<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03780257</url>
  </required_header>
  <id_info>
    <org_study_id>PQ-421a-001</org_study_id>
    <secondary_id>2018-002433-38</secondary_id>
    <nct_id>NCT03780257</nct_id>
  </id_info>
  <brief_title>Study to Evaluate Safety and Tolerability of QR-421a in Subjects With RP Due to Mutations in Exon 13 of the USH2A Gene</brief_title>
  <acronym>Stellar</acronym>
  <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</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>ProQR Therapeutics</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>ProQR Therapeutics</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to evaluate the safety and tolerability of QR-421a administered&#xD;
      via intravitreal injection (IVT) in subjects with Retinitis Pigmentosa (RP) due to mutations&#xD;
      in exon 13 of the USH2A gene.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The purpose of this study is to evaluate the safety and tolerability of QR-421a administered&#xD;
      via IVT in subjects with RP due to mutations in exon 13 of the USH2A gene. Subjects will&#xD;
      receive one single IVT injection of QR-421a or sham-procedure in one eye (subject's worse&#xD;
      eye) and will be followed up for 24 months.&#xD;
&#xD;
      Three dose levels of QR-421a will be evaluated: 50, 100, and 200 µg. Additional dose levels&#xD;
      (eg, 25 or 400 µg) may be evaluated based on ongoing safety and efficacy data monitoring.&#xD;
&#xD;
      Initial dose cohorts will include subjects randomized to sham-procedure or treatment with&#xD;
      QR-421a. Additional subjects may be allocated to treatment with QR-421a in subsequent or&#xD;
      initial dose cohorts.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">March 6, 2019</start_date>
  <completion_date type="Actual">October 14, 2021</completion_date>
  <primary_completion_date type="Actual">October 14, 2021</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Sequential Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Incidence and severity of ocular adverse events (AEs) in the treatment and contralateral eye</measure>
    <time_frame>24 months</time_frame>
    <description>Incidence and severity of ocular AEs</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence and severity of non-ocular AEs</measure>
    <time_frame>24 months</time_frame>
    <description>Incidence and severity of non-ocular AEs</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in DAC perimetry</measure>
    <time_frame>24 months</time_frame>
    <description>Change in Dark Adapted Chromatic (DAC) perimetry</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in static perimetry</measure>
    <time_frame>24 months</time_frame>
    <description>Change in static perimetry</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in EZ area by SD-OCT</measure>
    <time_frame>24 months</time_frame>
    <description>Change in Ellipsoid Zone (EZ) area/width by spectral domain optical coherence tomography (SD-OCT)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in BCVA</measure>
    <time_frame>24 months</time_frame>
    <description>Change in Best Corrected Visual Acuity (BCVA)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in LLVA</measure>
    <time_frame>24 months</time_frame>
    <description>Change in Low Luminance Visual Acuity (LLVA)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in microperimetry</measure>
    <time_frame>24 months</time_frame>
    <description>Change in microperimetry</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in FST</measure>
    <time_frame>24 months</time_frame>
    <description>Changes in Full-field Stimulus Threshold (FST)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in FAF</measure>
    <time_frame>24 months</time_frame>
    <description>Changes in Fundus autofluorescence (FAF)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>AUC (0-∞) of QR-421a in serum</measure>
    <time_frame>24 months</time_frame>
    <description>Area under the curve 0 hour to infinity [AUC(0-∞)] of QR-421a in serum</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>AUC (0-tlast) of QR-421a in serum</measure>
    <time_frame>24 months</time_frame>
    <description>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</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cmax of QR-421a in serum</measure>
    <time_frame>24 months</time_frame>
    <description>Maximum concentration (Cmax) of QR-421a in serum</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Tmax of QR-421a</measure>
    <time_frame>24 months</time_frame>
    <description>Time to maximum concentration (Tmax) of QR-421a</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>T1/2 of QR-421a</measure>
    <time_frame>24 months</time_frame>
    <description>Terminal elimination half-life (T1/2) of QR-421a</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum clearance (CL) of QR-421a</measure>
    <time_frame>24 months</time_frame>
    <description>Serum clearance (CL) of QR-421a</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Volume of distribution (Vd) of QR-421a</measure>
    <time_frame>24 months</time_frame>
    <description>Volume of distribution (Vd) of QR-421a</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">20</enrollment>
  <condition>Retinitis Pigmentosa</condition>
  <condition>Usher Syndrome Type 2</condition>
  <condition>Deaf Blind</condition>
  <condition>Retinal Disease</condition>
  <condition>Eye Diseases</condition>
  <condition>Eye Diseases, Hereditary</condition>
  <condition>Eye Disorders Congenital</condition>
  <condition>Vision Disorders</condition>
  <arm_group>
    <arm_group_label>QR-421a</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Single dose administration</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Sham-procedure (dose cohort 1&amp;2 only)</arm_group_label>
    <arm_group_type>Sham Comparator</arm_group_type>
    <description>Sham-procedure (no experimental drug administered)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>QR-421a</intervention_name>
    <description>RNA antisense oligonucleotide for intravitreal injection</description>
    <arm_group_label>QR-421a</arm_group_label>
    <other_name>RNA antisense oligonucleotide for intravitreal injection</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Sham-procedure (dose cohort 1&amp;2 only)</intervention_name>
    <description>Sham-procedure (no experimental drug administered)</description>
    <arm_group_label>Sham-procedure (dose cohort 1&amp;2 only)</arm_group_label>
    <other_name>Sham-procedure</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Male or female, ≥ 18 years of age.&#xD;
&#xD;
          2. Clinical presentation consistent with RP with Usher syndrome type 2 or non-syndromic&#xD;
             RP (NSRP), based on ophthalmic, audiologic, and vestibular examinations.&#xD;
&#xD;
          3. A molecular diagnosis of homozygosity or compound heterozygosity for 1 or more&#xD;
             pathogenic exon 13 mutations in the USH2A gene, based on genetic analysis upon Sponsor&#xD;
             approval.&#xD;
&#xD;
          4. Impairment of VF in the opinion of the Investigator, as determined by perimetry, with&#xD;
             a continuous area of central field greater than or equal to 10 degrees diameter in any&#xD;
             axis in the treatment eye, and evidence of functioning rods.&#xD;
&#xD;
          5. Willing and able to comply with the protocol, follow study instructions, attend study&#xD;
             visits as required and complete all study assessments.&#xD;
&#xD;
          6. Willing and able to provide informed consent for participation prior to performing any&#xD;
             study related procedures, and suitable verbal, auditory, written and/or tactile sign&#xD;
             language communication as to allow informed consent to be obtained, in the opinion of&#xD;
             the Investigator.&#xD;
&#xD;
          7. No limitations to SD-OCT image collection that would prevent high quality, reliable&#xD;
             images from being obtained in both eyes as determined by the investigator.&#xD;
&#xD;
          8. Reliable perimetry measurements in both eyes, as described in the Imaging Manual and&#xD;
             determined by the Investigator.&#xD;
&#xD;
          9. Clear ocular media and adequate pupillary dilation to permit good quality retinal&#xD;
             imaging, as assessed by the Investigator.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Presence of additional non-exon 13 USH2A pathogenic mutation(s) on the USH2A allele&#xD;
             carrying the exon 13 mutation in subjects who are compound heterozygous for mutations&#xD;
             in exon 13.&#xD;
&#xD;
          2. Presence of non-exon 13 USH2A pathogenic mutation(s) on both USH2A alleles in subjects&#xD;
             who are homozygous for mutations in exon 13.&#xD;
&#xD;
          3. Presence of pathogenic mutations in genes (other than the USH2A gene) associated with&#xD;
             Usher syndrome Type 2 or NSRP, or other inherited retinal degenerative diseases or&#xD;
             syndromes.&#xD;
&#xD;
          4. Presence of any significant ocular or non-ocular disease/disorder (or medication&#xD;
             and/or laboratory test abnormalities) which, in the opinion of the Investigator and&#xD;
             with concurrence of the Medical Monitor, may either put the subject at risk because of&#xD;
             participation in the study, may influence the results of the study, or the subject's&#xD;
             ability to participate in the study. This includes but is not limited to a subject&#xD;
             who: 1) is not an appropriate candidate for antisense oligonucleotide treatment, 2)&#xD;
             has cystoid macular edema (CME) in the treatment eye. CME is permissible if stable for&#xD;
             3 months (with or without treatment). Past CME is permissible if resolved for more&#xD;
             than 1 month.&#xD;
&#xD;
          5. History or presence of ocular herpetic diseases (including herpes simplex virus,&#xD;
             varicella zoster or cytomegalovirus) in either eye.&#xD;
&#xD;
          6. Presence of any active ocular infection in either eye.&#xD;
&#xD;
          7. Presence of any of the following lens opacities in the treatment eye: cortical opacity&#xD;
             ≥ +2, posterior subcapsular opacity ≥ +2, or a nuclear sclerosis ≥ +2, and which are:&#xD;
             1) clinically significant in the opinion of the Investigator, 2) would adequately&#xD;
             prevent clinical and photographic evaluation of the retina.&#xD;
&#xD;
          8. History of amblyopia in the treatment eye.&#xD;
&#xD;
          9. Worse than 6 diopters myopia in the treatment eye.&#xD;
&#xD;
         10. Receipt within 3 months prior to Screening of any intraocular or periocular surgery&#xD;
             (including refractive surgery), or an IVT injection or planned intraocular surgery or&#xD;
             procedure during the course of the study.&#xD;
&#xD;
         11. Current treatment or treatment within the past 12 months with therapies known to&#xD;
             influence the immune system (including but not limited to steroid implants,&#xD;
