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Study to Assess the Safety and Efficacy of OCU400 for Retinitis Pigmentosa and Leber Congenital Amaurosis

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ClinicalTrials.gov Identifier: NCT05203939
Recruitment Status : Recruiting
First Posted : January 24, 2022
Last Update Posted : October 25, 2023
Sponsor:
Information provided by (Responsible Party):
Ocugen

Study Description
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Brief Summary:

This is a Phase 1/2 Study to Assess the Safety and Efficacy of OCU400 in patients with retinitis pigmentosa associated with NR2E3 and RHO mutations and in patients with LCA due to mutation(s) in CEP290 gene (OCU400-101). To document prospective eye pathology in the above subjects Investigators will also conduct a Natural History Study (OCU400-104)i

This is a multicenter study, which will be conducted in two phases and will enroll up to a total of 24 subjects in the OCU400-101 and 100 subjects in the OCU400-104 study.


Condition or disease Intervention/treatment Phase
Retinitis Pigmentosa Leber Congenital Amaurosis Drug: OCU400 Low Dose Drug: OCU400 Med Dose Drug: OCU400 High Dose Phase 1 Phase 2

Detailed Description:

This study will be conducted in two phases enrolling up to 24 subjects. Treated subjects will receive a single subretinal injection of OCU400 in the study eye.

This is a multicenter, open-label, dose-ranging study in two subgroups of subjects with three consecutive cohorts.

A total of 18 adult RP subjects from each of the following subgroups with Biallelic autosomal recessive NR2E3 mutations, autosomal dominant NR2E3 mutations or Autosomal dominant RHO mutations will be selected for dose escalation.

For the Phase I portion of the study, the 3+3 design for sequential dose-escalating cohorts will be used with scheduled 3 dosing levels between 9 and 18 subjects will be used to follow the design.

3 adult LCA patients with CEP290 mutations and 3 pediatric subjects with RP and LCA, will be enrolled in the Phase 2 portion.

Sample Size Justification:

The trial will enroll up to 24 patients (18 adult RP, 3 adult LCA, 2 pediatric RP, and 1 pediatric LCA) in both Phase 1 and Phase 2 components.

Natural History Study (OCU400-104, A Prospective and Retrospective Natural History Study of RP and LCA):

This is an observatory study for the prospective natural history of RP and LCA in adult and pediatric subjects. The study will also collect and review retrospective data and ophthalmology examination of natural history and progression of disease for all subjects starting with the earliest timepoint on or after the date of their diagnosis of RP or LCA.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 124 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1/2 Study to Assess the Safety and Efficacy of OCU400 for Retinitis Pigmentosa Associated With NR2E3 and RHO Mutations and Leber Congenital Amaurosis With Mutation(s) in CEP290 Gene
Actual Study Start Date : January 24, 2022
Estimated Primary Completion Date : December 2024
Estimated Study Completion Date : December 2024

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Cohort 1 (Low Dose)
Biallelic autosomal recessive NR2E3 mutations subgroup or Autosomal dominant NR2E3 mutation or RHO mutations subgroup
 Drug: OCU400 Low Dose
subretinal injection of up to 1.66 × 10^10 vg/mL
Experimental: Cohort 2 (Mid Dose)
Biallelic autosomal recessive NR2E3 mutations subgroup or Autosomal dominant NR2E3 mutation or RHO mutations subgroup
 Drug: OCU400 Med Dose
subretinal injection of upto 3.33 × 10^10 vg/mL
Experimental: Cohort 3 (High Dose)
Biallelic autosomal recessive NR2E3 mutations subgroup or Autosomal dominant NR2E3 mutation, RHO mutations subgroup and LCA patients with CEP290
 Drug: OCU400 High Dose
subretinal injection of upto 1.66 × 10^11 vg/mL
Experimental: Pediatric Arm
Pediatric subjects will receive the medium dose concentration and will have subjects with RP and LCA
 Drug: OCU400 Med Dose
subretinal injection of upto 3.33 × 10^10 vg/mL
No Intervention: Natural History Study (OCU400-104)

A Prospective and Retrospective Natural History Study of RP and LCA:

This is an observatory study for the prospective natural history of RP and LCA in adult and pediatric subjects. The study will also collect and review retrospective data and ophthalmology examination of natural history and progression of disease for all subjects starting with earliest timepoint on or after the date of their diagnosis of RP or LCA.

