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Study to Evaluate Safety and Tolerability of QR-421a in Subjects With RP Due to Mutations in Exon 13 of the USH2A Gene (Stellar)

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ClinicalTrials.gov Identifier: NCT03780257
Recruitment Status : Recruiting
First Posted : December 19, 2018
Last Update Posted : May 23, 2019
Sponsor:
Information provided by (Responsible Party):
ProQR Therapeutics

Brief Summary:
The purpose of this study is to evaluate the safety and tolerability of QR-421a administered via intravitreal injection (IVT) in subjects with Retinitis Pigmentosa (RP) due to mutations in exon 13 of the USH2A gene.

Condition or disease Intervention/treatment Phase
Retinitis Pigmentosa Usher Syndrome Type 2 Deaf Blind Retinal Disease Eye Diseases Eye Diseases, Hereditary Eye Disorders Congenital Vision Disorders Drug: QR-421a Other: Sham-procedure Phase 1 Phase 2

Detailed Description:

The purpose of this study is to evaluate the safety and tolerability of QR-421a administered via IVT in subjects with RP due to mutations in exon 13 of the USH2A gene. Subjects will receive one single IVT injection of QR-421a or sham-procedure in one eye (subject's worse eye) and will be followed up for 48 weeks.

Three dose levels of QR-421a will be evaluated: 50, 100, and 200 µg. Additional dose levels (eg, 25 or 400 µg) may be evaluated based on ongoing safety and efficacy data monitoring.

Per dose cohort, a minimum of 4 subjects will be treated with QR-421a and a minimum of 2 subjects will receive the sham-procedure. The first subject in a dose cohort will receive QR-421a (open-label); subsequent subjects in the same dose cohort will be randomized to either QR-421a or sham-procedure.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 18 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: The first subject in a dose cohort will receive QR-421a (open-label); subsequent subjects in the same dose cohort will be randomized to either QR-421a or sham-procedure in a double-masked approach.
Primary Purpose: Treatment
Official Title: A First-in-Human Study to Evaluate the Safety and Tolerability of QR-421a in Subjects With Retinitis Pigmentosa (RP) Due to Mutations in Exon 13 of the USH2A Gene
Actual Study Start Date : March 6, 2019
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : July 2020


Arm Intervention/treatment
Experimental: QR-421a
Single dose administration
Drug: QR-421a
RNA antisense oligonucleotide for intravitreal injection
Other Name: RNA antisense oligonucleotide for intravitreal injection

Sham Comparator: Sham-procedure
Sham-procedure (no experimental drug administered)
Other: Sham-procedure
Sham-procedure (no experimental drug administered)




Primary Outcome Measures :
  1. Frequency and severity of ocular adverse events (AEs) in the treatment and contralateral eye [ Time Frame: 48 weeks ]
    Frequency and severity of ocular AEs

  2. Frequency and severity of non-ocular AEs [ Time Frame: 48 weeks ]
    Frequency and severity of non-ocular AEs


Secondary Outcome Measures :
  1. Change in DAC VF [ Time Frame: 48 weeks ]
    Change in Dark Adapted Chromatic (DAC) Visual Field

  2. Change in static VF [ Time Frame: 48 weeks ]
    Change in static Visual Field

  3. Change in EZ area by OCT [ Time Frame: 48 weeks ]
    Change in Ellipsoid Zone (EZ) area by optical coherence tomography (OCT)

  4. Change in BCVA [ Time Frame: 48 weeks ]
    Change in Best Corrected Visual Acuity (BCVA)

  5. Change in semi-kinetic VF [ Time Frame: 48 weeks ]
    Change in semi-kinetic Visual Field

  6. Change in microperimetry [ Time Frame: 48 weeks ]
    Change in microperimetry

  7. Changes in ERG [ Time Frame: 48 weeks ]
    Changes in ERG ((International Society for Clinical Electrophysiology of Vision [ISCEV] standard for full-field clinical ERG)

  8. Changes in NIRAF [ Time Frame: 48 weeks ]
    Changes in near-infrared autofluorescence (NIRAF)

  9. AUC (0-∞) of QR-421a in serum [ Time Frame: 48 weeks ]
    Area under the curve 0 hour to infinity [AUC(0-∞)] of QR-421a in serum

  10. AUC (0-tlast) of QR-421a in serum [ Time Frame: 48 weeks ]
    Area under the curve 0 hour to the final sample with a concentration greater than lower limit of quantification (LLOQ) [AUC(0-tlast)] of QR-421a in serum

