Macular Telangiectasia Type 2 (MacTel)
Conditions
Keywords
Ciliary Neurotrophic Factor (CNTF), Macular Telangiectasia Type 2, MacTel
Brief summary
This study is a phase 3, randomized, multi-center study to evaluate the efficacy and safety of the NT-501 implants in participants with macular telangiectasia type 2.
Detailed description
Phase 3, prospective, multicenter, masked, sham-controlled study with the overall study objective to evaluate the efficacy and safety of NT-501 for the treatment of MacTel. Secondary objective was to evaluate the safety of NT-501 in participants with MacTel. This was a multicenter study conducted at 20 study centers in the United States, Australia, France, and the United Kingdom.
Interventions
COMBINATION_PRODUCTNT-501
Each NT-501 implant consisted of hCNTF-secreting NTC-201-6A.02 cells encapsulated within supportive matrices and surrounded by a semipermeable polymer membrane. The NTC-201-6A cells continuously secrete CNTF from the NT-501 implant into the vitreous cavity. Implanted by a qualified Health Care Professional.
PROCEDURESham Procedure
The sham surgery involved a superficial conjunctival incision performed under local anesthetic and closure with a single suture.
Sponsors
The Lowy Medical Research Institute Limited
Neurotech Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Masking description
The subjects and all personnel at the image reading center remained masked to the treatment assignment throughout the study. In addition, the refractionist, VA examiner, and photographers/imagers were masked to treatment assignment (NT-501 implantation or sham procedure) at all follow-up visits. The ophthalmologist, surgeon, and clinic coordinator were instructed not to discuss the assigned treatment with the subject.
Intervention model description
After confirming eligibility in conjunction with the reading center, the study eye of each subject was randomized (1:1) to either have NT-501 implanted or to undergo the sham procedure.
Eligibility
Sex/Gender
ALL
Age
21 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: 1. Participant must have at least one study eye with a positive diagnosis of MacTel with evidence of fluorescein leakage typical of MacTel and at least one of the other features that include hyperpigmentation that is outside of a 500 micron radius from the center of the fovea, retinal opacification, crystalline deposits, right-angle vessels, or inner/outer lamellar cavities 2. Participant must have an Inner Segment - Outer Segment Junction Line (IS/OS) Photo Receptor (PR) break in the study eye(s) and en face EZ (area of IS/OS loss) as measured by spectral-domain optical coherence tomography (SD-OCT) between 0.16 mm\^2 and 2.00 mm\^2 3. Participant's best corrected visual acuity (BCVA) is a 54-letter score or better (20/80 or better) as measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) chart at screening. 4. Participant must have steady fixation in the foveal or parafoveal area and sufficiently clear media for good quality photographs 5. Participant must be greater than 21 years of age or less than 80 years of age at screening 6. Participant must be able to provide written informed consent to participate in the study, in accordance with the International Conference on Harmonisation Good Clinical Practices guidelines, and local regulations, before initiating any study-related procedures 7. Women of childbearing potential must agree to use highly effective contraception (Germany and France only) Key
Exclusion criteria
1. Participant is medically unable to comply with study procedures or follow-up visits 2. Participant received intravitreal steroid therapy for non-neovascular MacTel within the last 3 months 3. Participant has ever received intravitreal anti-vascular endothelial growth factor (VEGF) therapy in the study eye OR has, within the past 3 months, received intravitreal anti-VEGF in the fellow eye at randomization 4. Participant has evidence of ocular disease other than MacTel that, in the judgment of the examining physician, may confound the diagnosis, procedures or outcome of the study (eg, glaucoma, severe nonproliferative or proliferative diabetic retinopathy, uveitis) 5. Participant has a chronic requirement (eg, ≥ 4 weeks at a time) for ocular medications and/or has a diagnosed disease that, in the judgment of the examining physician, may be vision threatening or may affect the primary outcome (artificial tears are permitted) 6. Participant has evidence of intraretinal neovascularization or subretinal neovascularization (SRNV), as evidenced by hemorrhage, hard exudate, subretinal fluid or intraretinal fluid in either eye 7. Participant has evidence of central serous chorio-retinopathy in either eye 8. Participant has evidence of pathologic myopia in either eye 9. Participant has significant corneal or media opacities in either eye 10. Participant has had a vitrectomy, penetrating keratoplasty, trabeculectomy, or trabeculoplasty 11. Participant has any of the following lens opacities: cortical opacity \> standard 3, posterior subcapsular opacity \> standard 2, or a nuclear opacity \> standard 3 as measured on the Age-Related Eye Disease Study (AREDS) clinical lens grading system 12. Participant has undergone lens removal in the previous 3 months or YAG laser within 4 weeks 13. Participant was a participant in any other clinical trial of an intervention (drug or device) within the last 6 months 14. Participant is on chemotherapy 15. Participant is pregnant or breastfeeding 16. Participant has a history of malignancy that would compromise the 24-month study survival 17. Participant with a history of ocular herpes virus in either eye 18. Participant has, in the opinion of the investigator, any physical or mental condition that would increase the risk of participation in the study or may interfere with the study procedures, evaluations, and outcome assessments 19. Participant has evidence of intraretinal hyperreflectivity by OCT
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Rate of Change in the Area of EZ Area of Loss From Baseline Through Month 24 | End point timeframe is through Month 24. Baseline, Month 6, 12, 16, 20 and 24. Month 6 was collected but not included in the primary analyses. | The rate of change in the area of EZ loss (IS/OS; macular photoreceptor loss) from baseline through month 24, as assessed using SD-OCT in the study eye of subjects with MacTel. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in Aggregate Retinal Sensitivity Loss and Aggregate Interpolated Retinal Sensitivity Loss by Microperimetry (mITT Population) | Baseline through 24 months. | Change from baseline in retinal sensitivity loss as measured by as measured by Macular Integrity Assessment (MAIA) |
| Monocular Reading Speed (mITT Population) | Baseline through 24 months. | Change from baseline through Month 24 for Monocular reading speed assessed using International Reading Speed Texts (IReST) cards developed by the IReST Study Group 21 |
Countries
Australia, France, United Kingdom, United States
Participant flow
Recruitment details
Screening period for up to 30 days
Pre-assignment details
120 subjects enrolled (5 participants withdrew after randomization) but prior to the implantation/sham surgery procedure; 61 subjects in NT-501 arm and 59 subjects in sham arm.
Participants by arm
| Arm | Count |
|---|---|
| NT-501 Test product
NT-501: Each NT-501 implant consisted of hCNTF-secreting NTC-201-6A.02 cells encapsulated within supportive matrices and surrounded by a semipermeable polymer membrane. The NTC-201-6A cells continuously secrete CNTF from the NT-501 implant into the vitreous cavity. Implanted by a qualified Health Care Professional. | 58 |
| Sham A sham surgical procedure was performed to mimic the implant procedure; there was no comparator product.