Subjects will be seen up to a total of four times during the 12 months of the Observational Period, at baseline, 3 months, 6 months and 12 months.

A total of up to 100 subjects will be enrolled in the study, including:

Approximately 76 newly enrolled subjects consisting of 50 adult RP subjects 6 adult LCA subjects 20 pediatric RP/LCA subjects. Up to 24 subjects that reconsent from the OCU400-101 study (subjects from OCU400-101 will provide data on their untreated eye)
Experimental: Adult Arm
Following DSMB confirmation, adult LCA subjects with CEP290 mutation will receive a medium dose concentration of OCU400.
 Drug: OCU400 Med Dose
subretinal injection of upto 3.33 × 10^10 vg/mL


Outcome Measures
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Primary Outcome Measures :
  1. Study Drug-related adverse events (SDAE) [ Time Frame: 1 year ]
    Counts, frequencies and percentages of SDAEs. SDAE is a primary adverse event of interest and defined as AEs and SAEs that are direct subjects to the Study Drug only.

  2. Treatment-Emergent adverse events (TEAEs) [ Time Frame: 1 year ]
    Counts, frequencies and percentages TEAEs. TEAEs are defined as an event that was not present prior to administration of the dose of study drug and present after the dose, or if it represents the exacerbation of an event that was present prior to the dose.

  3. Serious adverse events (SAEs) [ Time Frame: 1 year ]
    Counts, frequencies and percentages of SAEs including Resulted in Death, Life-threatening, Hospitalization, Disabling/incapacitating, Congenital anomaly or birth defect and Medically significant AEs ( AE that did not meet any of the above criteria but could have jeopardized the subject and might have required medical or surgical intervention to prevent one of the outcomes listed above).


Secondary Outcome Measures :
  1. Best-corrected visual acuity (BCVA) [ Time Frame: 1 year (Changes from baseline) ]
    Measured as the ETDRS letter score on the EVA tester or E-ETDRS charts. Electronic ETDRS Visual Acuity Testing Protocol will be followed (confidential).

  2. Low-luminance visual acuity (LLVA) [ Time Frame: 1 year (Changes from baseline) ]
    Electronic Visual Acuity Tester (EVA) and a Sponsor specific Low-Luminance lens will be used. Early Treatment of Diabetic Retinopathy Study (ETDRS) will also be accepted as a backup.

  3. Slit-lamp biomicroscopy [ Time Frame: 1 year (Changes from baseline) ]
    Changes in visual function.

  4. Intraocular pressure (IOP) [ Time Frame: 1 year (Changes from baseline) ]
    IOP measurement by applanation or rebound tonometry. Confirmation with Goldmann tonometer if IOP reading is outside the normal range (8-21mmHg).

  5. Indirect ophthalmoscopy [ Time Frame: 1 year (Changes from baseline) ]
    If visual acuity is so poor that the participant is unable to count fingers or perceive hand motion, light perception will be tested with the indirect ophthalmoscope as the light source.

  6. anti-AAV5 (anti Adeno-associated virus type 5) [ Time Frame: 1 year ]
    Blood samples will be collected for the assessment. These samples will be analyzed using validated assays at a bioanalytical laboratory.

  7. anti-hNR2E3 antibodies (hNR2E3 gene) [ Time Frame: 1 year ]
    Blood samples will be collected for the assessment. These samples will be analyzed using validated assays at a bioanalytical laboratory.

  8. T-cell response [ Time Frame: 1 year ]
    Blood samples will be collected for the assessment. These samples will be analyzed using validated assays at a bioanalytical laboratory.


Other Outcome Measures:
  1. Multi-luminance mobility testing (MLMT) [ Time Frame: 1 year (Changes from baseline) ]
    Subjects will navigate a standardized mobility maze under set conditions as specified times during the study. The mobility testing will follow a standardized administration and data acquisition protocol and may only be administered by site staff certified in the methodology.

