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| ID | Type | Description | Link |
|---|---|---|---|
| 1U10EY023558-01A1 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Eye Institute (NEI) | NIH |
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The study is a dose-escalation study, phase 1. The objective of this proposed clinical trial is to evaluate the safety of mitochondrially targeted ND4 gene therapy with the adeno-associated viral vector in appropriate LHON patients.
The purpose of this dose-escalation study is to assess the safety and tolerability of scAAV2-P1ND4v2 (abbreviated as AAV-ND4) gene replacement therapy in subjects confirmed with the G11778A mutation in mtDNA responsible for Leber's Hereditary Optic Neuropathy. Ocular and systemic toxicity will be assessed following vector administration to determine if there are adverse changes that may be associated with vector administration.
This first-in-man (FIM) clinical trial will assess the safety, tolerability, and potential efficacy of a single intravitreal injection in patient groups reflecting the acute, pre-symptomatic, and chronic stages and manifestation of the LHON disease.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Low-dose (1.18x10e9 vg) | Experimental | Participants with Chronic Bilateral Severe Vision Loss were administered 200 µL of scAAV2-P1ND4v2 containing a dose of 1.18x10e9 vg. Participants with Acute Bilateral Severe Vision Loss were administered 200 µL of scAAV2-P1ND4v2 containing a dose of 1.18x10e9 vg. Participants with Acute Unilateral Severe Vision Loss were administered 200 µL of scAAV2-P1ND4v2 containing a dose of 1.18x10e9 vg |
|
| Medium dose (5.81x10e9 vg) | Experimental | Participants with Chronic Bilateral Severe Vision Loss were administered 200 µL of scAAV2-P1ND4v2 containing a dose of 5.81x10e9 vg. Participants with Acute Bilateral Severe Vision Loss were administered 200 µL of scAAV2-P1ND4v2 containing a dose of 5.81x10e9 vg. Participants with Acute Unilateral Severe Vision Loss were administered 200 µL of scAAV2-P1ND4v2 containing a dose of 5.81x10e9 vg. |
|
| High dose (2.40x10e10 vg) | Experimental | Participants with Chronic Bilateral Severe Vision Loss were administered 100 µL of scAAV2-P1ND4v2 containing a dose of 2.40x10e10 vg. |
|
| Higher dose (1x10e11vg) | Experimental | Participants with Chronic Bilateral Severe Vision Loss were administered 100 µL of scAAV2-P1ND4v2 containing a dose of 1x10e11vg. Participants with Acute Bilateral Severe Vision Loss were administered 100 µL of scAAV2-P1ND4v2 containing a dose of 1x10e11vg. Participants with Acute Unilateral Severe Vision Loss were administered 100 µL of scAAV2-P1ND4v2 containing a dose of 1x10e11vg. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| injection of scAAV2-P1ND4v2 1.18x10e9 vg (Low), | Drug | injection of Total Volume of each intravitreal injection is 200 µL |
|
| Measure | Description | Time Frame |
|---|---|---|
| Number of Treatment Related Adverse Events | Number of treatment-related adverse events will be assessed as per investigator with respective to relationship to the investigative product. | 3 years |
| Measure | Description | Time Frame |
|---|---|---|
| Best-corrected Visual Acuity | Best-corrected visual acuity(BCVA) was tested using the ETDRS Chart. The LogMAR visual acuity scale was adapted from the ETDRS chart to facilitate statistical analysis. Longitudinal analyses of BCVA changes at months 12, 24, and 36 versus baseline 2 were performed. | up to 36 months after treatment |
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Inclusion Criteria:
Exclusion Criteria:
Unwilling or unable to give consent,
Unable or unlikely to return for scheduled protocol visits
Pregnant or nursing women or unwillingness for subject with childbearing potential to use contraception during the first year of the study.
Optic disc drusen on exam or in previous history.
Ocular diseases or visual dysfunction conditions other than refractive error (e.g. amblyopia, glaucoma, etc.) in the eye selected for the injection.
Previous eye surgery in the eye selected for injection.
Aspartate transaminase (AST)/alanine transaminase (ALT) >5.0 x upper limit of normal (ULN); Total bilirubin >3 x ULN; Hemoglobin < 8 g/dL; neutrophil count <1.0 x 109/L; or platelet count < 50 x 109/L
a) Any laboratory screening test that meets the abnormality criteria stated above can be repeated once between Baseline one to Baseline 2.
