Gene Therapy for X-linked Retinitis Pigmentosa (XLRP) - Retinitis Pigmentosa GTPase Regulator (RPGR)

An Open Label, Multi-centre, Phase I/II Dose Escalation Trial of a Recombinant Adeno-associated Virus Vector (AAV2/5-hRKp.RPGR) for Gene Therapy of Adults and Children With X-linked Retinitis Pigmentosa Owing to Defects in Retinitis Pigmentosa GTPase Regulator (RPGR)

Status

Completed

Phases

Phase 1Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03252847

Enrollment

Registered

2017-08-17

Start date

2017-07-31

Completion date

2021-11-18

Last updated

2025-01-08

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

X-Linked Retinitis Pigmentosa

Keywords

XLRP RPGR

Brief summary

Phase 1 of the study is a dose escalation of the subretinal administration of AAV5-hRKp.RPGR vector to assess the safety of this vector in participants with XLRP caused by mutations in RPGR. Participants enrolled in Phase 1 were assigned to a dose group based on when they enrolled (i.e., sequential assignment). Phase 2 of the study is a cohort expansion of the subretinal administration of AAV5-hRKp.RPGR vector to assess the safety and efficacy of this vector in participants with XLRP caused by mutations in RPGR. Participants enrolled in Phase 2 were randomized to immediate or deferred treatment.

Detailed description

This is an open-label phase 1/2 dose-escalation and cohort expansion trial to determine the safety and efficacy of subretinal administration of AAV5-hRKp.RPGR vector in participants with XLRP caused by mutations in RPGR.

Interventions

GENETICAAV5-RPGR

Single, subretinal administration of AAV5-RPGR

Study design

Allocation

RANDOMIZED

Intervention model

SEQUENTIAL

Primary purpose

TREATMENT

Masking

NONE

Intervention model description

Biological

Eligibility

Sex/Gender

MALE

Age

5 Years to No maximum

Healthy volunteers

Inclusion criteria

Key inclusion Criteria: * Males aged 5 years or older * Have X-linked retinitis pigmentosa confirmed by a retinal specialist (CI or PI) Key

Exclusion criteria

• Have participated in another research study involving an investigational medicinal therapy for ocular disease within the last 6 months

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants Meeting the Primary Outcome Defined as Any of the Below Events Occurring During the 9 Weeks Following Administration, at Least Possibly Related to the Advanced Therapy Investigational Medicinal Product (ATIMP), Not Surgery Alone.	9 weeks	The primary outcome is defined as any of the below occurring during the 9 weeks following administration, at least possibly related to the Advanced Therapy Investigational Medicinal Product (ATIMP), not surgery alone: * Reduction in visual acuity by 15 Early Treatment Diabetic Retinopathy Study (ETDRS) letters or more * Severe unresponsive inflammation * Infective endophthalmitis * Ocular malignancy * Grade III or above non-ocular Suspected Unexpected Serious Adverse Reaction (SUSAR)

Secondary

Measure	Time frame	Description
Improvements in Retinal Function as Assessed by Static Perimetry	Baseline and Month 6	The number of responders in point-by-point data in Static Perimetry within the full visual field over time. A responder at a single time point is defined as a participant with at least 5 of the same loci with ≥7 dB improvement from baseline at the specific time point and one time point prior.
Quality of Life Measured by the Low Luminance Questionnaire (LLQ) Emotional Distress Domain Score	Baseline and Month 6	Change from baseline to Week 26 in LLQ Emotional Distress Domain Score in adults. LLQ uses a scale from 0 to 100, with higher scores reflecting less impairment. A positive change from baseline reflects improvement, and a negative reflects worsening.
Quality of Life Measured by the Low Luminance Questionnaire (LLQ) Extreme Lighting Domain Score	Baseline and Month 6	Change from baseline to Week 26 in LLQ Extreme Lighting Domain Score in adults. LLQ uses a scale from 0 to 100, with higher scores reflecting less impairment. A positive change from baseline reflects improvement, and a negative reflects worsening.
Improvements in Visual Function as Assessed by Visual Acuity	Baseline and Month 6	Change from baseline to Week 26 in best corrected visual acuity (BCVA) using Early Treatment Diabetic Retinopathy Study (ETDRS) chart letter score. The direction of improvement from baseline is an increase in the number of ETDRS letters read over time.
Quality of Life Measured by the Low Luminance Questionnaire (LLQ) Mobility Domain Score	Baseline and Month 6	Change from baseline to Week 26 in LLQ Mobility Domain Score in adults. LLQ uses a scale from 0 to 100, with higher scores reflecting less impairment. A positive change from baseline reflects improvement, and a negative reflects worsening.
Quality of Life Measured by the Low Luminance Questionnaire (LLQ) Peripheral Vision Domain Score	Baseline and Month 6	Change from baseline to Week 26 in LLQ Peripheral Vision Domain Score in adults. LLQ uses a scale from 0 to 100, with higher scores reflecting less impairment. A positive change from baseline reflects improvement, and a negative reflects worsening.
Quality of Life Measured by the Low Luminance Questionnaire (LLQ) General Dim Lighting Domain Score	Baseline and Month 6	Change from baseline to Week 26 in LLQ General Dim Lighting Domain score in adults. LLQ uses a scale from 0 to 100, with higher scores reflecting less impairment. A positive change from baseline reflects improvement, and a negative reflects worsening.

