Clinical Trial Results:
An Open-Label, Single Arm, Multiple Dose, Dose Escalation Study to Evaluate the Safety and Tolerability of QR-110 in Subjects with Leber’s Congenital Amaurosis (LCA) due to c.2991+1655A>G Mutation (p.Cys998X) in the CEP290 Gene
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Summary
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EudraCT number |
2017-000813-22 |
Trial protocol |
BE |
Global end of trial date |
02 Oct 2019
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Results information
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Results version number |
v1(current) |
This version publication date |
14 Mar 2021
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First version publication date |
14 Mar 2021
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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 |
PQ-110-001
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03140969 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
ProQR Therapeutics
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Sponsor organisation address |
Zernikedreef 9 , Leiden, Netherlands, 2333CK
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Public contact |
Lola Tome, ProQR Therapeutics, +31 881667000, Ltome@proqr.com
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Scientific contact |
Lola Tome, ProQR Therapeutics, +31 881667000, Ltome@proqr.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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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 |
21 Oct 2019
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
02 Oct 2019
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Global end of trial reached? |
Yes
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Global end of trial date |
02 Oct 2019
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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 objective of the study is to evaluate the safety and tolerability of QR-110 administered via intravitreal injection (IVT) in subjects with Leber Congenital Amaurosis type 10 (LCA10) due to the c.2991+1655A>G (p.Cys998X) mutation
The secondary objectives of the study were to evaluate the:
• Serum pharmacokinetics of QR-110 administered by IVT injection in subjects with LCA10 due to the c.2991+1655A>G (p.Cys998X) mutation
• Efficacy of QR-110 administered by IVT injection in subjects with LCA10 due to the c.2991+1655A>G (p.Cys998X) mutation
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Protection of trial subjects |
The study was conducted in accordance with ethical principles that have their origin in the Declaration of Helsinki and are consistent with ICH GCP. QR-110 was administered via IVT injection to maximize exposure to study drug at the intended target tissue, the retina. QR-110 was administered in a unilateral manner to the subject’s worse eye, a common practice in the development of ophthalmic products. Following IVT injection of QR-110, subjects were monitored for increases in intraocular pressure (IOP) and signs of inflammation and endophthalmitis during the post-injection period. Subjects were also seen at 1 and 7 days after each injection. If sedation or anesthesia was performed during the administration of the IVT injection, general health monitoring was provided by the study anesthesiologist pre- and post-sedation/anesthesia, according to local institutional guidelines. A Data Monitoring Committee (DMC) was involved to recommend on dose escalation and provided safety oversight for the study.
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Background therapy |
There are currently no approved therapies for the treatment of LCA10. | ||
Evidence for comparator |
No placebo or sham injections were administered. | ||
Actual start date of recruitment |
15 May 2017
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety, Efficacy | ||
Long term follow-up duration |
24 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 |
Belgium: 2
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Country: Number of subjects enrolled |
United States: 9
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Worldwide total number of subjects |
11
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EEA total number of subjects |
2
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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) |
2
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Adolescents (12-17 years) |
3
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Adults (18-64 years) |
6
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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 |
11 subjects were enrolled in this study. The study plan included up to 6 cohorts (3 adult and 3 pediatric). Each planned cohort was to have at least 2 subjects, and each dose level was to be tested in 1 adult cohort and 1 pediatric cohort. | |||||||||
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Pre-assignment
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Screening details |
Key inclusion criteria were: >= 6 years at Screening, a clinical diagnosis of LCA with a molecular diagnosis of homozygosity or compound heterozygosity for the c.2991+1655A>G (p.Cys998X) mutation in the CEP290 gene and a best-corrected visual acuity equal or better than light perception and equal or worse than logMAR +0.6 in the treatment eye | |||||||||
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Period 1
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Period 1 title |
Overall trial (overall period)
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Is this the baseline period? |
Yes | |||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | |||||||||
Blinding implementation details |
No randomization or masking has been used in this study.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Cohort 1: 160/80 μg (loading dose/maintenance dose) | |||||||||
Arm description |
One 160 μg loading dose, followed by up to three 80 μg maintenance doses. | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
QR-110
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Investigational medicinal product code |
QR-110
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Other name |
sepofarsen
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Pharmaceutical forms |
Concentrate for solution for injection
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Routes of administration |
Intravitreal use
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Dosage and administration details |
QR-110 solution for injection, 10 mg/mL. Subjects receive QR-110 by IVT injection.
QR-110 was to be administered once every 3 months for up to 4 doses per subject (ie, an initial loading dose at Day 1, followed by 3 maintenance doses at Month 3, 6 and 9).