Type I diabetes or the presence of diabetic retinopathy
History of neurodegenerative conditions (e.g. multiple sclerosis, neuromyelitis optica, Parkinson's disease)
History of autoimmune conditions (e.g. systemic lupus erythematosus)
Systemic diseases having ocular manifestations likely to confound assessment of study results. History of cancer within five years other than localized basal or squamous cell carcinoma not near the orbital area. Patients with a prior history of cancer will need documentation from their cancer specialist that the cancer was cured at least 5 years before study entry.
Allergy to pupil dilating drops or narrow angles precluding safe dilation.
No Light Perception (NLP) vision in either eye.
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| Name | Affiliation | Role |
|---|---|---|
| Byron Lam, MD | Bascom Palmer Eye Institute, Miller School of Medicine, University of Miami, Miami, FL 33136 | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Bascom Palmer Eye Institute, University of Miami | Miami | Florida | 33136 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 26606867 | Result | Feuer WJ, Schiffman JC, Davis JL, Porciatti V, Gonzalez P, Koilkonda RD, Yuan H, Lalwani A, Lam BL, Guy J. Gene Therapy for Leber Hereditary Optic Neuropathy: Initial Results. Ophthalmology. 2016 Mar;123(3):558-70. doi: 10.1016/j.ophtha.2015.10.025. Epub 2015 Nov 19. | |
| 28647203 | Result | Guy J, Feuer WJ, Davis JL, Porciatti V, Gonzalez PJ, Koilkonda RD, Yuan H, Hauswirth WW, Lam BL. Gene Therapy for Leber Hereditary Optic Neuropathy: Low- and Medium-Dose Visual Results. Ophthalmology. 2017 Nov;124(11):1621-1634. doi: 10.1016/j.ophtha.2017.05.016. Epub 2017 Jun 21. |
| Label | URL |
|---|---|
| Bascom Palmer News | View source |
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A total of 28 participants with G11778A Leber Hereditary Optic Neuropathy (LHON) were enrolled in the study. They were distributed in the following groups: chronic bilateral visual loss > 12 months (group 1, n=11), acute bilateral visual loss < 12 months (group 2, n=9), or unilateral visual loss (group 3, n=8). Each participant received a unilateral intravitreal injection. Group 1 was treated with low, medium, high and higher dose, group 2 and 3 were treated with low, medium, or higher dose.
Participants were enrolled at Bascom Palmer Eye Institute (Single institution study) in Florida, United States(US) from 14 July 2014 to 18 Nov 2020.
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| ID | Title | Description |
|---|---|---|
| FG000 | Low-dose (1.18x10e9 vg) | Participants with Chronic Bilateral Severe Vision Loss were administered 200 µL of scAAV2-P1ND4v2 containing a dose of 1.18x10e9 vg. Participants with Acute Bilateral Severe Vision Loss were administered 200 µL of scAAV2-P1ND4v2 containing a dose of 1.18x10e9 vg. Participants with Acute Unilateral Severe Vision Loss were administered were administrated 200 µL of scAAV2-P1ND4v2 containing a dose of 1.18x10e9 vg. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Feb 9, 2019 |
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|
| injection of scAAV2-P1ND4v2 5.81 X10e9 vg (Med) | Drug | injection of Total Volume of each intravitreal injection is 200 µL |
|
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| injection of scAAV2-P1ND4v2 2.4 X10e10vg (High) | Drug | injection of Total Volume of each intravitreal injection is 100 µL |
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| injection of scAAV2-P1ND4v2 1.0 X10e11vg (Higher) | Drug | injection of Total Volume of each intravitreal injection is 100 µL |
|
|
| 35271811 | Result | Lam BL, Feuer WJ, Davis JL, Porciatti V, Yu H, Levy RB, Vanner E, Guy J. Leber Hereditary Optic Neuropathy Gene Therapy: Adverse Events and Visual Acuity Results of All Patient Groups. Am J Ophthalmol. 2022 Sep;241:262-271. doi: 10.1016/j.ajo.2022.02.023. Epub 2022 Mar 7. |
| 37716450 | Result | Lam BL, Feuer WJ, Porciatti V, Davis JL, Zheng DD, Vanner EA, Savatovsky EJ, Alba DE, Guy J. Leber Hereditary Optic Neuropathy Gene Therapy: Longitudinal Relationships Among Visual Function and Anatomical Measures. Am J Ophthalmol. 2024 Jan;257:113-128. doi: 10.1016/j.ajo.2023.09.005. Epub 2023 Sep 15. |
| 35344016 | Result | Porciatti V, Alba DE, Feuer WJ, Davis J, Guy J, Lam BL. The Relationship Between Stage of Leber's Hereditary Optic Neuropathy and Pattern Electroretinogram Latency. Transl Vis Sci Technol. 2022 Mar 2;11(3):31. doi: 10.1167/tvst.11.3.31. |
| 38117686 | Result | Lam BL. Leber hereditary optic neuropathy gene therapy. Curr Opin Ophthalmol. 2024 May 1;35(3):244-251. doi: 10.1097/ICU.0000000000001028. Epub 2023 Dec 20. |
| 27631475 | Result | Lam BL, Burke SP, Wang MX, Nadayil GA, Rosa PR, Gregori G, Feuer WJ, Cuprill-Nilson S, Vandenbroucke R, Zhang X, Guy J. Macular Retinal Sublayer Thicknesses in G11778A Leber Hereditary Optic Neuropathy. Ophthalmic Surg Lasers Imaging Retina. 2016 Sep 1;47(9):802-10. doi: 10.3928/23258160-20160901-02. |
| 25342621 | Result | Koilkonda R, Yu H, Talla V, Porciatti V, Feuer WJ, Hauswirth WW, Chiodo V, Erger KE, Boye SL, Lewin AS, Conlon TJ, Renner L, Neuringer M, Detrisac C, Guy J. LHON gene therapy vector prevents visual loss and optic neuropathy induced by G11778A mutant mitochondrial DNA: biodistribution and toxicology profile. Invest Ophthalmol Vis Sci. 2014 Oct 23;55(12):7739-53. doi: 10.1167/iovs.14-15388. |
| 24398093 | Result | Guy J, Feuer WJ, Porciatti V, Schiffman J, Abukhalil F, Vandenbroucke R, Rosa PR, Lam BL. Retinal ganglion cell dysfunction in asymptomatic G11778A: Leber hereditary optic neuropathy. Invest Ophthalmol Vis Sci. 2014 Feb 10;55(2):841-8. doi: 10.1167/iovs.13-13365. |
| 24457989 | Result | Koilkonda RD, Yu H, Chou TH, Feuer WJ, Ruggeri M, Porciatti V, Tse D, Hauswirth WW, Chiodo V, Boye SL, Lewin AS, Neuringer M, Renner L, Guy J. Safety and effects of the vector for the Leber hereditary optic neuropathy gene therapy clinical trial. JAMA Ophthalmol. 2014 Apr 1;132(4):409-20. doi: 10.1001/jamaophthalmol.2013.7630. |
| 30194931 | Derived | Davis JL. The Blunt End: Surgical Challenges of Gene Therapy for Inherited Retinal Diseases. Am J Ophthalmol. 2018 Dec;196:xxv-xxix. doi: 10.1016/j.ajo.2018.08.038. Epub 2018 Sep 5. |
| FG001 | Medium Dose (5.81x10e9 vg) | Participants with Chronic Bilateral Severe Vision Loss were administered 200 µL of scAAV2-P1ND4v2 containing a dose of 5.81x10e9 vg. Participants with Acute Bilateral Severe Vision Loss were administered 200 µL of scAAV2-P1ND4v2 containing a dose of 5.81x10e9 vg. Participants with Acute Unilateral Severe Vision Loss were administered were administrated 200 µL of scAAV2-P1ND4v2 containing a dose of 5.81x10e9 vg. |
| FG002 | High Dose (2.40x10e10 vg) | Participants with Chronic Bilateral Severe Vision Loss were administered 100 µL of scAAV2-P1ND4v2 containing a dose of 2.40x10e10 vg. |
| FG003 | Higher Dose (1x10e11vg) | Participants with Chronic Bilateral Severe Vision Loss were administered 100 µL of scAAV2-P1ND4v2 containing a dose of 1x10e11vg. Participants with Acute Bilateral Severe Vision Loss were administrated 100 µL of scAAV2-P1ND4v2 containing a dose of 1x10e11vg. Participants with Acute Unilateral Severe Vision Loss were administered 100 µL of scAAV2-P1ND4v2 containing a dose of 1x10e11vg. |
| Chronic Bilateral |
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| Acute Bilateral |
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| Acute Unilateral |
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| COMPLETED |
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| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | Low-dose (1.18x10e9 vg) | Participants with Chronic Bilateral Severe Vision Loss were administered 200 µL of scAAV2-P1ND4v2 containing a dose of 1.18x10e9 vg. Participants with Acute Bilateral Severe Vision Loss were administered 200 µL of scAAV2-P1ND4v2 containing a dose of 1.18x10e9 vg. Participants with Acute Unilateral Severe Vision Loss were administered 200 µL of scAAV2-P1ND4v2 containing a dose of 1.18x10e9 vg. |
| BG001 | Medium Dose (5.81x10e9 vg) | Participants with Chronic Bilateral Severe Vision Loss were administered 200 µL of scAAV2-P1ND4v2 containing a dose of 5.81x10e9 vg. Participants with Acute Bilateral Severe Vision Loss were administrated 200 µL of scAAV2-P1ND4v2 containing a dose of 5.81x10e9 vg. Participants with Acute Unilateral Severe Vision Loss were administered 200 µL of scAAV2-P1ND4v2 containing a dose of 5.81x10e9 vg. |
| BG002 | High Dose (2.40x10e10 vg) | Participants with Chronic Bilateral Severe Vision Loss were administered 100 µL of scAAV2-P1ND4v2 containing a dose of 2.40x10e10 vg. |
| BG003 | Higher Dose (1x10e11vg) | Participants with Chronic Bilateral Severe Vision Loss were administered 100 µL of scAAV2-P1ND4v2 containing a dose of 1x10e11vg. Participants with Acute Bilateral Severe Vision Loss were administrated 100 µL of scAAV2-P1ND4v2 containing a dose of 1x10e11vg. Participants with Acute Unilateral Severe Vision Loss were administered 100 µL of scAAV2-P1ND4v2 containing a dose of 1x10e11vg. |
| BG004 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Full Range | years |
| |||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Number of Treatment Related Adverse Events | Number of treatment-related adverse events will be assessed as per investigator with respective to relationship to the investigative product. | One subject for medium dose was a loss to follow up after month 06. One subject for low dose missed visits for month 12, month 24 and month 36 | Posted | Count of Participants | Participants | 3 years |
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| Secondary | Best-corrected Visual Acuity | Best-corrected visual acuity(BCVA) was tested using the ETDRS Chart. The LogMAR visual acuity scale was adapted from the ETDRS chart to facilitate statistical analysis. Longitudinal analyses of BCVA changes at months 12, 24, and 36 versus baseline 2 were performed. | One subject for low dose missed visits 12, 24, and 36 months but he completed the majority of the other study visits. One subject for medium dose was a loss to follow up after visit 6 months. One subject for higher dose missed a visit 12 months to the COVID-19 pandemic. | Posted | Mean | Standard Deviation | logMar | up to 36 months after treatment |
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3 Years
Participants were followed for AE for 3 years. In addition to the SAE definition for clinicaltrial.gov, this study also considered an SAE a decrease in acuity in the injected eye to 0.3 logMAR units (15-letter equivalent) worse than the worst acuity measured in the uninjected fellow eye at the current or any prior study visit.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Low-dose (1.18x10e9 vg) | Participants with Chronic Bilateral Severe Vision Loss were administered 200 µL of scAAV2-P1ND4v2 containing a dose of 1.18x10e9 vg. Participants with Acute Bilateral Severe Vision Loss were administered 200 µL of scAAV2-P1ND4v2 containing a dose of 1.18x10e9 vg. Participants with Acute Unilateral Severe Vision Loss were administered 200 µL of scAAV2-P1ND4v2 containing a dose of 1.18x10e9 vg. | 0 | 9 | 1 | 9 | 3 | 9 |
| EG001 | Medium Dose (5.81x10e9 vg) | Participants with Chronic Bilateral Severe Vision Loss were administered 200 µL of scAAV2-P1ND4v2 containing a dose of 5.81x10e9 vg. Participants with Acute Bilateral Severe Vision Loss were administrated 200 µL of scAAV2-P1ND4v2 containing a dose of 5.81x10e9 vg. Participants with Acute Unilateral Severe Vision Loss were administered 200 µL of scAAV2-P1ND4v2 containing a dose of 5.81x10e9 vg. | 0 | 9 | 1 | 9 | 3 | 9 |