Sham Procedure: The sham surgery involved a superficial conjunctival incision performed under local anesthetic and closure with a single suture. | 57 |
| Total | 115 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | COVID-19 | 0 | 1 |
| Overall Study | Eligible and did not enroll in amendment | 4 | 4 |
| Overall Study | Withdrawal by Subject | 3 | 2 |
Baseline characteristics
| Characteristic | NT-501 | Sham | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 21 Participants | 20 Participants | 41 Participants |
| Age, Categorical Between 18 and 65 years | 37 Participants | 37 Participants | 74 Participants |
| Age, Continuous | 61.1 years STANDARD_DEVIATION 8.01 | 60.2 years STANDARD_DEVIATION 8.39 | 60.7 years STANDARD_DEVIATION 8.17 |
| Baseline Ocular Characteristics (mITT) - Area of EZ loss (mm^2) | 0.513 Area of EZ loss (mm^2) STANDARD_DEVIATION 0.4773 | 0.487 Area of EZ loss (mm^2) STANDARD_DEVIATION 0.3576 | 0.501 Area of EZ loss (mm^2) STANDARD_DEVIATION 0.4206 |
| Baseline Ocular Characteristics (mITT) - Monocular Reading Speed | 92.09 words per minute STANDARD_DEVIATION 43.717 | 96.01 words per minute STANDARD_DEVIATION 54.01 | 94.03 words per minute STANDARD_DEVIATION 48.907 |
| Baseline Ocular Characteristics (mITT) - Ocular Visual Acuity | 70.8 Best-corrected visual acuity (letters) STANDARD_DEVIATION 9.11 | 73.3 Best-corrected visual acuity (letters) STANDARD_DEVIATION 8.64 | 72.0 Best-corrected visual acuity (letters) STANDARD_DEVIATION 8.93 |
| Baseline Ocular Characteristics (mITT) - Pupil Diameter | 3.59 Pupil diameter (mm) STANDARD_DEVIATION 0.882 | 3.36 Pupil diameter (mm) STANDARD_DEVIATION 0.822 | 3.47 Pupil diameter (mm) STANDARD_DEVIATION 0.856 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 5 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 57 Participants | 52 Participants | 109 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Intraocular Pressure (mmHg) | 16.2 mmHg STANDARD_DEVIATION 2.61 | 16.3 mmHg STANDARD_DEVIATION 3.16 | 16.2 mmHg STANDARD_DEVIATION 2.88 |
| Natural Lens Present No | 14 Participants | 9 Participants | 23 Participants |
| Natural Lens Present Yes | 44 Participants | 48 Participants | 92 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 3 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants | 3 Participants | 8 Participants |
| Race (NIH/OMB) White | 50 Participants | 48 Participants | 98 Participants |
| Sex: Female, Male Female | 39 Participants | 40 Participants | 79 Participants |
| Sex: Female, Male Male | 19 Participants | 17 Participants | 36 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 58 | 1 / 57 |
| other Total, other adverse events | 54 / 58 | 47 / 57 |
| serious Total, serious adverse events | 12 / 58 | 7 / 57 |
Outcome results
Primary
The Rate of Change in the Area of EZ Area of Loss From Baseline Through Month 24
The rate of change in the area of EZ loss (IS/OS; macular photoreceptor loss) from baseline through month 24, as assessed using SD-OCT in the study eye of subjects with MacTel.
Time frame: End point timeframe is through Month 24. Baseline, Month 6, 12, 16, 20 and 24. Month 6 was collected but not included in the primary analyses.
Population: The efficacy and safety of the NT-501 implant that delivers a daily dose of CNTF in comparison to sham surgery with no implant, in participants with confirmed MacTel.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NT-501 | The Rate of Change in the Area of EZ Area of Loss From Baseline Through Month 24 | 0.075 mm^2 | Standard Error 0.0123 |
| Sham | The Rate of Change in the Area of EZ Area of Loss From Baseline Through Month 24 | 0.166 mm^2 | Standard Error 0.0125 |
p-value: <0.000195% CI: [-0.13, -0.06]Mixed Models Analysis
Secondary
Mean Change in Aggregate Retinal Sensitivity Loss and Aggregate Interpolated Retinal Sensitivity Loss by Microperimetry (mITT Population)
Change from baseline in retinal sensitivity loss as measured by as measured by Macular Integrity Assessment (MAIA)
Time frame: Baseline through 24 months.
