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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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03780257
Recruitment Status : Recruiting
First Posted : December 19, 2018
Last Update Posted : July 29, 2020
Sponsor:
Information provided by (Responsible Party):
ProQR Therapeutics

Tracking Information
First Submitted Date  ICMJE December 17, 2018
First Posted Date  ICMJE December 19, 2018
Last Update Posted Date July 29, 2020
Actual Study Start Date  ICMJE March 6, 2019
Estimated Primary Completion Date December 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 23, 2019)
  • Incidence and severity of ocular adverse events (AEs) in the treatment and contralateral eye [ Time Frame: 24 months ]
    Incidence and severity of ocular AEs
  • Incidence and severity of non-ocular AEs [ Time Frame: 24 months ]
    Incidence and severity of non-ocular AEs
Original Primary Outcome Measures  ICMJE
 (submitted: December 17, 2018)
  • Frequency and severity of ocular adverse events (AEs) in the treatment and contralateral eye [ Time Frame: 48 weeks ]
    Frequency and severity of ocular AEs
  • Frequency and severity of non-ocular AEs [ Time Frame: 48 weeks ]
    Frequency and severity of non-ocular AEs
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 27, 2020)
  • Change in DAC perimetry [ Time Frame: 24 months ]
    Change in Dark Adapted Chromatic (DAC) perimetry
  • Change in static perimetry [ Time Frame: 24 months ]
    Change in static perimetry
  • 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)
  • Change in BCVA [ Time Frame: 24 months ]
    Change in Best Corrected Visual Acuity (BCVA)
  • Change in LLVA [ Time Frame: 24 months ]
    Change in Low Luminance Visual Acuity (LLVA)
  • Change in microperimetry [ Time Frame: 24 months ]
    Change in microperimetry
  • Changes in FST [ Time Frame: 24 months ]
    Changes in Full-field Stimulus Threshold (FST)
  • Changes in FAF [ Time Frame: 24 months ]
    Changes in Fundus autofluorescence (FAF)
  • 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
  • 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
  • Cmax of QR-421a in serum [ Time Frame: 24 months ]
    Maximum concentration (Cmax) of QR-421a in serum
  • Tmax of QR-421a [ Time Frame: 24 months ]
    Time to maximum concentration (Tmax) of QR-421a
  • T1/2 of QR-421a [ Time Frame: 24 months ]
    Terminal elimination half-life (T1/2) of QR-421a
  • Serum clearance (CL) of QR-421a [ Time Frame: 24 months ]
    Serum clearance (CL) of QR-421a
  • Volume of distribution (Vd) of QR-421a [ Time Frame: 24 months ]
    Volume of distribution (Vd) of QR-421a
Original Secondary Outcome Measures  ICMJE
 (submitted: December 17, 2018)
  • Change in DAC VF [ Time Frame: 48 weeks ]
    Change in Dark Adapted Chromatic (DAC) Visual Field
  • Change in static VF [ Time Frame: 48 weeks ]
    Change in static Visual Field
  • Change in EZ area by OCT [ Time Frame: 48 weeks ]
    Change in Ellipsoid Zone (EZ) area by optical coherence tomography (OCT)
  • Change in BCVA [ Time Frame: 48 weeks ]
    Change in Best Corrected Visual Acuity (BCVA)
  • Change in semi-kinetic VF [ Time Frame: 48 weeks ]
    Change in semi-kinetic Visual Field
  • Change in microperimetry [ Time Frame: 48 weeks ]
    Change in microperimetry
  • Changes in ERG [ Time Frame: 48 weeks ]
    Changes in ERG ((International Society for Clinical Electrophysiology of Vision [ISCEV] standard for full-field clinical ERG)
  • Changes in NIRAF [ Time Frame: 48 weeks ]
    Changes in near-infrared autofluorescence (NIRAF)
  • 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
  • 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
  • Cmax of QR-421a in serum [ Time Frame: 48 weeks ]
    Maximum concentration (Cmax) of QR-421a in serum
  • Tmax of QR-421a [ Time Frame: 48 weeks ]
    Time to maximum concentration (Tmax) of QR-421a
  • T1/2 of QR-421a [ Time Frame: 48 weeks ]
    Terminal elimination half-life (T1/2) of QR-421a
  • Serum clearance (CL) of QR-421a [ Time Frame: 48 weeks ]
    Serum clearance (CL) of QR-421a
  • Volume of distribution (Vd) of QR-421a [ Time Frame: 48 weeks ]
    Volume of distribution (Vd) of QR-421a
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study to Evaluate Safety and Tolerability of QR-421a in Subjects With RP Due to Mutations in Exon 13 of the USH2A Gene
Official Title  ICMJE 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
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.
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Retinitis Pigmentosa
  • Usher Syndrome Type 2
  • Deaf Blind
  • Retinal Disease
  • Eye Diseases
  • Eye Diseases, Hereditary
  • Eye Disorders Congenital
  • Vision Disorders
Intervention  ICMJE
  • Drug: QR-421a
    RNA antisense oligonucleotide for intravitreal injection
    Other Name: RNA antisense oligonucleotide for intravitreal injection
  • Other: Sham-procedure (dose cohort 1&2 only)
    Sham-procedure (no experimental drug administered)
    Other Name: Sham-procedure
Study Arms  ICMJE
  • Experimental: QR-421a
    Single dose administration
    Intervention: Drug: QR-421a
  • Sham Comparator: Sham-procedure (dose cohort 1&2 only)
    Sham-procedure (no experimental drug administered)
    Intervention: Other: Sham-procedure (dose cohort 1&2 only)
Publications * Miah KM, Hyde SC, Gill DR. Emerging gene therapies for cystic fibrosis. Expert Rev Respir Med. 2019 Aug;13(8):709-725. doi: 10.1080/17476348.2019.1634547. Epub 2019 Jun 27. Review.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: December 17, 2018)
18
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 2022
Estimated Primary Completion Date December 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: ProQR Clinical Trial Manager +31(0)88 166 7000 info@proqr.com
Listed Location Countries  ICMJE Belgium,   Canada,   France,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03780257
Other Study ID Numbers  ICMJE PQ-421a-001
2018-002433-38 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party ProQR Therapeutics
Study Sponsor  ICMJE ProQR Therapeutics
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: ProQR Medical Monitor ProQR Therapeutics
Study Director: ProQR Clinical Trial Manager ProQR Therapeutics
PRS Account ProQR Therapeutics
Verification Date July 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP