Nonexudative Age-Related Macular Degeneration, Unspecified Eye, Intermediate Dry Stage
Conditions
Keywords
eye disease, retinal disorder, CNTF, AMD, Atrophic AMD
Brief summary
The purpose of this study is to look at the safety and effectiveness of CNTF implants on vision in participants with atrophic macular degeneration. This research is being done because there are no effective therapies for people with atrophic macular degeneration. Age-related macular degeneration (AMD) is a condition that affects the macula, the central part of the retina that we use for seeing details. There are two types of AMD, one is the wet type in which new blood vessels grow, also known as choroidal neovascularization (CNV), but the other is the dry type in which the healthy cells die, and that is the target of this study. This is called atrophic macular degeneration. The implant is a small capsule that contains human retinal pigment epithelium cells. These cells have been given the ability to make CNTF and release it through the capsule membrane into the surrounding fluid. In this study, two different CNTF dose levels will be used: a high dose and a low dose, as well as a sham surgery (or placebo) group.
Detailed description
Histopathologic studies of multiple forms of retinal neurodegenerative diseases have demonstrated the possibility of using the neurotrophic factor CNTF as an effective approach to reducing photoreceptor cell loss. Consequently, it had been hypothesized that the use of the implanted NT-501 capsule, which secretes CNTF into the vitreous, might be beneficial in people with atrophic macular degeneration. The purpose of this pilot study was to accumulate preliminary data on the effect of the intraocular NT-501 implant on visual acuity in patients with atrophic macular degeneration. The study had a double-masked, multi-center, randomized, parallel group design. Eligible patients were randomized on a 2:1:1 basis to the higher CNTF output NTC-201-6A.02 implant, the lower CNTF output NTC-201-10.02 implant or to sham surgery, respectively. The surgeon designated by the Principal Investigator (PI), the PI, vision examiners, reading center graders, and patients were all masked as to the dose of the implant. The patients and the vision examiners were masked as to which treatment was received. Approximately 48 patients with geographic atrophy compatible with category 3 or 4 AMD were planned to be enrolled. All patients were to be followed clinically for 18 months. Patients randomized to the CNTF implants were implanted at baseline, had the option of being explanted at or after 12 months, and all were followed clinically for 18 months. Follow-up for safety occurred throughout the study period.
Interventions
COMBINATION_PRODUCTHigh Dose NT-501 implant
High Dose NT-501
COMBINATION_PRODUCTLow Dose NT-501 implant
Low Dose NT-501
OTHERSham
Sham Procedure
Sponsors
Neurotech Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Study inclusion criteria: 1. To participate in this study, the participant had to understand and sign the protocol's informed consent (if the participant's vision was impaired to the point where it was not possible to read the informed consent document, the informed consent document was read in its entirety to the participant). 2. Women of childbearing potential (women with last menses \<1 year prior to screening) had to agree to use an effective form of birth control from study onset until they completed the 18 month study visit. 3. Participant had to be medically able to undergo ophthalmic surgery for NT-501 implant. 4. Best-corrected visual acuity in the study eye between 20/50 and 20/200 (68-34 letter score) as measured using EVA. 5. Presence in the study and/or fellow eye of geographic atrophy (GA) compatible with category 3 or 4 age-related macular degeneration (AMD) as defined by AREDS (AREDS, 2001). Also, the GA in the study eye had to be associated with vision loss as assessed by a vision test. GA was defined as one or more well-defined, usually more or less circular patches of partial or complete depigmentation of the RPE, typically with exposure of underlying choroidal blood vessels. Even if much of the RPE appeared to be preserved and large choroidal vessels were not visible, a roundish patch of RPE partial depigmentation might still be classified as early GA. A patch had to be at least 175 microns in area. 6. Participants had steady fixation in the study eye in the foveal or parafoveal area with media clear enough for good quality photographs. Study
Exclusion criteria
1. Participant less than 50 years of age (to minimize geographic atrophy from causes other than AMD). 2. Participant medically unable to comply with study procedures or follow-up visits. 3. Participant had evidence of ocular disease other than AMD that might confound the outcome of the study (e.g., diabetic retinopathy, uveitis, etc.). 4. Participant had chronic requirement (e.g., \> or = 4 weeks at a time) for ocular medications or had disease(s), that in the judgment of the examining physician, were vision threatening or might affect the primary outcome (artificial tears were permitted). 5. Participant had evidence of classic or occult choroidal neovascularization in either eye, which might include serous RPE detachment, stippling on a fluorescein angiogram, macular edema, evidence of hemorrhage and lipid, and disciform scar. 6. Participant had a requirement for acyclovir and/or related products during study duration. To be eligible for this study, the participant had to discontinue use of these products prior to enrollment and could not continue with the products until after they had completed the study. 7. Participant had evidence of central serous chorio-retinopathy (CSR) in either eye. 8. Participant had evidence of pathologic myopia in either eye. 9. Participant had evidence of pseudovitelliform macular degeneration (a dominantly inherited disease characterized by a round or oval yellow subretinal macular deposit) in either eye. 10. Participant was receiving systemic steroids or other immunosuppressive medications. 11. Participant with evidence of vitreo-retinal traction maculopathy in either eye. 12. Participant had a history of laser, photodynamic therapy (PDT), intravitreal injection of antivascular endothelial growth factor (VEGF) agent, or any previous treatment for AMD other than AREDS or equivalent supplement formulation. 13. Prior history of vitrectomy, penetrating keratoplasty, trabeculectomy or trabeculoplasty. 14. Participant had any of the following lens opacities: cortical opacity \> standard 3, posterior subcapsular opacity \> standard 3, or a nuclear opacity \> standard 3 as measured on the AREDS clinical lens grading system. 15. Participant had undergone lens removal in the last 3 months. 16. Participant had participated in any other clinical trial of a drug or within the last 6 months. 17. Participant was on chemotherapy. 18. Participant was on ocular or systemic medications known to be toxic to the lens, retina, or optic nerve. 19. Participant was pregnant or lactating. 20. Participant had other retinal disease(s). 21. Participant had a history of malignancy, except study participants with a history of successfully treated cancer (≥5 years prior to inclusion in the trial). 22. Participant was considered immunodeficient or had a known history of HIV. 23. Participant with a history of ocular herpes zoster. 24. Participant's fellow eye visual acuity worse than 20/400. 25. Participant had undergone LASIK surgery or other refractive surgery for either eye in less than 6 months prior to screening. 26. Participants with severe hearing disabilities in both ears. 27. Participants with unmanaged diabetes, patients with CME, or retinopathy in either eye. 28. Participant had a history of retinal detachment in either eye. 29. Participant who had been diagnosed and treated for amblyopia as an infant. 30. Participant with a history of Pars Plana Vitrectomy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| BCVA Response Defined as an Increased in 10 Letters at 1 Year Post-implant | 1 year post-implant | Response is defined as a improvement from baseline at Month 12 in monocular best visual acuity (BCVA) in the study eye of at least 10 letters as assessed by standard Early Treatment Diabetic Retinopathy Study (ETDRS) chart. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Change in BCVA Over the 18-month Follow-up Period | From initial implant 18 months post-implant | Change from baseline at post-baseline visits in monocular best visual acuity (BCVA) as assessed by standard Early Treatment Diabetic Retinopathy Study (ETDRS) chart. |
Countries
United States
Participant flow
Recruitment details
The study had a double-masked, multi-center, randomized, parallel group design. Patients were randomized on a 2:1:1 basis to the higher CNTF output NTC-201-6A.02 implant, the lower CNTF output NTC-201-10.02 implant or to sham surgery. A total of 53 patients were randomized to the treatment groups: 27 patients to the higher CNTF output NTC-201-6A.02 implant, 13 patients to the lower CNTF output NTC-201-10.02 implant and 13 patients to sham surgery.
Pre-assignment details
Two patients withdrew following randomization but prior to the implantation/sham surgery procedure (one in the low-output implant arm and one in the sham surgery arm). Four patients withdrew early, all in the high dose treatment group. In two cases, withdrawal was due to AEs; one patient was lost to follow up and one withdrew consent.