Population: All treated participants (mITT population)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| NT-501 | Mean Change in Aggregate Retinal Sensitivity Loss and Aggregate Interpolated Retinal Sensitivity Loss by Microperimetry (mITT Population) | Month 24 Change from Baseline | 25.27 dB | Standard Deviation 34.238 |
| NT-501 | Mean Change in Aggregate Retinal Sensitivity Loss and Aggregate Interpolated Retinal Sensitivity Loss by Microperimetry (mITT Population) | Baseline Actual | 63.86 dB | Standard Deviation 80.642 |
| NT-501 | Mean Change in Aggregate Retinal Sensitivity Loss and Aggregate Interpolated Retinal Sensitivity Loss by Microperimetry (mITT Population) | Month 24 Actual | 86.50 dB | Standard Deviation 96.17 |
| Sham | Mean Change in Aggregate Retinal Sensitivity Loss and Aggregate Interpolated Retinal Sensitivity Loss by Microperimetry (mITT Population) | Baseline Actual | 58.30 dB | Standard Deviation 62.272 |
| Sham | Mean Change in Aggregate Retinal Sensitivity Loss and Aggregate Interpolated Retinal Sensitivity Loss by Microperimetry (mITT Population) | Month 24 Change from Baseline | 43.02 dB | Standard Deviation 41.763 |
| Sham | Mean Change in Aggregate Retinal Sensitivity Loss and Aggregate Interpolated Retinal Sensitivity Loss by Microperimetry (mITT Population) | Month 24 Actual | 100.15 dB | Standard Deviation 85.991 |
| Aggregate Interpolated Retinal Sensitivity Loss (dB) - NT-501 | Mean Change in Aggregate Retinal Sensitivity Loss and Aggregate Interpolated Retinal Sensitivity Loss by Microperimetry (mITT Population) | Month 24 Actual | 60330.58 dB | Standard Deviation 81883.302 |
| Aggregate Interpolated Retinal Sensitivity Loss (dB) - NT-501 | Mean Change in Aggregate Retinal Sensitivity Loss and Aggregate Interpolated Retinal Sensitivity Loss by Microperimetry (mITT Population) | Baseline Actual | 42588.33 dB | Standard Deviation 64255.621 |
| Aggregate Interpolated Retinal Sensitivity Loss (dB) - NT-501 | Mean Change in Aggregate Retinal Sensitivity Loss and Aggregate Interpolated Retinal Sensitivity Loss by Microperimetry (mITT Population) | Month 24 Change from Baseline | 19244.29 dB | Standard Deviation 24911.285 |
| Aggregate Interpolated Retinal Sensitivity Loss (dB) - Sham | Mean Change in Aggregate Retinal Sensitivity Loss and Aggregate Interpolated Retinal Sensitivity Loss by Microperimetry (mITT Population) | Baseline Actual | 33684.07 dB | Standard Deviation 40566.334 |
| Aggregate Interpolated Retinal Sensitivity Loss (dB) - Sham | Mean Change in Aggregate Retinal Sensitivity Loss and Aggregate Interpolated Retinal Sensitivity Loss by Microperimetry (mITT Population) | Month 24 Change from Baseline | 29749.64 dB | Standard Deviation 27021.695 |
| Aggregate Interpolated Retinal Sensitivity Loss (dB) - Sham | Mean Change in Aggregate Retinal Sensitivity Loss and Aggregate Interpolated Retinal Sensitivity Loss by Microperimetry (mITT Population) | Month 24 Actual | 62598.85 dB | Standard Deviation 57942.882 |
Secondary
Monocular Reading Speed (mITT Population)
Change from baseline through Month 24 for Monocular reading speed assessed using International Reading Speed Texts (IReST) cards developed by the IReST Study Group 21
Time frame: Baseline through 24 months.
Population: All treated participants (mITT population) without missing data
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| NT-501 | Monocular Reading Speed (mITT Population) | Baseline Actual | 92.09 Reading Speed (words per minute) | Standard Deviation 43.717 |
| NT-501 | Monocular Reading Speed (mITT Population) | Month 24 Actual | 85.70 Reading Speed (words per minute) | Standard Deviation 50.512 |
| NT-501 | Monocular Reading Speed (mITT Population) | Month 24 Change from Baseline | -6.18 Reading Speed (words per minute) | Standard Deviation 29.188 |
| Sham | Monocular Reading Speed (mITT Population) | Baseline Actual | 96.01 Reading Speed (words per minute) | Standard Deviation 54.01 |
| Sham | Monocular Reading Speed (mITT Population) | Month 24 Actual | 84.38 Reading Speed (words per minute) | Standard Deviation 42.917 |
| Sham | Monocular Reading Speed (mITT Population) | Month 24 Change from Baseline | -12.20 Reading Speed (words per minute) | Standard Deviation 42.188 |