CNTF Implants for CNGB3 Achromatopsia

A Phase I/II Study of the NT-501 Intraocular Implant Releasing Ciliary Neurotrophic Factor (CNTF) in Participants With CNGB3 Achromatopsia

Status

Completed

Phases

Phase 1Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01648452

Acronym

CNTF-CNGB3-1

Enrollment

Registered

2012-07-24

Start date

2012-07-31

Completion date

2015-10-31

Last updated

2016-11-21

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Achromatopsia, Eye Disease

Keywords

Achromatopsia, Ciliary Neurotrophic Factor, CNTF

Brief summary

Background: * Achromatopsia is an inherited condition that causes vision loss because cells in the retina do not work properly. It causes loss of acuity, sensitivity to light, and loss of color vision. There are no effective treatments for achromatopsia. * Four genes currently are known to cause achromatopsia. One of these, the cyclic nucleotide-gated channel beta 3 (CNGB3) gene, is the cause in about 50 percent of people. * CNTF is a natural chemical found in the body that promotes survival and function of nerve cells. CNTF has been shown to be effective in treating retinal disease in animals and can slow vision loss. * CNTF has also been studied in over 250 people with retinal disease other than achromatopsia. In these studies, a CNTF implant was placed into the eye during a simple surgery. The implant releases CNTF inside the eye, near the retina. These studies suggested that a CNTF implant might help vision in some eye diseases. Objectives: * To learn whether a CNTF implant is safe for people with CNGB3 achromatopsia. * To learn whether CNTF can improve visual acuity or color vision, and whether it may reduce sensitivity to light in people with CNGB3 achromatopsia. Eligibility: You may be able to take part in this study if you: * Are at least 18 years old. * Test positive for mutations in the CNGB3 gene and have no mutations in another achromatopsia gene. * Have 20/100 vision or worse in at least one eye. * Are not pregnant or nursing. Design: * To determine if you can take part, we will ask about your medical history and do a physical examination and an eye examination. Blood and urine samples will be taken. * This study requires 11 visits to the National Eye Institute over 3 years. * One visit will be for the implant surgery. The implant will be placed in one eye only. * Study visits will take place 1 day after implant surgery, and again 1 week later and 1 month, 3 months, 6 months, 1 year, 1.5 years and 3 years later. These visits will help us evaluate the safety and benefit of the implant on your eye. * At the 3 year visit, you can choose to keep the CNTF implant in your eye, or you can have us remove it.

Detailed description

Objective: The objective of this study is to evaluate the safety of ocular NT-501 device with encapsulated NT-201 cells releasing Ciliary Neurotrophic Factor (CNTF) to the retina of participants affected with CNGB3 achromatopsia. Study Population: Five participants affected with CNGB3 achromatopsia will be enrolled, with one eye treated per participant. Design: This is a Phase I/II, prospective, single-center study. One eye of each participant will receive a vitreous NT-501 device implant releasing CNTF. The study will be completed once the final participant has received three years of follow-up. Outcome Measures: The primary outcome is the number and severity of adverse events and systemic and ocular toxicities at six months post-implantation. Additional safety of ocular CNTF implants in participants with CNGB3 achromatopsia will be determined from assessment of retinal function, ocular structure and occurrence of adverse events at all time points. Secondary outcomes include changes in visual function including visual acuity and color vision, electroretinogram (ERG) responses, and retinal imaging with optical coherence tomography (OCT).

Interventions

BIOLOGICALNT-501 CNTF-releasing implant

20 ng/day released into the eye

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

To be eligible, the following inclusion criteria must be met, where applicable. * Participant must be 18 years of age or older. * Participant must carry two alleles for CNGB3 gene mutations and no cyclic nucleotide-gated channel alpha 3 (CNGA3) sequence variations as confirmed in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. * Participant must understand and sign the protocol informed consent. * Both female participants of childbearing potential and male participants able to father children must have (or have a partner who has) had a hysterectomy or vasectomy, be completely abstinent from intercourse, or must agree to use contraception during the first six months following implantation. Acceptable forms of contraception include:hormonal contraception (i.e., birth control pills, injected hormones, dermal patch or vaginal ring), intrauterine device, barrier methods (diaphragm, condom) with spermicide, or surgical sterilization (tubal ligation).

Exclusion criteria

A participant is not eligible if any of the following

Design outcomes

Primary

Measure	Time frame	Description
Number of Adverse Events at Six Months Post-Implantation	Day 1, Week 1, Week 4, Week 12, Week 24 post-implantation	The primary outcome is the total number of adverse events reported within six months post-implantation.
Number of Severe Adverse Events at Six Months Post-Implantation	Day 1, Week 1, Week 4, Week 12, Week 24 post-implantation	The number of severe adverse events reported within six months post-implantation.
Number of Ocular Adverse Events at Six Months Post-Implantation	Day 1, Week 1, Week 4, Week 12, Week 24 post-implantation	The number of eye-related adverse events reported within six months post-implantation.
Number of Non-Ocular Adverse Events at Six Months Post-Implantation	Day 1, Week 1, Week 4, Week 12, Week 24 post-implantation	The number of non eye-related adverse events reported within six months post-implantation.

Secondary

Measure	Time frame	Description
Number of Participants Who Experienced an Improvement in Visual Acuity of Greater Than 0.3 logMAR (Logarithm of the Minimum Angle of Resolution) Post-Implantation in the Study Eye.	Day 1, Week 1, Week 4, Week 12, Week 24, Week 52, Week 78, Week 156 post-implantation	Improvement of visual acuity was assessed on both the study and control eyes. Visual acuity was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Acuity is measured as letters read on an ETDRS eye chart and the letters read equate to Snellen measurements. For example, if a participant reads between 84 and 88 letters, the equivalent Snellen measurement is 20/20. . The LogMAR scale \[expressed as the (decadic) logarithm of the minimum angle of resolution (range from +1.00 to -0.30)\] converts the geometric sequence of a traditional chart to a linear scale. It measures VA loss; positive values indicate vision loss, whereas negative values denote normal or better VA. A lower LogMAR value indicates better VA. For example, a visual acuity of 20/20 corresponds to a logMAR value of zero (0), and a visual acuity of 20/100 corresponds to a LogMAR value of 0.7.
Number of Participants Who Experienced an Improvement in Visual Acuity of Greater Than 0.3 logMAR (Logarithm of the Minimum Angle of Resolution) Post-Implantation in the Untreated Control Eye.	Day 1, Week 1, Week 4, Week 12, Week 24, Week 52, Week 78, Week 156 post-implantation	Improvement of visual acuity was assessed on both the study and control eyes. Visual acuity was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Acuity is measured as letters read on an ETDRS eye chart and the letters read equate to Snellen measurements. For example, if a participant reads between 84 and 88 letters, the equivalent Snellen measurement is 20/20. . The LogMAR scale \[expressed as the (decadic) logarithm of the minimum angle of resolution (range from +1.00 to -0.30)\] converts the geometric sequence of a traditional chart to a linear scale. It measures VA loss; positive values indicate vision loss, whereas negative values denote normal or better VA. A lower LogMAR value indicates better VA. For example, a visual acuity of 20/20 corresponds to a logMAR value of zero (0), and a visual acuity of 20/100 corresponds to a LogMAR value of 0.7.
Number of Participants Who Experienced an Increase in Either the Rod or Cone Electroretinogram (ERG) Responses of More Than 75% Post-Implantation in the Study Eye.	Day 1, Week 1, Week 4, Week 12, Week 24, Week 52, Week 78, Week 156 post-implantation	Full-ﬁeld ERGs were recorded according to International Society of Clinical Electrophysiology of Vision Standards (ISCEV).
Number of Adverse Events at All Time Points Post-Implantation	Day 1, Week 1, Week 4, Week 12, Week 24, Week 52, Week 78, Week 156 post-implantation	The total number of adverse events reported from Day 1 post-implantation through study completion at Year 3.
Number of Participants Who Experienced an Improvement in Color Discrimination and/or Matching Post-Implantation in the Study Eye.	Day 1, Week 1, Week 4, Week 12, Week 24, Week 52, Week 78, Week 156 post-implantation	Color hue discrimination was tested by the Nagel anomaloscope, American Optical Hardy Rand Rittler (AOHRR) color plates, and a low vision version of the Cambridge Color Test (LvCCT) implemented on a ViSaGe System (Cambridge Research Systems Ltd., Rochester, UK) using custom-written software. Hardy Rand Rittler testing followed the guidelines accompanying the test and administered under a Macbeth Lamp at 300 lux.
Number of Participants Who Experienced an Improvement in Color Discrimination and/or Matching Post-Implantation in the Untreated Control Eye.	Day 1, Week 1, Week 4, Week 12, Week 24, Week 52, Week 78, Week 156 post-implantation	Color hue discrimination was tested by the Nagel anomaloscope, American Optical Hardy Rand Rittler (AOHRR) color plates, and a low vision version of the Cambridge Color Test (LvCCT) implemented on a ViSaGe System (Cambridge Research Systems Ltd., Rochester, UK) using custom-written software. Hardy Rand Rittler testing followed the guidelines accompanying the test and administered under a Macbeth Lamp at 300 lux.
Number of Participants Who Experienced an Increase in Either the Rod or Cone Electroretinogram (ERG) Responses of More Than 75% Post-Implantation in the Untreated Control Eye.	Day 1, Week 1, Week 4, Week 12, Week 24, Week 52, Week 78, Week 156 post-implantation	Full-ﬁeld ERGs were recorded according to International Society of Clinical Electrophysiology of Vision Standards (ISCEV).
Number of Severe Adverse Events at All Time Points Post-Implantation	Day 1, Week 1, Week 4, Week 12, Week 24, Week 52, Week 78, Week 156 post-implantation	The total number of severe adverse events reported from Day 1 post-implantation through study completion at Year 3. Although there were two serious adverse events (SAEs) reported during the study, only one event's severity was classified as severe.
Number of Ocular Adverse Events at All Time Points Post-Implantation	Day 1, Week 1, Week 4, Week 12, Week 24, Week 52, Week 78, Week 156 post-implantation	The total number of eye-related adverse events reported from Day 1 post-implantation through study completion at Year 3.
Number of Non-Ocular Adverse Events at All Time Points Post-Implantation	Day 1, Week 1, Week 4, Week 12, Week 24, Week 52, Week 78, Week 156 post-implantation	The total number of non eye-related adverse events reported from Day 1 post-implantation through study completion at Year 3.

Countries

United States

Participant flow

Participants by arm

Arm	Count
NT-501 CNTF-releasing Implant Participants received an ocular implantation of a NT-501 CNTF-releasing capsule (20 ng/day) in one eye (the study eye) at baseline.	5
Total	5

Baseline characteristics

Characteristic	NT-501 CNTF-releasing Implant
Age, Categorical <=18 years	0 Participants
Age, Categorical >=65 years	0 Participants
Age, Categorical Between 18 and 65 years	5 Participants
Age, Continuous	35.6 years STANDARD_DEVIATION 11.37
Region of Enrollment United States	5 participants
Sex: Female, Male Female	2 Participants
Sex: Female, Male Male	3 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	5 / 5	2 / 5
serious Total, serious adverse events	1 / 5	1 / 5

Outcome results

Primary

Number of Adverse Events at Six Months Post-Implantation

The primary outcome is the total number of adverse events reported within six months post-implantation.

Time frame: Day 1, Week 1, Week 4, Week 12, Week 24 post-implantation

Arm	Measure	Value (NUMBER)
NT-501 CNTF-releasing Implant	Number of Adverse Events at Six Months Post-Implantation	10 Adverse Events

Primary

Number of Non-Ocular Adverse Events at Six Months Post-Implantation

The number of non eye-related adverse events reported within six months post-implantation.

Time frame: Day 1, Week 1, Week 4, Week 12, Week 24 post-implantation

Arm	Measure	Value (NUMBER)
NT-501 CNTF-releasing Implant	Number of Non-Ocular Adverse Events at Six Months Post-Implantation	1 Adverse Events

Primary

Number of Ocular Adverse Events at Six Months Post-Implantation

The number of eye-related adverse events reported within six months post-implantation.

Time frame: Day 1, Week 1, Week 4, Week 12, Week 24 post-implantation

Arm	Measure	Value (NUMBER)
NT-501 CNTF-releasing Implant	Number of Ocular Adverse Events at Six Months Post-Implantation	9 Adverse Events

Primary

Number of Severe Adverse Events at Six Months Post-Implantation

The number of severe adverse events reported within six months post-implantation.

Time frame: Day 1, Week 1, Week 4, Week 12, Week 24 post-implantation

Arm	Measure	Value (NUMBER)
NT-501 CNTF-releasing Implant	Number of Severe Adverse Events at Six Months Post-Implantation	1 Adverse Events

Secondary

Number of Adverse Events at All Time Points Post-Implantation

The total number of adverse events reported from Day 1 post-implantation through study completion at Year 3.