Clinical Trial Results:
An open label, multi-centre, Phase I/II dose escalation trial of a recombinant adeno-associated virus vector (AAV5-hRKp.RPGR) for gene therapy of adults and children with X-linked Retinitis Pigmentosa owing to defects in Retinitis Pigmentosa GTPase Regulator (RPGR)
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Summary
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EudraCT number |
2016-003967-21 |
Trial protocol |
GB Outside EU/EEA |
Global end of trial date |
18 Nov 2021
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Results information
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Results version number |
v1(current) |
This version publication date |
15 Dec 2022
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First version publication date |
15 Dec 2022
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
MGT009
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03252847 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
MeiraGTx UK II Ltd
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Sponsor organisation address |
92 Britannia Walk, London, United Kingdom, N1 7NQ
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Public contact |
Gwen Vanneste, MeiraGTx UK II Ltd, Gwen.Vanneste@meiragtx.com
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Scientific contact |
Robert Zeldin, MeiraGTx UK II Ltd, Robert.Zeldin@meiragtx.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-002827-PIP01-20 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
18 Mar 2022
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
18 Nov 2021
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Global end of trial reached? |
Yes
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Global end of trial date |
18 Nov 2021
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The primary research objective is to assess the safety of AAV5-hRKp.RPGR for RGPR-ORF15 gene replacement in the retina of patients with RPGR X-linked Retinitis Pigmentosa (XLRP).
Safety is defined as the absence of an Advanced Therapy Investigational Medicinal Product (ATIMP)-related reduction in visual acuity by 15 Early Treatment Diabetic Retinopathy Study (ETDRS) letters or more, severe unresponsive inflammation, infective endophthalmitis, ocular malignancy and grade III or above non-ocular Suspected Unexpected Serious Adverse Reaction (SUSAR).
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Protection of trial subjects |
Only participants who met the study entry criteria were enrolled in the study. All participants were free to withdraw from the study at any time for any reason. All participants were closely monitored throughout the study. Safety was evaluated based on adverse events (including dose-limiting events), clinical laboratory assessments, vital sign measurements, and physical examinations for the 12-month duration of the study. In addition, participants in Study MGT009 were encouraged to join the long-term follow-up safety study MGT010 (up to 5 years after the intervention).
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
31 Jul 2017
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety, Regulatory reason | ||
Long term follow-up duration |
12 Months | ||
Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 31
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Country: Number of subjects enrolled |
United States: 14
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Worldwide total number of subjects |
45
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EEA total number of subjects |
0
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
1
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Adolescents (12-17 years) |
2
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Adults (18-64 years) |
42
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
Participants were recruited from a total of 5 sites, 2 sites in the United Kingdom (UK) and 3 sites in the United States (US). | ||||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
n/a | ||||||||||||||||||||||||||||||
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Period 1
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Period 1 title |
Overall (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||||||||||||||
Blinding implementation details |
Participants were enrolled in the dose escalation phase, the dose confirmation phase (paediatric participants), or the randomized expansion phase of this open-label study. Participants in the dose escalation phase and the dose confirmation phase were not randomized. Participants enrolled in the expansion phase were randomized to immediate treatment or deferred treatment. Treatment assignment was not blinded.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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immediate low dose group | ||||||||||||||||||||||||||||||
Arm description |
Participants in this group received the low dose of AAV5-hRKp.RPGR in one eye in either the dose escalation phase or the expansion phase of the study | ||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
AAV5-hRKp.RPGR
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Intraocular use
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Dosage and administration details |
AAV5-hRKp.RPGR solution is administered by intraocular injection into the subretinal space.
In the dose escalation and dose confirmation phases, AAV5-hRKp.RPGR was administered to the worse-seeing eye as identified by the participant and investigator, taking into consideration ocular dominance and visual acuity. In the expansion phase of the study, AAV5-hRKp.RPGR was administered to 1 randomized eye.
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Arm title
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immediate intermediate dose group | ||||||||||||||||||||||||||||||
Arm description |
Participants in this group received the intermediate dose of AAV5-hRKp.RPGR in one eye in either the dose escalation phase, dose confirmation phase or expansion phase of the study | ||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
AAV5-hRKp.RPGR
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Intraocular use
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Dosage and administration details |
AAV5-hRKp.RPGR solution is administered by intraocular injection into the subretinal space.
In the dose escalation and dose confirmation phases, AAV5-hRKp.RPGR was administered to the worse-seeing eye as identified by the participant and investigator, taking into consideration ocular dominance and visual acuity. In the expansion phase of the study, AAV5-hRKp.RPGR was administered to 1 randomized eye.
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Arm title
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immediate high dose group | ||||||||||||||||||||||||||||||
Arm description |
Participants in this group received the high dose of AAV5-hRKp.RPGR in one eye in the dose escalation phase. | ||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
AAV5-hRKp.RPGR
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Intraocular use
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Dosage and administration details |
AAV5-hRKp.RPGR solution is administered by intraocular injection into the subretinal space.
In the dose escalation and dose confirmation phases, AAV5-hRKp.RPGR was administered to the worse-seeing eye as identified by the participant and investigator, taking into consideration ocular dominance and visual acuity. In the expansion phase of the study, AAV5-hRKp.RPGR was administered to 1 randomized eye.
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Arm title
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deferred group (prior to treatment) | ||||||||||||||||||||||||||||||
Arm description |
Treatment of participants in this group was deferred for 6 months | ||||||||||||||||||||||||||||||
Arm type |
No intervention | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
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Baseline characteristics reporting groups
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Reporting group title |
immediate low dose group
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Reporting group description |
Participants in this group received the low dose of AAV5-hRKp.RPGR in one eye in either the dose escalation phase or the expansion phase of the study | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
immediate intermediate dose group
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Reporting group description |
Participants in this group received the intermediate dose of AAV5-hRKp.RPGR in one eye in either the dose escalation phase, dose confirmation phase or expansion phase of the study | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
immediate high dose group
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Reporting group description |
Participants in this group received the high dose of AAV5-hRKp.RPGR in one eye in the dose escalation phase. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
deferred group (prior to treatment)
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Reporting group description |
Treatment of participants in this group was deferred for 6 months | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Safety Analysis Set
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Subject analysis set type |
Safety analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Includes all participants who enrolled and received treatment in the study (as treated).
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End points reporting groups
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Reporting group title |
immediate low dose group
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Reporting group description |
Participants in this group received the low dose of AAV5-hRKp.RPGR in one eye in either the dose escalation phase or the expansion phase of the study | ||
Reporting group title |
immediate intermediate dose group
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Reporting group description |
Participants in this group received the intermediate dose of AAV5-hRKp.RPGR in one eye in either the dose escalation phase, dose confirmation phase or expansion phase of the study | ||
Reporting group title |
immediate high dose group
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Reporting group description |
Participants in this group received the high dose of AAV5-hRKp.RPGR in one eye in the dose escalation phase. | ||
Reporting group title |
deferred group (prior to treatment)
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Reporting group description |
Treatment of participants in this group was deferred for 6 months | ||
Subject analysis set title |
Safety Analysis Set
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
Includes all participants who enrolled and received treatment in the study (as treated).
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End point title |
The primary safety outcome was defined as absence of any of the below occurring during the 9 weeks following administration, at least possibly related to AAV5-hRKp.RPGR, not surgery alone [1] | ||||||||||||||||||
End point description |
The primary safety outcome was defined as absence of any of the below occurring during the 9 weeks following administration, at least possibly related to AAV5-hRKp.RPGR, not surgery alone:
• Reduction in visual acuity by 15 ETDRS letters or more
• Severe unresponsive inflammation
• Infective endophthalmitis
• Ocular malignancy
• Grade III or above non-ocular suspected unexpected serious adverse reaction (SUSAR)
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End point type |
Primary
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End point timeframe |
Within 9 weeks following administration of AAV5-hRKp.RPGR
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was performed on the primary endpoint. The analysis was descriptive. |
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| Notes [2] - The primary endpoint was analyzed for participants in the dose escalation phase only. |
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| No statistical analyses for this end point | |||||||||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Data from Immediate-treatment participants are included from signing of ICF until their 12-month visit. Data of deferred-treatment participants are included from signing of ICF until the time of surgery (i.e., control group).
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Adverse event reporting additional description |
There were 3 SAEs (all non-fatal) reported during the study, 2 in the immediate treatment group (preferred terms retinal detachment and uveitis), and 1 in the deferred treatment group (preferred term intraocular pressure increased).
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
24.1
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Reporting groups
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Reporting group title |
Total
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Reporting group description |
Data from Immediate-treatment participants are included from signing of ICF until their 12-month visit. Data of deferred-treatment participants are included from signing of ICF until the time of surgery. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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10 Mar 2017 |
To incorporate the flow chart for the dose escalation, dose of drugs used at the time of administration of AAV5-hRKp.RPGR and reconsenting the children as they progress through the age brackets. |
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12 Apr 2017 |
To extend the course of post-surgery prophylactic steroids from 4 weeks to 8 weeks. Consequently, the duration for considering dose-limiting events was extended from 6 weeks to 9 weeks to cover the period of steroid administration and one additional week and other minor clarifications. |
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25 May 2017 |
To add 2 additional exclusion criteria, and to refer to a barrier and spermicide form of contraception, rather than double barrier method and also to clarify that only males should have been included in the study. |
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13 Nov 2017 |
To update the medium and high dose, to reduce the gap between participant 1 and 2/3 in a cohort from 9 weeks to 4 weeks, to update the prophylactic post-administrative steroid regimen in children, and to clarify safety reporting and confirmatory safety dose for children.
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27 Feb 2018 |
To clarify the allowance of data obtained from the natural history study be used for screening and or baseline assessments (with consent from participants) in order to avoid unnecessary testing of participants and to clarify that more than 1 surgeon at a site may inject vector.
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11 Feb 2019 |
To include a randomized component to the expansion phase of the study, to include further QOL measurement tool, to reduce the follow-up from 18 to 12 months and to include an Interim Analysis at 3- and 6-months post-treatment for patients in the low/intermediate dose treatment arms of the randomized component of the study.
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09 Aug 2019 |
To amend and clarify the inclusion and exclusion criteria for the study. To remove FST at all assessments and to remove ERG at screening to reduce the assessment burden on patients. To add Low Luminance Visual Acuity testing and include additional Patient-Reported Outcome measures, to add a Clinician-Reported Outcome measure and include Treatment Experience interviews. To correct minor errors in the Patient Visit Schedule.
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22 Jun 2020 |
To include guidance on the management of patients during COVID 19 pandemic, to update wording on steroid risks and local steroid use and to correct minor errors.
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