Participants by arm
| Arm | Count |
|---|---|
| Low Dose NT-501 implant: Low Dose | 13 |
| Low Dose NT-501 implant: Low Dose | 13 |
| High Dose NT-501 implant: High Dose | 27 |
| High Dose NT-501 implant: High Dose | 27 |
| Sham No implant (Sham Procedure) | 13 |
| Sham No implant (Sham Procedure) | 13 |
| Total | 106 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 | 0 |
| Overall Study | Exclusionary event prior to implant procedure | 1 | 0 | 0 |
| Overall Study | Lost to Follow-up | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 1 |
Baseline characteristics
| Characteristic | Low Dose | High Dose | Sham | Total |
|---|---|---|---|---|
| Age, Continuous | 78.3 Years STANDARD_DEVIATION 5.6 | 74.9 Years STANDARD_DEVIATION 7.5 | 74.5 Years STANDARD_DEVIATION 6 | 75.6 Years STANDARD_DEVIATION 6.8 |
| Baseline BCVA Treated Eye | 49.9 Letter score (# of letters read correct) STANDARD_DEVIATION 10.2 | 53.5 Letter score (# of letters read correct) STANDARD_DEVIATION 9 | 56.3 Letter score (# of letters read correct) STANDARD_DEVIATION 6.6 | 53.2 Letter score (# of letters read correct) STANDARD_DEVIATION 8.6 |
| Baseline BCVA Untreated Eye | 55.7 Letter score (# of letters read correct) STANDARD_DEVIATION 23.2 | 55.0 Letter score (# of letters read correct) STANDARD_DEVIATION 21.6 | 68.1 Letter score (# of letters read correct) STANDARD_DEVIATION 9.1 | 59.6 Letter score (# of letters read correct) STANDARD_DEVIATION 18 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 13 Participants | 27 Participants | 13 Participants | 53 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ocular History Years since first diagnosed with AMD | 6.75 Years STANDARD_DEVIATION 6.81 | 8.39 Years STANDARD_DEVIATION 6.82 | 9.84 Years STANDARD_DEVIATION 9.06 | 8.34 Years STANDARD_DEVIATION 7.36 |
| Ocular History Years since ocular disease | 2.89 Years STANDARD_DEVIATION 3.54 | 3.44 Years STANDARD_DEVIATION 4.34 | 5.93 Years STANDARD_DEVIATION 9.63 | 3.92 Years STANDARD_DEVIATION 5.92 |
| Ocular History Years since ocular surgery | 5.99 Years STANDARD_DEVIATION 6.13 | 4.73 Years STANDARD_DEVIATION 4.31 | 2.49 Years STANDARD_DEVIATION 1.66 | 4.65 Years STANDARD_DEVIATION 4.64 |
| Ocular History Years since ocular treatment | 1.60 Years STANDARD_DEVIATION 0 | 5.18 Years STANDARD_DEVIATION 3.68 | 2.63 Years STANDARD_DEVIATION 0 | 3.65 Years STANDARD_DEVIATION 2.79 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 13 Participants | 27 Participants | 13 Participants | 53 Participants |
| Sex: Female, Male Female | 6 Participants | 17 Participants | 5 Participants | 28 Participants |
| Sex: Female, Male Male | 7 Participants | 10 Participants | 8 Participants | 25 Participants |
| Type of Ocular History Ocular Disease | 13 Participants | 27 Participants | 13 Participants | 53 Participants |
| Type of Ocular History Ocular Surgery | 9 Participants | 13 Participants | 6 Participants | 28 Participants |
| Type of Ocular History Ocular Treatment | 1 Participants | 2 Participants | 1 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 1 / 27 | 0 / 12 |
| other Total, other adverse events | 4 / 12 | 8 / 27 | 2 / 12 |
| serious Total, serious adverse events | 1 / 12 | 10 / 27 | 1 / 12 |
Outcome results
Primary
BCVA Response Defined as an Increased in 10 Letters at 1 Year Post-implant
Response is defined as a improvement from baseline at Month 12 in monocular best visual acuity (BCVA) in the study eye of at least 10 letters as assessed by standard Early Treatment Diabetic Retinopathy Study (ETDRS) chart.
Time frame: 1 year post-implant
Population: N=number of eyes assessed in all treated participants (mITT population)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Low Dose | BCVA Response Defined as an Increased in 10 Letters at 1 Year Post-implant | No Response | 9 eyes |
| Low Dose | BCVA Response Defined as an Increased in 10 Letters at 1 Year Post-implant | Response | 3 eyes |
| High Dose | BCVA Response Defined as an Increased in 10 Letters at 1 Year Post-implant | No Response | 24 eyes |
| High Dose | BCVA Response Defined as an Increased in 10 Letters at 1 Year Post-implant | Response | 3 eyes |
| Sham | BCVA Response Defined as an Increased in 10 Letters at 1 Year Post-implant | Response | 1 eyes |
| Sham | BCVA Response Defined as an Increased in 10 Letters at 1 Year Post-implant | No Response | 11 eyes |
Secondary
The Change in BCVA Over the 18-month Follow-up Period
Change from baseline at post-baseline visits in monocular best visual acuity (BCVA) as assessed by standard Early Treatment Diabetic Retinopathy Study (ETDRS) chart.
Time frame: From initial implant 18 months post-implant
Population: N=number of eyes assessed in all treated participants (mITT population)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Low Dose | The Change in BCVA Over the 18-month Follow-up Period | 1 month post-implant - Treated | -0.1 Letter score (number of letters) | Standard Deviation 6.6 |
| Low Dose | The Change in BCVA Over the 18-month Follow-up Period | 1 month post-implant - Untreated | 1.0 Letter score (number of letters) | Standard Deviation 6.1 |
| Low Dose | The Change in BCVA Over the 18-month Follow-up Period | 3 months post-implant - Treated | -4.4 Letter score (number of letters) | Standard Deviation 7.9 |
| Low Dose | The Change in BCVA Over the 18-month Follow-up Period | 3 months post-implant - Untreated | -0.5 Letter score (number of letters) | Standard Deviation 4.4 |
| Low Dose | The Change in BCVA Over the 18-month Follow-up Period | 4 months post-implant - Treated | -0.8 Letter score (number of letters) | Standard Deviation 11.2 |
| Low Dose | The Change in BCVA Over the 18-month Follow-up Period | 4 months post-implant - Untreated | -1.0 Letter score (number of letters) | Standard Deviation 5.4 |
| Low Dose | The Change in BCVA Over the 18-month Follow-up Period | 6 months post-implant - Treated | -0.1 Letter score (number of letters) | Standard Deviation 11.8 |
| Low Dose | The Change in BCVA Over the 18-month Follow-up Period | 6 months post-implant - Untreated | -1.6 Letter score (number of letters) | Standard Deviation 9.3 |
| Low Dose | The Change in BCVA Over the 18-month Follow-up Period | 12 months post-implant - Treated | -0.3 Letter score (number of letters) | Standard Deviation 15.9 |
| Low Dose | The Change in BCVA Over the 18-month Follow-up Period | 12 months post-implant - Untreated | -4.6 Letter score (number of letters) | Standard Deviation 17.9 |
| Low Dose | The Change in BCVA Over the 18-month Follow-up Period | 18 months post-implant - Treated | -1.8 Letter score (number of letters) | Standard Deviation 18.4 |
| Low Dose | The Change in BCVA Over the 18-month Follow-up Period | 18 months post-implant - Untreated | -7.0 Letter score (number of letters) | Standard Deviation 14.6 |
| High Dose | The Change in BCVA Over the 18-month Follow-up Period | 18 months post-implant - Untreated | -3.7 Letter score (number of letters) | Standard Deviation 13.5 |
| High Dose | The Change in BCVA Over the 18-month Follow-up Period | 1 month post-implant - Treated | 1.5 Letter score (number of letters) | Standard Deviation 5.5 |
| High Dose | The Change in BCVA Over the 18-month Follow-up Period | 6 months post-implant - Treated | 2.7 Letter score (number of letters) | Standard Deviation 5.3 |
| High Dose | The Change in BCVA Over the 18-month Follow-up Period | 12 months post-implant - Treated | -0.2 Letter score (number of letters) | Standard Deviation 8.4 |
| High Dose | The Change in BCVA Over the 18-month Follow-up Period | 1 month post-implant - Untreated | 2.9 Letter score (number of letters) | Standard Deviation 6.5 |
| High Dose | The Change in BCVA Over the 18-month Follow-up Period | 4 months post-implant - Untreated | 2.9 Letter score (number of letters) | Standard Deviation 7.2 |
| High Dose | The Change in BCVA Over the 18-month Follow-up Period | 18 months post-implant - Treated | -5.3 Letter score (number of letters) | Standard Deviation 15 |
| High Dose | The Change in BCVA Over the 18-month Follow-up Period | 3 months post-implant - Treated | 3.0 Letter score (number of letters) | Standard Deviation 4.7 |
| High Dose | The Change in BCVA Over the 18-month Follow-up Period | 6 months post-implant - Untreated | 1.5 Letter score (number of letters) | Standard Deviation 7.7 |
| High Dose | The Change in BCVA Over the 18-month Follow-up Period | 4 months post-implant - Treated | 3.0 Letter score (number of letters) | Standard Deviation 5.9 |
| High Dose | The Change in BCVA Over the 18-month Follow-up Period | 3 months post-implant - Untreated | 2.3 Letter score (number of letters) | Standard Deviation 6.1 |
| High Dose | The Change in BCVA Over the 18-month Follow-up Period | 12 months post-implant - Untreated | -1.8 Letter score (number of letters) | Standard Deviation 14.4 |
| Sham | The Change in BCVA Over the 18-month Follow-up Period | 3 months post-implant - Untreated | -0.5 Letter score (number of letters) | Standard Deviation 6.7 |
| Sham | The Change in BCVA Over the 18-month Follow-up Period | 4 months post-implant - Treated | 2.9 Letter score (number of letters) | Standard Deviation 7.7 |
| Sham | The Change in BCVA Over the 18-month Follow-up Period | 12 months post-implant - Untreated | -6.0 Letter score (number of letters) | Standard Deviation 9.6 |
| Sham | The Change in BCVA Over the 18-month Follow-up Period | 4 months post-implant - Untreated | 0.3 Letter score (number of letters) | Standard Deviation 7.3 |
| Sham | The Change in BCVA Over the 18-month Follow-up Period | 6 months post-implant - Treated | -0.4 Letter score (number of letters) | Standard Deviation 7.7 |
| Sham | The Change in BCVA Over the 18-month Follow-up Period | 6 months post-implant - Untreated | -1.9 Letter score (number of letters) | Standard Deviation 6.1 |
| Sham | The Change in BCVA Over the 18-month Follow-up Period | 18 months post-implant - Treated | -4.1 Letter score (number of letters) | Standard Deviation 13.7 |
| Sham | The Change in BCVA Over the 18-month Follow-up Period | 1 month post-implant - Treated | 1.4 Letter score (number of letters) | Standard Deviation 6.2 |
| Sham | The Change in BCVA Over the 18-month Follow-up Period | 1 month post-implant - Untreated | 0.5 Letter score (number of letters) | Standard Deviation 3.1 |
| Sham | The Change in BCVA Over the 18-month Follow-up Period | 12 months post-implant - Treated | -1.3 Letter score (number of letters) | Standard Deviation 11.1 |
| Sham | The Change in BCVA Over the 18-month Follow-up Period | 3 months post-implant - Treated | 2.1 Letter score (number of letters) | Standard Deviation 8.8 |
| Sham | The Change in BCVA Over the 18-month Follow-up Period | 18 months post-implant - Untreated | -8.5 Letter score (number of letters) | Standard Deviation 11.1 |