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Arm title
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Cohort 2: 320/160 μg (loading dose/maintenance dose) | |||||||||
Arm description |
One 320 μg loading dose, followed by up to three 160 μg maintenance doses. | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
QR-110
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Investigational medicinal product code |
QR-110
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Other name |
sepofarsen
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Pharmaceutical forms |
Concentrate for solution for injection
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Routes of administration |
Intravitreal use
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Dosage and administration details |
QR-110 solution for injection, 10 mg/mL. Subjects receive QR-110 by IVT injection.
QR-110 was to be administered once every 3 months for up to 4 doses per subject (ie, an initial loading dose at Day 1, followed by 3 maintenance doses at Month 3, 6 and 9.).
Following the observed incidence of cataracts and retinal events, the Sponsor decided in consultation with the DMC to stop administration of the 320/160 µg doses, and to prolong the dosing interval for subjects in the 160/80 µg dose group.
While the protocol allowed testing of up to 3 dose levels, no dose escalation was performed to the 500 μg/270 μg dose based on efficacy observations; instead, additional subjects were allocated to the 160 μg/80 μg and 320 μg/160 μg dose cohorts.
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Baseline characteristics reporting groups
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Reporting group title |
Cohort 1: 160/80 μg (loading dose/maintenance dose)
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Reporting group description |
One 160 μg loading dose, followed by up to three 80 μg maintenance doses. | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Cohort 2: 320/160 μg (loading dose/maintenance dose)
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Reporting group description |
One 320 μg loading dose, followed by up to three 160 μg maintenance doses. | ||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Cohort 1: 160/80 μg (loading dose/maintenance dose)
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Reporting group description |
One 160 μg loading dose, followed by up to three 80 μg maintenance doses. | ||
Reporting group title |
Cohort 2: 320/160 μg (loading dose/maintenance dose)
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Reporting group description |
One 320 μg loading dose, followed by up to three 160 μg maintenance doses. | ||
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End point title |
Frequency of Ocular AEs in Treatment Eyes [1] | |||||||||
End point description |
Frequency of all ocular treatment emergent adverse events (TEAEs) in the treatment eyes (ie, treated eyes)
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End point type |
Primary
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End point timeframe |
From baseline until End of Study (12 months)
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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: Incidence and severity of adverse events were summarized descriptively. |
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| No statistical analyses for this end point | ||||||||||
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End point title |
Severity of Ocular AEs [2] | ||||||||||||||||||
End point description |
Number of subjects with mild, moderate or severe ocular treatment emergent adverse events (TEAEs)
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End point type |
Primary
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End point timeframe |
From baseline until End of Study (12 months)
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| Notes [2] - 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: Incidence and severity of adverse events were summarized descriptively. |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Frequency of Ocular AEs in Contralateral Eyes (CE) [3] | |||||||||
End point description |
Frequency of all ocular treatment emergent adverse events (TEAEs) in contralateral eyes (ie, untreated eyes)
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End point type |
Primary
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End point timeframe |
From baseline to End of Study (Month 12)
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| Notes [3] - 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: Incidence and severity of adverse events were summarized descriptively. |
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| No statistical analyses for this end point | ||||||||||
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End point title |
Frequency of non-ocular AEs | |||||||||
End point description |
Frequency of all non-ocular Adverse Events (AEs)
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End point type |
Secondary
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End point timeframe |
From baseline until End of Study (12 months)
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| No statistical analyses for this end point | ||||||||||
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End point title |
Severity of non-ocular AEs | ||||||||||||||||||
End point description |
Number of subjects with mild, moderate or severe non-ocular adverse events (AEs).
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End point type |
Secondary
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End point timeframe |
From baseline until End of Study (12 months)
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
BCVA change from baseline in Treatment Eye (TE) | ||||||||||||
End point description |
Change of BCVA value at Month 12 versus BCVA value at baseline in the treatment eye (= treated eye).
Baseline defined as the average pre-treatment value (ie, the average of Screening and Day 1 [pre-dose] values).
Smaller values are indicative of better status.
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End point type |
Secondary
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End point timeframe |
From baseline until End of study (12 months).
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Red FST Change from Baseline in Treatment Eye (TE) | ||||||||||||
End point description |
Change from Month 12 to baseline in retinal sensitivity in the treatment eye (= treated eye) based on red FST.
Data from 1 subject is missing.
Month 12 data for 1 subject was imputed using LOCF.
Smaller values are indicative of better status.
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End point type |
Secondary
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End point timeframe |
From baseline until End of Study (Month 12)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Blue FST Change from Baseline in Treatment Eye (TE) | ||||||||||||
End point description |
Change from Month 12 to baseline in retinal sensitivity based on blue FST in the treatment eye (= treated eye).
Data from 1 subject is missing.
Month 12 data for 1 subject was imputed using LOCF.
Smaller values are indicative of better status.
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End point type |
Secondary
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End point timeframe |
From Baseline until End of Study (Month 12)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Mobility Course Composite Score Change from Baseline in Treatment Eye (TE) | ||||||||||||
End point description |
Change from Month 12 to baseline in mobility course composite score in the treatment eye (ie, treated eye). The mobility course composite score represents the most difficult course and light level combination passed.
Data from 1 subject is missing.
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End point type |
Secondary
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End point timeframe |
From baseline until End of Study (Month 12)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Red FST Change from Baseline in Contralateral Eye (CE) | ||||||||||||
End point description |
Change from Month 12 to baseline in retinal sensitivity in the untreated contralateral eye, based on red FST.
Data from 1 subject is missing.
Month 12 data for 1 subject was imputed using LOCF.
Smaller values are indicative of better status.
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End point type |
Secondary
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End point timeframe |
From baseline until End of Study (Month 12)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
BCVA change from baseline in Contralateral Eye (CE) | ||||||||||||
End point description |
Change of BCVA value at Month 12 versus BCVA value at baseline in the untreated contralateral eye.
Baseline defined as the average pre-treatment value (ie, the average of Screening and Day 1 [pre-dose] values).
Smaller values are indicative of better status.
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End point type |
Secondary
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End point timeframe |
From baseline to End of Study (12 months)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Blue FST Change from Baseline in Contralateral Eye (CE) | ||||||||||||
End point description |
Change from Month 12 to baseline in retinal sensitivity in the untreated contralateral eye, based on blue FST.
Data from 1 subject is missing.
Month 12 data for 1 subject was imputed using LOCF.
Smaller values are indicative of better status.
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End point type |
Secondary
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End point timeframe |
from baseline until End of Study (Month 12)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Mobility Course Composite Score Change from Baseline in Contralateral Eye (CE) | ||||||||||||
End point description |
Change from baseline to Month 12 in Mobility Course Composite Score in the contralateral eye (ie, untreated eyes). The mobility course composite score represents the most difficult course and light level combination passed.
Data from 1 subject missing.
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End point type |
Secondary
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End point timeframe |
From baseline until End of Study (Month 12)
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Serum pharmacokinetics | ||||||||||||
End point description |
PK calculations were not performed, since all measurements indicated serum levels were below the LLOQ (1.02 ng/mL) following administration of up to 4 doses, except for one subject who had a QR-110 level of 1.53 ng/mL which is slightly above the LLOQ ; this occurred 3 hours after the first (loading) dose of 320 μg and was not observed at subsequent timepoints for PK sampling.
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End point type |
Secondary
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End point timeframe |
Samples for analysis of QR-110 serum concentration were taken pre-dose and 3 hours post-dose on Day
1 and at the end of the study in all subjects.
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| Notes [4] - All levels were below LLOQ [5] - Only 1 subject showed levels above LLOQ (1.53 ng/mL) |
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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 |
(S)AEs were collected from screening, and classed as medical history, non-treatment emergent AE or AE
depending on relation to study drug administration.
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Adverse event reporting additional description |
Ten of 11 subjects experienced a total of 61 AEs, of which 33 were treatment related. Reported ocular AEs were mostly mild in severity. The most common AEs were cataract-related (8 of 11 subjects), resulting in an SAE for 6 subjects. Three subjects had an AE indicative of retinal changes. AEs of special interest are depicted.
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Assessment type |
Non-systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
20
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Reporting groups
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Reporting group title |
cohort 1: 160/80 μg
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Reporting group description |
Subjects received one 160 μg loading dose, followed by up to three 80 μg maintenance doses. | |||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
cohort 2: 320/160 μg
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Reporting group description |
Subjects received one 320 μg loading dose, followed by up to three 160 μg maintenance doses. Following the observed incidence of cataracts and retinal events, the Sponsor decided in consultation with the DMC to stop administration of the 320/160 µg doses, and to prolong the dosing interval for subjects in the 160/80 µg dose group. | |||||||||||||||||||||||||||||||||||||||||||||||||||
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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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18 May 2017 |
Revisions made to historic genotyping and sequencing requirements (non-substantial amendment) |
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08 Nov 2017 |
Revisions made to add the Cardiff Visual Ability Questionnaire for Children
Clarification of Exclusion Criteria 7 through 9 regarding acceptable laboratory values at Screening
Revisions to endpoints to enhance nature and quality of data derived from the study (non-substantial amendment) |
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04 Jun 2018 |
Revised BCVA for Inclusion Criteria (substantial amendment not submitted in Belgium) |
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27 Jul 2018 |
Revised efficacy assessments and subject disposition, demographics and baseline disease characteristics to indicate that the average of the measures represented a more accurate assessment of the baseline value, considering all collected values and stabilizing the baseline.
Revised BCVA for inclusion criteria
Allowed for interim analyses to support the design of subsequent QR-110 clinical studies.
Revised Schedule of Events
This substantial amendment was not submitted in Belgium
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02 Aug 2018 |
Added exploratory endpoints that can be done at the investigator’s discretion at any protocol visit (non-substantial). |
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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 | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/30559420 |
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