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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)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT03780257
Recruitment Status : Active, not recruiting
First Posted : December 19, 2018
Last Update Posted : September 16, 2021
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 (dose cohort 1&2 only) 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 24 months.

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.

Initial dose cohorts will include subjects randomized to sham-procedure or treatment with QR-421a. Additional subjects may be allocated to treatment with QR-421a in subsequent or initial dose cohorts.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 20 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
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 : October 2021
Estimated Study Completion Date : October 2021

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 (dose cohort 1&2 only)
Sham-procedure (no experimental drug administered)
Other: Sham-procedure (dose cohort 1&2 only)
Sham-procedure (no experimental drug administered)
Other Name: Sham-procedure

Primary Outcome Measures :
  1. Incidence and severity of ocular adverse events (AEs) in the treatment and contralateral eye [ Time Frame: 24 months ]
    Incidence and severity of ocular AEs

  2. Incidence and severity of non-ocular AEs [ Time Frame: 24 months ]
    Incidence and severity of non-ocular AEs

Secondary Outcome Measures :
  1. Change in DAC perimetry [ Time Frame: 24 months ]
    Change in Dark Adapted Chromatic (DAC) perimetry

  2. Change in static perimetry [ Time Frame: 24 months ]
    Change in static perimetry

  3. Change in EZ area by SD-OCT [ Time Frame: 24 months ]
    Change in Ellipsoid Zone (EZ) area/width by spectral domain optical coherence tomography (SD-OCT)

  4. Change in BCVA [ Time Frame: 24 months ]
    Change in Best Corrected Visual Acuity (BCVA)

  5. Change in LLVA [ Time Frame: 24 months ]
    Change in Low Luminance Visual Acuity (LLVA)

  6. Change in microperimetry [ Time Frame: 24 months ]
    Change in microperimetry

  7. Changes in FST [ Time Frame: 24 months ]
    Changes in Full-field Stimulus Threshold (FST)

  8. Changes in FAF [ Time Frame: 24 months ]
    Changes in Fundus autofluorescence (FAF)

  9. AUC (0-∞) of QR-421a in serum [ Time Frame: 24 months ]
    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: 24 months ]
    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: 24 months ]
    Maximum concentration (Cmax) of QR-421a in serum

  12. Tmax of QR-421a [ Time Frame: 24 months ]
    Time to maximum concentration (Tmax) of QR-421a

  13. T1/2 of QR-421a [ Time Frame: 24 months ]
    Terminal elimination half-life (T1/2) of QR-421a

  14. Serum clearance (CL) of QR-421a [ Time Frame: 24 months ]
    Serum clearance (CL) of QR-421a

  15. Volume of distribution (Vd) of QR-421a [ Time Frame: 24 months ]
    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

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. 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.
  4. Impairment of VF in the opinion of the Investigator, as determined by perimetry, with a continuous area of central field greater than or equal to 10 degrees diameter in any axis in the treatment eye, and evidence of functioning rods.
  5. Willing and able to comply with the protocol, follow study instructions, attend study visits as required and complete all study assessments.
  6. Willing and able to provide informed consent for participation prior to performing any study related procedures, and suitable verbal, auditory, written and/or tactile sign language communication as to allow informed consent to be obtained, in the opinion of the Investigator.
  7. No limitations to SD-OCT image collection that would prevent high quality, reliable images from being obtained in both eyes as determined by the investigator.
  8. Reliable perimetry measurements in both eyes, as described in the Imaging Manual and determined by the Investigator.
  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. Presence of any significant ocular or non-ocular disease/disorder (or medication and/or laboratory test abnormalities) which, in the opinion of the Investigator and with concurrence of the Medical Monitor, may either put the subject at risk because of participation in the study, may influence the results of the study, or the subject's ability to participate in the study. This includes but is not limited to a subject who: 1) is not an appropriate candidate for antisense oligonucleotide treatment, 2) has cystoid macular edema (CME) in the treatment eye. CME is permissible if stable for 3 months (with or without treatment). Past CME is permissible if resolved for more than 1 month.
  5. History or presence of ocular herpetic diseases (including herpes simplex virus, varicella zoster or cytomegalovirus) in either eye.
  6. Presence of any active ocular infection in either eye.
  7. Presence of any of the following lens opacities in the treatment eye: cortical opacity ≥ +2, posterior subcapsular opacity ≥ +2, or a nuclear sclerosis ≥ +2, and which are: 1) clinically significant in the opinion of the Investigator, 2) would adequately prevent clinical and photographic evaluation of the retina.
  8. History of amblyopia in the treatment eye.
  9. Worse than 6 diopters myopia in the treatment eye.
  10. Receipt within 3 months prior to Screening of any intraocular or periocular surgery (including refractive surgery), or an IVT injection or planned intraocular surgery or procedure during the course of the study.
  11. Current treatment or treatment within the past 12 months with therapies known to influence the immune system (including but not limited to steroid implants, cytostatics, interferons, tumor necrosis factor (TNF)-binding proteins, drugs acting on immunophilins, or antibodies with known impact on the immune system). Subjects that have been treated with systemic steroids within the past 12 months or that require intermittent use of topical steroids may be considered for inclusion following approval by the Medical Monitor.
  12. A history of glaucoma or an IOP greater than 24 mmHg in either eye that is not controlled with medication or surgery at the time of informed consent.
  13. Use of any investigational drug or device within 90 days or 5 half-lives preceding the first dose of study medication, whichever is longer, or plans to participate in another study of an investigational drug or device during the PQ-421a-001 study period.
  14. Any prior treatment with genetic or stem-cell therapy for ocular or non-ocular disease.
  15. History of malignancy within 5 years prior to Screening, except adequately treated squamous or basal cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated.
  16. Known hypersensitivity to antisense oligonucleotides or any constituents of the injection.
  17. Pregnant and breastfeeding subjects. Females of childbearing potential and males must comply with using highly effective methods of contraception as defined in Section 6.2.2. Women of non-childbearing potential may be included without the use of adequate birth control, provided they meet the criteria in the protocol.

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 identifier (NCT number): NCT03780257

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United States, Massachusetts
Center for Clinical Research Operations, Massachusetts Eye and Ear
Boston, Massachusetts, United States, 02114
United States, Michigan
University of Michigan, Kellogg Eye Center
Ann Arbor, Michigan, United States, 48105
United States, Oregon
Casey Eye Institute, Oregon Health & Science University
Portland, Oregon, United States, 97239
United States, Texas
Retina Foundation of the Southwest
Dallas, Texas, United States, 75231
Centre for Innovative Medicine, Department of Paediatric Surgery, Montreal Children's Hospital at the McGill University Health Centre
Montréal, Canada, H4A 3J1
Hôpital Gui de Chauliac - CHRU de Montpellier - Maladies Sensorielles Génétique
Montpellier, France, 34295
Centre de maladies rares CHNO des Quinze Vingts
Paris, France, 75012
Sponsors and Collaborators
ProQR Therapeutics
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Study Director: ProQR Medical Monitor ProQR Therapeutics
Study Director: ProQR Clinical Trial Manager ProQR Therapeutics
Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: ProQR Therapeutics Identifier: NCT03780257    
Other Study ID Numbers: PQ-421a-001
2018-002433-38 ( EudraCT Number )
First Posted: December 19, 2018    Key Record Dates
Last Update Posted: September 16, 2021
Last Verified: September 2021
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
exon 13
RNA therapies
antisense oligonucleotide
exon skipping
mutations in exon 13 of the USH2A gene
Additional relevant MeSH terms:
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Usher Syndromes
Vision Disorders
Eye Diseases
Retinitis Pigmentosa
Retinal Diseases
Eye Diseases, Hereditary
Eye Abnormalities
Genetic Diseases, Inborn
Pathologic Processes
Retinal Dystrophies
Retinal Degeneration
Sensation Disorders
Neurologic Manifestations
Nervous System Diseases
Deaf-Blind Disorders
Hearing Loss
Hearing Disorders
Ear Diseases
Otorhinolaryngologic Diseases
Hearing Loss, Sensorineural
Abnormalities, Multiple
Congenital Abnormalities