  2. Changes in ellipsoid zone width/length on wide-field 45° SD-OCT [ Time Frame: 1 year (Changes from baseline) ]
    Ellipsoid zone area/outer segment length will be determined by Spectral Domain Optical Coherence Tomography (SD-OCT) using standardized systems and acquisition protocols.

  3. Contrast sensitivity [ Time Frame: 1 year (Changes from baseline) ]
    Contrast sensitivity will be conducted using Pelli-Robson chart.

  4. Full Field Light Stimulation Threshold (FST) [ Time Frame: 1 year (Changes from baseline) ]
    FST will be completed at scheduled times throughout the study period

  5. Static Visual Fields [ Time Frame: 1 year (Changes from baseline) ]
    The Octopus 900 will be used with a standardized white-on-white full field and a blue-on-yellow with full field

  6. Vision on Quality of Life [ Time Frame: 1 year (Changes from baseline) ]
    The National Eye Institute Visual Function Questionnaire 25 (NEI-VFQ25) and the Michigan Retinal Degeneration Questionnaire (MRDQ) questionnaires will be administered to assess the impact of vision on quality of subject's life.

  7. Full Field Electroretinogram [ Time Frame: 1 year (Changes from baseline) ]
    The International Society for Clinical Electrophysiology of Vision (ISCEV) guidelines will be followed for conducting ff-ERG (Full-field Electroretinography)

  8. Wide-field fundus autofluorescence (wf-FAF) [ Time Frame: 1 year (Changes from baseline) ]
    The intensity of FAF will be evaluated using 55° posterior pole scanning.


Eligibility Criteria
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Ages Eligible for Study:   6 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Diagnosis and main criteria for inclusion:

Subjects meeting all inclusion criteria and none of the exclusion criteria are eligible for study participation.

Inclusion Criteria for Adult RP

  1. Males or females ≥18 years of age at the time of informed consent.
  2. Confirmed genetic diagnosis of biallelic autosomal recessive NR2E3 mutations or autosomal dominant NR2E3 mutation for Subgroup 1 or autosomal dominant RHO mutations for Subgroup 2.
  3. For subjects in Cohort 1-3, BCVA ≤ 20/50 or visual field less than 20° in any meridian, as measured by a III4e isopter or equivalent in study eye.
  4. Unable to perform a Multi-Luminance Mobility Testing (MLMT) using study eye at 1 lux, the lowest luminance level tested.

Exclusion Criteria for Adult RP

  1. Subject lacks evidence of outer nuclear layer
  2. Considered unsuitable for any reason that may either place the subject at increased risk during participation or interfere with the interpretation of the study outcomes by the Investigator, or the Sponsor after reviewing medical, ocular, and psychiatric history, clinical examination, and laboratory evaluation, as determined by the Investigator
  3. Previous treatment with a gene-therapy or cell therapy product.
  4. Previous treatment with any investigational drug or device within one year.
  5. Any contraindications for subretinal injection.

Inclusion Criteria for Adult LCA

  1. Males or females at least 18 years of age at the time of informed consent.
  2. Clinical diagnosis of LCA and confirmed genetic diagnosis of CEP290 mutation.
  3. Best corrected visual acuity (BCVA) equal to or worse than LogMAR +0.7 but equal to or better than LogMAR 3.5 (light perception) in the study eye.
  4. Detectable outer nuclear layer in the macular region as determined by spectral-domain optical coherence tomography (SD-OCT).

Exclusion Criteria for Adult LCA

  1. Any symptom of central nervous system involvement/disease that would impact the ability to measure visual function
  2. Any contraindications for subretinal injection.
  3. Any intraocular surgery within 6 months.
  4. Active ocular/intraocular infection (e.g., conjunctivitis, keratitis, scleritis, endophthalmitis)

Inclusion Criteria for Pediatric RP

  1. Males or females 6 - 17 years of age (inclusive) at the time of parental permission and/or assent, whichever is applicable.
  2. Confirmed genetic diagnosis of biallelic autosomal recessive NR2E3 mutations or autosomal dominant NR2E3 mutation for Subgroup 1 or autosomal dominant RHO mutations for Subgroup 2.
  3. BCVA ≤ 20/32 or visual field less than 20° in any meridian, as measured by a III4e isopter or equivalent in study eye.
  4. Able to perform a Multi-Luminance Mobility Testing (MLMT) using study eye, but unable to pass the MLMT at 1 lux, the lowest luminance level tested.

Exclusion Criteria for Pediatric RP

  1. Subject lacks evidence of outer nuclear layer as determined by spectral-domain optical coherence tomography (SD-OCT).
  2. Previous treatment with a gene-therapy or cell therapy product.
  3. Previous treatment with any investigational drug or device within one year.
  4. Any contraindications for subretinal injection.
  5. Breast-feeding, pregnancy, or inability to practice strict contraception within the Treatment Observation Period for subjects of childbearing potential.
  6. Active ocular/intraocular infection (e.g., conjunctivitis, keratitis, scleritis, endophthalmitis)

Inclusion Criteria for Pediatric LCA

  1. Males or females 6 - 17 years of age (inclusive) at the time of parental permission and/or assent, whichever is applicable.
  2. Clinical diagnosis of LCA and confirmed genetic diagnosis of CEP290 mutation.
  3. Best corrected visual acuity (BCVA) equal to or worse than LogMAR +0.7 but equal to or better than LogMAR 3.5 (light perception) in the study eye.
  4. Detectable outer nuclear layer in the macular region as determined by spectral-domain optical coherence tomography (SD-OCT).

Exclusion Criteria for Pediatric LCA

  1. Any symptom of central nervous system involvement/disease that would impact the ability to measure visual function
  2. Any contraindications for subretinal injection.
  3. Active ocular/intraocular infection (e.g., conjunctivitis, keratitis, scleritis, endophthalmitis)
  4. Breast-feeding, pregnancy, or inability to practice strict contraception within the Treatment Observation Period for subjects of childbearing potential.
Contacts and Locations
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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): NCT05203939


Contacts
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Contact: Murthy Chavali, PhD 405-714-4198 murthy.chavali@ocugen.com
Contact: Sahar Matloob, MD, ACRP-CP 610-871-6270 sahar.matloob@ocugen.com

Locations
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United States, Arizona
Associated Retina Consultants Recruiting
Phoenix, Arizona, United States, 85020
Principal Investigator: Benjamin Bakall         
United States, California
Ocugen Site 5 - University of California, San Diego (UCSD) - Shiley Eye Institute Recruiting
La Jolla, California, United States, 92093
Contact: Borooah         
United States, Florida
Ocugen Site 3 - Bascom Palmer Eye Institute Recruiting
Miami, Florida, United States, 33136
Contact: Lam         
United States, Georgia
Ocugen Site 6 - Emory University Recruiting
Atlanta, Georgia, United States, 30322
Contact: Jain         
United States, Oregon
Ocugen Site 2 - Casey Eye Institute - OHSU Recruiting
Portland, Oregon, United States, 97239
Contact: Yang         
United States, Pennsylvania
Ocugen Site 8 - Mid Atlantic Retina - Wills Eye Hospital Recruiting
Philadelphia, Pennsylvania, United States, 19107
Contact: Pulido         
United States, Texas
Ocugen Site 1 - Retina Foundation of the Southwest Recruiting
Dallas, Texas, United States, 75231
Contact: Kirsten Locke         
Principal Investigator: David Birch, PhD         
Sponsors and Collaborators
Ocugen
Investigators
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Study Director: Huma Qamar, MD, MPH, CMI Ocugen
More Information
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Additional Information:

Publications:

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Responsible Party: Ocugen
ClinicalTrials.gov Identifier: NCT05203939    
Other Study ID Numbers: OCU400-101
First Posted: January 24, 2022    Key Record Dates
Last Update Posted: October 25, 2023
Last Verified: October 2023
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 Ocugen:
NR2E3
Rhodopsin
Enhanced S-cone syndrome
Cep290
Additional relevant MeSH terms:
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Blindness
Retinitis
Retinitis Pigmentosa
Leber Congenital Amaurosis
Retinal Diseases
Eye Diseases
Eye Diseases, Hereditary
 Retinal Dystrophies
Retinal Degeneration
Genetic Diseases, Inborn
Vision Disorders
Sensation Disorders
Neurologic Manifestations
Nervous System Diseases