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Study to Evaluate the Efficacy Safety and Tolerability of Ultevursen in Subjects With RP Due to Mutations in Exon 13 of the USH2A Gene (Sirius)

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.
 
ClinicalTrials.gov Identifier: NCT05158296
Recruitment Status : Active, not recruiting
First Posted : December 15, 2021
Last Update Posted : September 16, 2022
Sponsor:
Information provided by (Responsible Party):
ProQR Therapeutics

Brief Summary:
The purpose of this study is to evaluate the efficacy safety and tolerability of ultevursen 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: Ultevursen Other: Sham-procedure Phase 2 Phase 3

Detailed Description:

The purpose of this study is to evaluate the efficacy safety and tolerability of ultevursen administered via intravitreal injection (IVT) in subjects with Retinitis Pigmentosa (RP) due to mutations in exon 13 of the USH2A gene.

The below dose levels of ultevursen will be evaluated with the loading dose administered at Day 1 and maintenance dose administered at Month 3 and every 6 months thereafter:

  1. Loading dose of 180 µg, maintenance dose of 60 µg
  2. Loading dose of 60 µg, maintenance dose of 60 µg

Dose levels will include subjects randomized to sham-procedure or treatment with ultevursen.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 81 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Double-masked, randomized, controlled, multiple-dose study. Subjects will be randomized to one of three treatment groups:

  1. Group 1: Ultevursen 180/60 µg (180 µg loading dose administered on Day 1, 60 µg maintenance dose administered at Month 3 and every 6 months thereafter)
  2. Group 2: Ultevursen 60/60 µg (60 µg loading dose administered on Day 1, 60 µg maintenance dose administered at Month 3 and every 6 months thereafter; n = 27)
  3. Group 3: Sham-procedure (administered on Day 1, Month 3 and every 6 months thereafter; n = 27)
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Subject, site staff (study coordinator, imaging technician, etc) and Investigator will be completely masked. Physician performing IVT and post-IVT monitoring will know if subject is receiving sham or treatment, but will be masked to the dose level. Pharmacist is the only site staff that will be completely unmasked.
Primary Purpose: Treatment
Official Title: A Double-Masked, Randomized, Controlled, Multiple-Dose Study to Evaluate the Efficacy, Safety and Tolerability of Ultevursen in Subjects With Retinitis Pigmentosa (RP) Due to Mutations in Exon 13 of the USH2A Gene (Sirius)
Actual Study Start Date : December 8, 2021
Estimated Primary Completion Date : December 2024
Estimated Study Completion Date : December 2024


Arm Intervention/treatment
Experimental: Ultevursen 180/60 µg
180 µg loading dose administered on Day 1, 60 µg maintenance dose administered at Month 3 and every 6 months thereafter
Drug: Ultevursen
RNA antisense oligonucleotide for intravitreal injection
Other Name: RNA antisense oligonucleotide for intravitreal injection

Experimental: Ultevursen 60/60 µg
60 µg loading dose administered on Day 1, 60 µg maintenance dose administered at Month 3 and every 6 months thereafter
Drug: Ultevursen
RNA antisense oligonucleotide for intravitreal injection
Other Name: RNA antisense oligonucleotide for intravitreal injection

Sham Comparator: Sham-procedure
Sham-procedure (no experimental drug administered) on Day 1, Month 3 and every 6 months thereafter
Other: Sham-procedure
Sham-procedure (no experimental drug administered)




Primary Outcome Measures :
  1. Mean change from baseline in BCVA [ Time Frame: 18 months of treatment versus sham-procedure ]
    Mean change from baseline in best corrected visual acuity(BCVA) based on the Early Treatment Diabetic Retinopathy Study (ETDRS) chart


Secondary Outcome Measures :
  1. Proportion of patients who maintain vision defined by BCVA loss less than 15 Letters (ETDRS) [ Time Frame: 27 months ]
    Proportion of patients who maintain vision defined by BCVA loss less than 15 Letters based on ETDRS

  2. Change from baseline in other analyses of BCVA [ Time Frame: 27 months ]
    Change from baseline in other analyses of BCVA

  3. Change from baseline in ellipsoid zone (EZ) area and width as imaged by spectral domain optical coherence tomography (SD-OCT) [ Time Frame: 27 months ]
    Change from baseline in ellipsoid zone (EZ) area and width as imaged by spectral domain optical coherence tomography (SD-OCT)

  4. Change from baseline in Low Luminance Visual Acuity (LLVA) [ Time Frame: 27 months ]
    Change from baseline in Low Luminance Visual Acuity (LLVA)

  5. Change from baseline in Microperimetry [ Time Frame: 27 months ]
    Change from baseline in Microperimetry

  6. Change from baseline in Full-field Stimulus Threshold (FST) [ Time Frame: 27 months ]
    Change from baseline in Full-field Stimulus Threshold (FST)

  7. Change from baseline in PRO measures [ Time Frame: 27 months ]
    As assessed by the Veteran Affairs Low Vision Visual Functioning Questionnaire (VA LV VFQ-20), Patient Global Impressions of Severity (PGI-S) and Patient Global Impressions of Change (PGI-C)

  8. Ocular and non-ocular adverse events (AEs) [ Time Frame: 27 months ]
    Ocular and non-ocular adverse events (AEs)

  9. Cmax of ultevursen in serum [ Time Frame: 27 months ]
    Maximum concentration (Cmax) of ultevursen in serum



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

Inclusion Criteria:

  1. Male or female, ≥ 18 years of age OR a minor (12 to < 18 years) with permission from a parent or legal guardian. The lower age limit for pediatric populations is subject to local regulatory and ethics committee requirements.
  2. An adult willing to comply with the protocol, follow study instructions, attend study visits as required and willing and able to complete all study assessments. OR A minor able to complete all study assessments and comply with the protocol and has a parent or caregiver willing and able to follow study instructions, and attend study visits with the subject as required.
  3. Clinical presentation consistent with RP with Usher syndrome type 2 or nonsyndromic form of RP (NSRP), based on ophthalmic, audiologic, and vestibular examinations.
  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 at screening.
  5. BCVA between ≥30 and ≤68 letters (approximate Snellen equivalent 20/250 - 20/50) in the treatment eye using the mean BCVA reading at screening. Subjects with a mean BCVA between >68 and ≤73 letters will be allowed with documented historic evidence of a BCVA equivalent decline of >5 letters in both eyes.
  6. BCVA between ≥30 and ≤73 letters (approximate Snellen equivalent 20/250 - 20/40) in the contralateral eye (CE), using the mean BCVA reading at Screening.
  7. A difference in mean BCVA readings at Screening between the TE and CE of

    ≤10 letters (based on ETDRS). BCVA differences between eyes that are greater than 10 letters may be allowed however, the Investigator should discuss the case with the Medical Monitor.

  8. Stable BCVA in the TE and CE, defined as 2 separate BCVA measurements at Screening that fall within ≤ 5 letters for each respective eye.
  9. A visible EZ layer on SD-OCT in the TE, as determined by the Investigator.
  10. 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.
  11. Reliable BCVA, perimetry, and other measurements in both eyes, as described in the Study Reference Manual and Imaging Manual and determined by the Investigator.
  12. No visually significant ocular media opacities and adequate pupillary dilation to permit good quality retinal imaging in both eyes, 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 have monoallelic exon-13 mutations.
  2. Presence of non-exon 13 USH2A pathogenic mutation(s) on both USH2A alleles in subjects who have biallelic exon 13 mutations.
  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. Note: The confirmed presence of homozygous or compound heterozygous known disease-causing mutations in other genes involved in recessive retinal dystrophies (RD), or the confirmed presence of known disease-causing mutations in genes involved in dominant or X-linked retinal dystrophies is exclusionary.
  4. Presence of any significant ocular (in either eye) 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 has uncontrolled cystoid macular edema (CME). 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 study 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 either eye that resulted in significant vision loss, in the opinion of the Investigator.
  9. 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 in either eye during the course of the study. For YAG laser treatment of a posterior capsular opacity, receipt within 1 month prior to Screening or planned procedure in either eye during the course of the study.
  10. 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.
  11. A history of glaucoma or an IOP greater than 21 mmHg in either eye that is not controlled with medication or surgery. IOP measurements between 21 and 24 mmHg may be allowed however, the Investigator should discuss the case with the Medical Monitor.
  12. 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 course of the study.
  13. Any prior treatment with genetic or stem-cell therapy for ocular or non-ocular disease.
  14. History of malignancy within 2 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.
  15. Known hypersensitivity to antisense oligonucleotides or any constituents of the injection.
  16. Pregnant and breastfeeding subjects. Females of childbearing potential and males must comply with using highly effective methods of contraception as defined in the protocol. Women of non-childbearing potential may be included without the use of adequate birth control.

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): NCT05158296


Locations
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United States, California
Shiley Eye Institute - UC San Diego
San Diego, California, United States, 92093-0946
University of California, San Francisco
San Francisco, California, United States, 94158
United States, Florida
University of Miami, Bascom Palmer Eye Institute
Miami, Florida, United States, 33136
United States, Georgia
Emory Eye Center
Atlanta, Georgia, United States, 30322
United States, Maryland
Wilmer Eye Institute, Johns Hopkins Hospital
Baltimore, Maryland, United States, 21287
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, New York
Columbia University
New York, New York, United States, 10032
United States, Texas
Retina Foundation of the Southwest
Dallas, Texas, United States, 75231
United States, Wisconsin
University of Wisconsin - Madison
Madison, Wisconsin, United States, 53705
Germany
Universitaetsklinikum Tuebingen Department für Augenheilkunde
Tuebingen, Germany, 72076
Netherlands
RadboudUMC
Nijmegen, Netherlands, 6525 GA
Het Oogziekenhuis Rotterdam
Rotterdam, Netherlands, 3011 BH
United Kingdom
Oxford Eye Hospital
Headington, Oxford, United Kingdom, OX3 9DU
Moorfields Eye Hospital
London, United Kingdom
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: NCT05158296    
Other Study ID Numbers: PQ-421a-003
2021-002729-74 ( EudraCT Number )
First Posted: December 15, 2021    Key Record Dates
Last Update Posted: September 16, 2022
Last Verified: September 2022
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
Sirius
IVT
mutations in exon 13 of the USH2A gene
NSRP
Non-Syndromic RP
Inherited Retinal Disorders
Usher Syndrome
Intravitreal Injection
ultevursen
Additional relevant MeSH terms:
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Usher Syndromes
Vision Disorders
Eye Diseases
Retinitis
Retinitis Pigmentosa
Retinal Diseases
Eye Diseases, Hereditary
Eye Abnormalities
Genetic Diseases, Inborn
Retinal Dystrophies
Retinal Degeneration
Sensation Disorders
Neurologic Manifestations
Nervous System Diseases
Deaf-Blind Disorders
Deafness
Hearing Loss
Hearing Disorders
Ear Diseases
Otorhinolaryngologic Diseases
Hearing Loss, Sensorineural
Blindness
Abnormalities, Multiple
Congenital Abnormalities