  11. Cmax of QR-421a in serum [ Time Frame: 48 weeks ]
    Maximum concentration (Cmax) of QR-421a in serum

  12. Tmax of QR-421a [ Time Frame: 48 weeks ]
    Time to maximum concentration (Tmax) of QR-421a

  13. T1/2 of QR-421a [ Time Frame: 48 weeks ]
    Terminal elimination half-life (T1/2) of QR-421a

  14. Serum clearance (CL) of QR-421a [ Time Frame: 48 weeks ]
    Serum clearance (CL) of QR-421a

  15. Volume of distribution (Vd) of QR-421a [ Time Frame: 48 weeks ]
    Volume of distribution (Vd) of QR-421a



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Male or female, ≥ 18 years of age.
  2. Clinical presentation consistent with RP with Usher syndrome type 2 or non-syndromic RP (NSRP), based on ophthalmic, audiologic, and vestibular examinations.
  3. An ERG result consistent with RP with Usher syndrome type 2 or NSRP.
  4. A molecular diagnosis of homozygosity or compound heterozygosity for 1 or more pathogenic exon 13 mutations in the USH2A gene, based on genetic analysis upon Sponsor approval.
  5. A BCVA less than or equal to Logarithm of the Minimum Angle of Resolution (LogMAR) +0.2 in the worse eye.
  6. Semi-Automated Kinetic VF V4e (Octopus 900): Continuous area of central field greater than or equal to 10 degrees diameter (equivalent in area: 78.53981634 deg2) in both eyes.
  7. No limitations to OCT image collection that would prevent high quality, reliable images from being obtained in both eyes (including outer segment [OS] thickness and volume, outer nuclear layer [ONL] thickness, total receptor (TR) thickness, EZ horizontal and vertical widths, apparent continuous EZ area, central macula thickness [CMT], grading of cystic macular lesions [CML] if any), as determined by the reading center.
  8. Reliable perimetry measurements in both eyes, as described in the Study Reference Manual and determined by the reading center.
  9. Clear ocular media and adequate pupillary dilation to permit good quality retinal imaging, as assessed by the Investigator.

Exclusion Criteria:

  1. Presence of additional non-exon 13 USH2A pathogenic mutation(s) on the USH2A allele carrying the exon 13 mutation in subjects who are compound heterozygous for mutations in exon 13.
  2. Presence of non-exon 13 USH2A pathogenic mutation(s) on both USH2A alleles in subjects who are homozygous for mutations in exon 13.
  3. Presence of pathogenic mutations in genes (other than the USH2A gene) associated with Usher syndrome Type 2 or NSRP, or other inherited retinal degenerative diseases or syndromes.
  4. Any contraindication to IVT injection according to the Investigator's clinical judgment and international guidelines.
  5. Nystagmus or unstable fixation.
  6. Amblyopia.
  7. Prior receipt of intraocular surgery or procedure or IVT injection within 12 weeks prior to study start or planned intraocular surgery or procedure during the course of the study.
  8. Any prior treatment with genetic therapy.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03780257


Contacts
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Contact: ProQR Clinical Trial Manager +31(0)88 166 7000 clinical@proqr.com

Locations
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United States, Massachusetts
Center for Clinical Research Operations, Massachusetts Eye and Ear Recruiting
Boston, Massachusetts, United States, 02114
Contact    617-573-6060    OphthalmologyClinicalResearch@meei.harvard.edu   
United States, Michigan
University of Michigan, Kellogg Eye Center Recruiting
Ann Arbor, Michigan, United States, 48105
Contact: Lindsay Godsey    734-936-9798    godseyli@med.umich.edu   
United States, Oregon
Casey Eye Institute, Oregon Health & Science University Recruiting
Portland, Oregon, United States, 97239
Contact: Tamila Williams    503-494-4491    willtami@ohsu.edu   
United States, Texas
Retina Foundation of the Southwest Recruiting
Dallas, Texas, United States, 75231
Contact: Martin Klein    214-363-3911 ext 116    mklein@retinafoundation.org   
Belgium
UZ Gent, Department Ophthalmology Recruiting
Gent, Belgium, 9000
Contact: Bart Leroy, Prof Dr    +32 (9) 332 5342    Bart.Leroy@UGent.be   
France
Centre de maladies rares CHNO des Quinze Vingts Recruiting
Paris, France, 75012
Contact: Céline Devisme    +33 1 40 02 14 57    cdevisme@15-20.fr   
Contact: Charlène Da silveira    +33 1 40 02 14 55    cdasilveira@15-20.fr   
Sponsors and Collaborators
ProQR Therapeutics
Investigators
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Study Director: ProQR Medical Monitor ProQR Therapeutics
Study Director: ProQR Clinical Trial Manager ProQR Therapeutics

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Responsible Party: ProQR Therapeutics
ClinicalTrials.gov Identifier: NCT03780257     History of Changes
Other Study ID Numbers: PQ-421a-001
2018-002433-38 ( EudraCT Number )
First Posted: December 19, 2018    Key Record Dates
Last Update Posted: May 23, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by ProQR Therapeutics:
Retinitis Pigmentosa
USH2A
RP
exon 13
RNA therapies
antisense oligonucleotide
exon skipping
STELLAR
IVT
mutations in exon 13 of the USH2A gene
NSRP
Additional relevant MeSH terms:
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Usher Syndromes
Vision Disorders
Retinitis
Retinitis Pigmentosa
Retinal Diseases
Eye Diseases, Hereditary
Eye Abnormalities
Genetic Diseases, Inborn
Disease
Eye Diseases
Pathologic Processes
Retinal Dystrophies
Retinal Degeneration
Sensation Disorders
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Deaf-Blind Disorders
Deafness
Hearing Loss
Hearing Disorders
Ear Diseases
Otorhinolaryngologic Diseases
Hearing Loss, Sensorineural
Blindness
Abnormalities, Multiple
Congenital Abnormalities