             cytostatics, interferons, tumor necrosis factor (TNF)-binding proteins, drugs acting&#xD;
             on immunophilins, or antibodies with known impact on the immune system). Subjects that&#xD;
             have been treated with systemic steroids within the past 12 months or that require&#xD;
             intermittent use of topical steroids may be considered for inclusion following&#xD;
             approval by the Medical Monitor.&#xD;
&#xD;
         12. A history of glaucoma or an IOP greater than 24 mmHg in either eye that is not&#xD;
             controlled with medication or surgery at the time of informed consent.&#xD;
&#xD;
         13. Use of any investigational drug or device within 90 days or 5 half-lives preceding the&#xD;
             first dose of study medication, whichever is longer, or plans to participate in&#xD;
             another study of an investigational drug or device during the PQ-421a-001 study&#xD;
             period.&#xD;
&#xD;
         14. Any prior treatment with genetic or stem-cell therapy for ocular or non-ocular&#xD;
             disease.&#xD;
&#xD;
         15. History of malignancy within 5 years prior to Screening, except adequately treated&#xD;
             squamous or basal cell carcinoma of the skin or carcinoma in situ of the cervix that&#xD;
             has been successfully treated.&#xD;
&#xD;
         16. Known hypersensitivity to antisense oligonucleotides or any constituents of the&#xD;
             injection.&#xD;
&#xD;
         17. Pregnant and breastfeeding subjects. Females of childbearing potential and males must&#xD;
             comply with using highly effective methods of contraception as defined in Section&#xD;
             6.2.2. Women of non-childbearing potential may be included without the use of adequate&#xD;
             birth control, provided they meet the criteria in the protocol.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>ProQR Medical Monitor</last_name>
    <role>Study Director</role>
    <affiliation>ProQR Therapeutics</affiliation>
  </overall_official>
  <overall_official>
    <last_name>ProQR Clinical Trial Manager</last_name>
    <role>Study Director</role>
    <affiliation>ProQR Therapeutics</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Center for Clinical Research Operations, Massachusetts Eye and Ear</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02114</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Michigan, Kellogg Eye Center</name>
      <address>
        <city>Ann Arbor</city>
        <state>Michigan</state>
        <zip>48105</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Casey Eye Institute, Oregon Health &amp; Science University</name>
      <address>
        <city>Portland</city>
        <state>Oregon</state>
        <zip>97239</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Retina Foundation of the Southwest</name>
      <address>
        <city>Dallas</city>
        <state>Texas</state>
        <zip>75231</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centre for Innovative Medicine, Department of Paediatric Surgery, Montreal Children's Hospital at the McGill University Health Centre</name>
      <address>
        <city>Montréal</city>
        <zip>H4A 3J1</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hôpital Gui de Chauliac - CHRU de Montpellier - Maladies Sensorielles Génétique</name>
      <address>
        <city>Montpellier</city>
        <zip>34295</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centre de maladies rares CHNO des Quinze Vingts</name>
      <address>
        <city>Paris</city>
        <zip>75012</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
    <country>France</country>
    <country>United States</country>
  </location_countries>
  <removed_countries>
    <country>Belgium</country>
  </removed_countries>
  <verification_date>April 2022</verification_date>
  <study_first_submitted>December 17, 2018</study_first_submitted>
  <study_first_submitted_qc>December 17, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 19, 2018</study_first_posted>
  <last_update_submitted>April 19, 2022</last_update_submitted>
  <last_update_submitted_qc>April 19, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">April 20, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Retinitis Pigmentosa</keyword>
  <keyword>USH2A</keyword>
  <keyword>RP</keyword>
  <keyword>exon 13</keyword>
  <keyword>RNA therapies</keyword>
  <keyword>antisense oligonucleotide</keyword>
  <keyword>exon skipping</keyword>
  <keyword>STELLAR</keyword>
  <keyword>IVT</keyword>
  <keyword>mutations in exon 13 of the USH2A gene</keyword>
  <keyword>NSRP</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Usher Syndromes</mesh_term>
    <mesh_term>Vision Disorders</mesh_term>
    <mesh_term>Eye Diseases</mesh_term>
    <mesh_term>Retinitis</mesh_term>
    <mesh_term>Retinitis Pigmentosa</mesh_term>
    <mesh_term>Retinal Diseases</mesh_term>
    <mesh_term>Eye Diseases, Hereditary</mesh_term>
    <mesh_term>Eye Abnormalities</mesh_term>
    <mesh_term>Genetic Diseases, Inborn</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <pending_results>
    <submitted>November 9, 2022</submitted>
    <returned>December 7, 2022</returned>
    <submitted>December 12, 2022</submitted>
    <returned>January 4, 2023</returned>
  </pending_results>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03780257
org study id: PQ-421a-001
secondary id: 2018-002433-38
nct id: NCT03780257
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
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.