| EG002 | High Dose (2.40x10e10 vg) | Participants with Chronic Bilateral Severe Vision Loss were administered 100 µL of scAAV2-P1ND4v2 containing a dose of 2.40x10e10 vg. | 0 | 3 | 0 | 3 | 1 | 3 |
| EG003 | Higher Dose (1x10e11vg) | Participants with Chronic Bilateral Severe Vision Loss were administered 100 µL of scAAV2-P1ND4v2 containing a dose of 1x10e11vg. Participants with Acute Bilateral Severe Vision Loss were administered 100 µL of scAAV2-P1ND4v2 containing a dose of 1x10e11vg. Participants with Acute Unilateral Severe Vision Loss were administered 100 µL of scAAV2-P1ND4v2 containing a dose of 1x10e11vg. | 0 | 7 | 0 | 7 | 7 | 7 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Visual Acuity Loss | Eye disorders | Systematic Assessment | SAE will be considered a decrease in acuity in the injected eye to 0.3 logMAR units (15-letter equivalent) worse than the worst acuity measured in the uninjected fellow eye at the current or any prior study visit. |
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Uveitis | Eye disorders | Systematic Assessment | One participant of Low Dose had two different episodes of Uveitis |
| |
| Corneal Abrasion | Eye disorders | Systematic Assessment | Causality: not related to research. One participant of Higher dose had 2 different adverse events: Corneal abrasion and Uveitis. |
| |
| Elevated Liver Enzymes | Metabolism and nutrition disorders | Systematic Assessment | causality: not related to research |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Byron Lam. | Bascom Palmer Eye Institute. | 305 326 6021 | blam@med.miami.edu |
| Mar 29, 2024 |
| Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Sep 20, 2020 | May 20, 2024 | ICF_001.pdf |
| ID | Term |
|---|---|
| D029242 | Optic Atrophy, Hereditary, Leber |
| ID | Term |
|---|---|
| D015418 | Optic Atrophies, Hereditary |
| D009896 | Optic Atrophy |
| D009901 | Optic Nerve Diseases |
| D003389 | Cranial Nerve Diseases |
| D009422 | Nervous System Diseases |
| D020271 | Heredodegenerative Disorders, Nervous System |
| D019636 | Neurodegenerative Diseases |
| D015785 | Eye Diseases, Hereditary |
| D005128 | Eye Diseases |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D028361 | Mitochondrial Diseases |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
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| ID | Term |
|---|---|
| D064235 | Matrilin Proteins |
| ID | Term |
|---|---|
| D016326 | Extracellular Matrix Proteins |
| D012596 | Scleroproteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
Not provided
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| Male |
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| Not Hispanic or Latino |
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| Unknown or Not Reported |
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| Asian |
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| Native Hawaiian or Other Pacific Islander |
|
| Black or African American |
|
| White |
|
| More than one race |
|
| Unknown or Not Reported |
|
| OG002 | High Dose (2.40x10e10 vg) | Participants with Chronic Bilateral Severe Vision Loss were administered 100 µL of scAAV2-P1ND4v2 containing a dose of 2.40x10e10 vg. |
| OG003 | Higher Dose (1x10e11vg) | Participants with Chronic Bilateral Severe Vision Loss were administered 100 µL of scAAV2-P1ND4v2 containing a dose of 1x10e11vg. Participants with Acute Bilateral Severe Vision Loss were administered 100 µL of scAAV2-P1ND4v2 containing a dose of 1x10e11vg. Participants with Acute Unilateral Severe Vision Loss were administered 100 µL of scAAV2-P1ND4v2 containing a dose of 1x10e11vg. |
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