular SUSAR.
|Secondary objectives of the trial
|The secondary research objective is to determine whether AAV2/5-hRKp.RPGR for RGPR-ORF15 gene replacement in the retina can slow/halt progressive deterioration in retinal structure or visual function, and improve retinal function, visual function and quality of life in patients with RPGR XLRP.
|Trial contains a sub-study
|Principal inclusion criteria
|Inclusion in the trial will be limited to individuals who meet the following criteria:
1. Are males aged 5 years or older
2. Have X-linked retinitis pigmentosa confirmed by a retinal specialist (CI or PI)
3. Have relatively symmetrical retinal disease - both structurally and functionally defined as < 15 letters [Best Corrected Visual Acuity (BCVA)] difference between eyes
4. Have a predicted disease-causing missense or null mutation in RPGR confirmed in an
5. Evidence of relative preservation of retinal structure at the macula
6. Evidence of impaired navigation in dim illumination on Mobility assessment in both eyes monocularly; defined by either an inability to complete the visual mobility maze at the 1 lux level, or the time taken to complete the maze at either 1 or 4 lux being greater or equal to 12 seconds.
7. Are able to give informed consent or assent, with the guidance of their parent/guardian where appropriate: children aged 5-6 years will not be asked to provide assent
8. Are able to undertake age appropriate clinical assessments at the trial sites as specified in the protocol
9. Are willing to use barrier and spermicide form of contraception or will be sexually abstinent (when this is in line with the participant’s preferred and usual lifestyle) for at least 12 months following ATIMP administration
10. Are willing to give consent for the use of blood and blood components collected through the trial for the investigation of immune responses to the ATIMP
|Principal exclusion criteria
|Individuals will be excluded if they meet any of the following criteria:
1. Have a known allergy to any of the non-investigational drugs to be used in the trial as defined in Section 5.4.1
2. Have participated in another research study involving an investigational medicinal therapy for ocular disease within the last 6 months
3. Have any other condition that the CI/PI considers makes them inappropriate for entry into the trial, inclusive of but not limited to a history of the following:
o Uncontrolled hypertension defined as a systolic value ≥160mmHg or diastolic value ≥100mmHg.
o Uncontrolled diabetes mellitus defined as an HbA1c ≥9% (75mmol/mol) at screening.
o Uncontrolled heart failure (NYHA class II-IV).
o Any history of tuberculosis
o Chronic kidney disease (defined as eGFR ≤60ml/min calculated using Cockroft Gault or MDRD equations.
o Immunocompromised state (including long term immunosuppressant therapy).
o Osteoporosis (defined as presence of 1 or more non-traumatic “fragility” fractures or proven BMD of 2.5SD less than anticipated as demonstrated on DEXA scan).
o Active peptic ulcer disease or uncontrolled gastro-oesophageal reflux. o Severe affective disorder or past history of drug induced psychosis
4. Use of high dose regular non-steroidal anti-inflammatory drugs at the time of screening.
5. Have an ocular or systemic disorder that may preclude subretinal surgery and/or interfere with interpretation of the study results
6. Have had intraocular surgery within 3 months of screening
7. Have recently (within 4 weeks of last dose of concomitant immunosuppressive therapy) received a live vaccine
8. Have a condition that requires glucocorticoid replacement therapy, such as in endocrine diseases, if this would interfere with the immunosuppressive regime.
9. Have known chronic hepatitis B infection as indicated by detectable surface antigen. Entry with negative surface antigens but positive hepatitis core antibody will be allowed however additional monitoring throughout the trial may be required.
10. Are unwilling to consider the possibility of entry into a subsequent longer term follow up study
|E.5 End points
|Primary end point(s)
|The primary outcome is defined as absence of any of the below occurring during the 9 weeks following administration, at least possibly related to the ATIMP, not surgery alone:
Reduction in visual acuity by 15 ETDRS letters or more
Severe unresponsive inflammation
Grade III or above non-ocular SUSAR
|Timepoint(s) of evaluation of this end point
|This endpoint will be evaluated at 1 day, 3 days, 1 week, 2 weeks, 4 weeks, 6 weeks, 9 weeks, 12 weeks, 24 weeks, 9 months, 12 months, and 18 months after subretinal administration of the intervention.
Safety will be assessed for 12 months after the intervention in this study, and a further 4 years in a separate follow on study.
|Secondary end point(s)
|The secondary outcomes are measures of the efficacy of the ATIMP; these will be performed on an individual participant basis and will be descriptive in nature.
- Slowing or halting of progressive deterioration in retinal structure or visual function that is greater than the baseline variation for that test and is sustained for at least 2 consecutive assessments. Slowing or halting of progression over time may be facilitated by comparing identical structural and functional assessments acquired prior to intervention/injection to better determine rate of change over time in this slowly progressive disease #.
#Historical images will be collected wherever possible with written informed consent from the participants
- Any improvements in visual function from baseline that are greater than the baseline variation and are sustained for at least two consecutive assessments.
- Any improvement in retinal function from pre-intervention that is greater than basleine variation and measurable by electrophysiology (pattern ERG, multifocal ERG or full-field ERG).
- Quality of life will be measured by the Impact of Visual Impairment (IVI) questionnaire, the low Luminance Questionnaire (LLQ) and the EQ5D-5L and EQ5D-5Y as appropriate.
|Timepoint(s) of evaluation of this end point
|Secondary endpoints will be evaluated at various time-points between 12 weeks and 18 months after subretinal administration of the intervention.
|E.6 and E.7 Scope of the trial
|Scope of the trial
|Trial type and phase
|Human pharmacology (Phase I)
|First administration to humans
|Other trial type description
|Therapeutic exploratory (Phase II)
|Therapeutic confirmatory (Phase III)
|Therapeutic use (Phase IV)
|E.8 Design of the trial
| Comparator of controlled trial
|Other medicinal product(s)
The trial involves single site in the Member State concerned
| The trial involves multiple sites in the Member State concerned
|The trial involves multiple Member States
|E.8.6 Trial involving sites outside the EEA
|Trial being conducted both within and outside the EEA
|Trial being conducted completely outside of the EEA
|If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
|Trial has a data monitoring committee
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|E.8.9 Initial estimate of the duration of the trial
|In the Member State concerned years
|In the Member State concerned months
|In the Member State concerned days
|In all countries concerned by the trial years
|In all countries concerned by the trial months
|In all countries concerned by the trial days