Countries

United Kingdom, United States

Participant flow

Recruitment details

Participants were recruited from 5 sites (2 in the UK and 3 in the US) between 31 Jul 2017 and 18 Nov 2021. 49 participants were enrolled in the study; 4 participants discontinued before receiving treatment. The study consisted of 2 phases: dose escalation (Phase 1) followed by dose expansion (Phase 2). In Phase 1, 13 participants enrolled in 1 of 3 treatment groups. In Phase 2, 36 participants were randomized to an active treatment arm or a control arm with treatment deferred for 6 months.

Participants by arm

Arm	Count
Immediate Low Dose AAV5-hRKp.RPGR Subretinal administration of a single low dose of AAV5-hRKp.RPGR in either Phase 1 or Phase 2 of the study (prespecified pooling). AAV5-hRKp.RPGR: AAV gene therapy for defects in the RPGR gene	11
Immediate Intermediate Dose AAV5-hRKp.RPGR Subretinal administration of a single intermediate dose of AAV5-hRKp.RPGR in either Phase 1 or Phase 2 of the study (prespecified pooling). AAV5-hRKp.RPGR: AAV gene therapy for defects in the RPGR gene	17
Immediate High Dose AAV5-hRKp.RPGR Subretinal administration of a single high dose of AAV5-hRKp.RPGR in either Phase 1 or Phase 2 of the study (prespecified pooling). AAV5-hRKp.RPGR: AAV gene therapy for defects in the RPGR gene	4
Deferred Group Treatment of participants in this Phase 2 study group was deferred for 6 months	13
Total	45

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003	FG004	FG005	FG006
Overall Study	Other: Patient decision	0	0	0	0	1	0	0
Overall Study	Withdrawal by Subject	0	0	1	0	0	0	0

Baseline characteristics

Characteristic	Immediate Low Dose AAV5-hRKp.RPGR	Immediate Intermediate Dose AAV5-hRKp.RPGR	Immediate High Dose AAV5-hRKp.RPGR	Deferred Group	Total
Age, Categorical <=18 years	0 Participants	3 Participants	0 Participants	0 Participants	3 Participants
Age, Categorical >=65 years	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical Between 18 and 65 years	11 Participants	14 Participants	4 Participants	13 Participants	42 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants	1 Participants	0 Participants	2 Participants	3 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	11 Participants	16 Participants	4 Participants	11 Participants	42 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	0 Participants	0 Participants	1 Participants	0 Participants	1 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants	2 Participants	0 Participants	0 Participants	3 Participants
Race (NIH/OMB) White	10 Participants	15 Participants	3 Participants	13 Participants	41 Participants
Region of Enrollment United Kingdom	8 participants	12 participants	3 participants	8 participants	31 participants
Region of Enrollment United States	3 participants	5 participants	1 participants	5 participants	14 participants
Sex: Female, Male Female	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Sex: Female, Male Male	11 Participants	17 Participants	4 Participants	13 Participants	45 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk	EG005 affected / at risk
deaths Total, all-cause mortality	0 / 11	0 / 17	0 / 4	0 / 13	0 / 7	0 / 6
other Total, other adverse events	11 / 11	17 / 17	4 / 4	1 / 13	7 / 7	6 / 6
serious Total, serious adverse events	2 / 11	0 / 17	0 / 4	0 / 13	1 / 7	0 / 6

Outcome results

Primary

Number of Participants Meeting the Primary Outcome Defined as Any of the Below Events Occurring During the 9 Weeks Following Administration, at Least Possibly Related to the Advanced Therapy Investigational Medicinal Product (ATIMP), Not Surgery Alone.

The primary outcome is defined as any of the below occurring during the 9 weeks following administration, at least possibly related to the Advanced Therapy Investigational Medicinal Product (ATIMP), not surgery alone: * Reduction in visual acuity by 15 Early Treatment Diabetic Retinopathy Study (ETDRS) letters or more * Severe unresponsive inflammation * Infective endophthalmitis * Ocular malignancy * Grade III or above non-ocular Suspected Unexpected Serious Adverse Reaction (SUSAR)

Time frame: 9 weeks

Population: The primary endpoint was analyzed for participants in the dose escalation phase (i.e., study Phase 1) only

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Immediate Low Dose AAV5-hRKp.RPGR	Number of Participants Meeting the Primary Outcome Defined as Any of the Below Events Occurring During the 9 Weeks Following Administration, at Least Possibly Related to the Advanced Therapy Investigational Medicinal Product (ATIMP), Not Surgery Alone.	0 Participants
Immediate Intermediate Dose AAV5-hRKp.RPGR	Number of Participants Meeting the Primary Outcome Defined as Any of the Below Events Occurring During the 9 Weeks Following Administration, at Least Possibly Related to the Advanced Therapy Investigational Medicinal Product (ATIMP), Not Surgery Alone.	0 Participants
Immediate High Dose AAV5-hRKp.RPGR	Number of Participants Meeting the Primary Outcome Defined as Any of the Below Events Occurring During the 9 Weeks Following Administration, at Least Possibly Related to the Advanced Therapy Investigational Medicinal Product (ATIMP), Not Surgery Alone.	0 Participants
Deferred Group	Number of Participants Meeting the Primary Outcome Defined as Any of the Below Events Occurring During the 9 Weeks Following Administration, at Least Possibly Related to the Advanced Therapy Investigational Medicinal Product (ATIMP), Not Surgery Alone.	0 Participants

Secondary

Improvements in Retinal Function as Assessed by Static Perimetry

The number of responders in point-by-point data in Static Perimetry within the full visual field over time. A responder at a single time point is defined as a participant with at least 5 of the same loci with ≥7 dB improvement from baseline at the specific time point and one time point prior.