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.
allocation: Randomized
intervention model: Sequential Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Incidence and severity of ocular adverse events (AEs) in the treatment and contralateral eye
time frame: 24 months
description: Incidence and severity of ocular AEs
measure: Incidence and severity of non-ocular AEs
time frame: 24 months
description: Incidence and severity of non-ocular AEs
measure: Change in DAC perimetry
time frame: 24 months
description: Change in Dark Adapted Chromatic (DAC) perimetry
measure: Change in static perimetry
time frame: 24 months
description: Change in static perimetry
measure: Change in EZ area by SD-OCT
time frame: 24 months
description: Change in Ellipsoid Zone (EZ) area/width by spectral domain optical coherence tomography (SD-OCT)
measure: Change in BCVA
time frame: 24 months
description: Change in Best Corrected Visual Acuity (BCVA)
measure: Change in LLVA
time frame: 24 months
description: Change in Low Luminance Visual Acuity (LLVA)
measure: Change in microperimetry
time frame: 24 months
description: Change in microperimetry
measure: Changes in FST
time frame: 24 months
description: Changes in Full-field Stimulus Threshold (FST)
measure: Changes in FAF
time frame: 24 months
description: Changes in Fundus autofluorescence (FAF)
measure: AUC (0-∞) of QR-421a in serum
time frame: 24 months
description: Area under the curve 0 hour to infinity [AUC(0-∞)] of QR-421a in serum
measure: AUC (0-tlast) of QR-421a in serum
time frame: 24 months
description: 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
measure: Cmax of QR-421a in serum
time frame: 24 months
description: Maximum concentration (Cmax) of QR-421a in serum
measure: Tmax of QR-421a
time frame: 24 months
description: Time to maximum concentration (Tmax) of QR-421a
measure: T1/2 of QR-421a
time frame: 24 months
description: Terminal elimination half-life (T1/2) of QR-421a
measure: Serum clearance (CL) of QR-421a
time frame: 24 months
description: Serum clearance (CL) of QR-421a
measure: Volume of distribution (Vd) of QR-421a
time frame: 24 months
description: Volume of distribution (Vd) of QR-421a
arm group label: QR-421a
arm group type: Experimental
description: Single dose administration
arm group label: Sham-procedure (dose cohort 1&2 only)
arm group type: Sham Comparator
description: Sham-procedure (no experimental drug administered)
intervention type: Drug
intervention name: QR-421a
description: RNA antisense oligonucleotide for intravitreal injection
arm group label: QR-421a
other name: RNA antisense oligonucleotide for intravitreal injection
intervention type: Other
intervention name: Sham-procedure (dose cohort 1&2 only)
description: Sham-procedure (no experimental drug administered)
arm group label: Sham-procedure (dose cohort 1&2 only)
other name: Sham-procedure
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: ProQR Medical Monitor
role: Study Director
affiliation: ProQR Therapeutics
last name: ProQR Clinical Trial Manager
role: Study Director
affiliation: ProQR Therapeutics
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Canada
country: France
country: United States
country: Belgium
responsible party type: Sponsor
mesh term: Usher Syndromes
mesh term: Vision Disorders
mesh term: Eye Diseases
mesh term: Retinitis
mesh term: Retinitis Pigmentosa
mesh term: Retinal Diseases
mesh term: Eye Diseases, Hereditary
mesh term: Eye Abnormalities
mesh term: Genetic Diseases, Inborn
sharing ipd: No
submitted: November 9, 2022
returned: December 7, 2022
submitted: December 12, 2022
returned: January 4, 2023