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

• Register: ClinicalTrials.gov
• Last refreshed on: 2 May 2022
• Main ID: NCT03780257
• Date of registration: 17/12/2018
• Prospective Registration: Yes
• Primary sponsor: ProQR Therapeutics
• Public title: Study to Evaluate Safety and Tolerability of QR-421a in Subjects With RP Due to Mutations in Exon 13 of the USH2A Gene Stellar
• Scientific 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
• Date of first enrolment: March 6, 2019
• Target sample size: 20
• Recruitment status: Completed
• URL: https://clinicaltrials.gov/show/NCT03780257
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Sequential Assignment. Primary purpose: Treatment. Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor).
• Phase: Phase 1/Phase 2

Countries of recruitment

Belgium, Canada, France, United States

Contacts

• Name: ProQR Clinical Trial Manager
• Affiliation: ProQR Therapeutics

• Name: ProQR Medical Monitor
• Affiliation: ProQR Therapeutics

Key inclusion & exclusion 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. 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.



Age minimum: 18 Years
Age maximum: N/A
Gender: All

Health Condition(s) or Problem(s) studied

Retinitis Pigmentosa

Eye Diseases, Hereditary

Usher Syndrome Type 2

Eye Disorders Congenital

Vision Disorders

Retinal Disease

Deaf Blind

Eye Diseases

Intervention(s)

Other: Sham-procedure (dose cohort 1&2 only)

Drug: QR-421a

Primary Outcome(s)

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

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

Secondary Outcome(s)

Change in EZ area by SD-OCT [Time Frame: 24 months]

Changes in FST [Time Frame: 24 months]

Cmax of QR-421a in serum [Time Frame: 24 months]

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

Tmax of QR-421a [Time Frame: 24 months]

Change in DAC perimetry [Time Frame: 24 months]

Change in LLVA [Time Frame: 24 months]

AUC (0-tlast) of QR-421a in serum [Time Frame: 24 months]

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

Change in BCVA [Time Frame: 24 months]

AUC (0-8) of QR-421a in serum [Time Frame: 24 months]

Change in microperimetry [Time Frame: 24 months]

Change in static perimetry [Time Frame: 24 months]

Changes in FAF [Time Frame: 24 months]

T1/2 of QR-421a [Time Frame: 24 months]

Secondary ID(s)

PQ-421a-001

2018-002433-38

Source(s) of Monetary Support

Please refer to primary and secondary sponsors