CNTF Implants for CNGB3 Achromatopsia (CNTF-CNGB3-1)

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

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.

Study Overview

• Status: Completed
• Conditions: Eye Disease; Achromatopsia
• Intervention / Treatment: Biological: NT-501 CNTF-releasing implant

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).

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center, 9000 Rockville Pike

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 exclusion criteria are present.

• Participant has a history of other ocular disease likely to contribute significantly to visual loss (e.g., optic neuropathy, glaucoma, uveitis, or other retinal disease).
• Participant is judged by the investigator as not sufficiently healthy to safely undergo ophthalmic surgery.
• Participant is on anticoagulant therapy that cannot be safely stopped peri-operatively at the implant procedure. Patients on warfarin will always be excluded. Patients on aspirin will be asked to stop the medication at least seven days prior to the surgery (when not contraindicated by the underlying medical condition). The stoppage period for other anticoagulant medications is based on the best clinical judgment of the investigator surgeon and is variable depending on the patient's medical condition and the type of medication.
• Participant has had diagnosis or treatment of a malignancy (excluding non-melanoma skin cancer) within the previous five years.
• Participant has received investigational treatment in another clinical study related to an ocular condition in the last six months.
• Participant is pregnant, lactating or planning to become pregnant in the first six months following implantation.

Study Eye Eligibility Criteria:

The participant must have at least one eye meeting all inclusion criteria and none of the exclusion criteria listed below.

Study Eye Inclusion Criteria:

The study eye must have a best-corrected Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity letterscore of ≤ 53 (i.e., ≤ 20/100). The visual acuity from the first baseline visit (Baseline 1) will be used for eligibility determination in case of a change in visual acuity at the second baseline visit (Baseline 2).

Study Eye Exclusion Criteria:

• The study eye has a choroidal nevus or ocular neoplasm with potential risk for malignant transformation.
• The study eye is judged by the investigator, based on history or examination findings, as high-risk for retinal detachment, vitreous hemorrhage, infection, or uveitis.
• The study eye has lens, cornea, or other media opacities precluding adequate visualization and testing of the retina.
• The study eye has undergone intraocular surgery within 12 months prior to enrollment.

Study Eye Selection Criteria in Cases of Bilateral Disease:

• As this is a genetic condition that usually affects both eyes to a similar degree, if both eyes of a participant meet the study eye eligibility criteria and have comparable visual acuity, the study eye will be selected at the investigator's medical judgment after consultation with the participant.
• In case of an eye with lower visual acuity, that eye will be selected as the study eye.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: NT-501 CNTF-releasing implant; Ocular implantation of a NT-501 CNTF-releasing capsule (20 ng/day) in one eye (the study eye) at baseline	Biological: NT-501 CNTF-releasing implant; 20 ng/day released into the eye

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Day 1, Week 1, Week 4, Week 12, Week 24 post-implantation
Number of Severe Adverse Events at Six Months Post-Implantation	The number of severe adverse events reported within six months post-implantation.	Day 1, Week 1, Week 4, Week 12, Week 24 post-implantation
Number of Ocular Adverse Events at Six Months Post-Implantation	The number of eye-related adverse events reported within six months post-implantation.	Day 1, Week 1, Week 4, Week 12, Week 24 post-implantation
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.	Day 1, Week 1, Week 4, Week 12, Week 24 post-implantation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Day 1, Week 1, Week 4, Week 12, Week 24, Week 52, Week 78, Week 156 post-implantation
Number of Severe Adverse Events at All Time Points 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."	Day 1, Week 1, Week 4, Week 12, Week 24, Week 52, Week 78, Week 156 post-implantation
Number of Ocular Adverse Events at All Time Points Post-Implantation	The total number of eye-related adverse events reported from Day 1 post-implantation through study completion at Year 3.	Day 1, Week 1, Week 4, Week 12, Week 24, Week 52, Week 78, Week 156 post-implantation
Number of Non-Ocular Adverse Events at All Time Points Post-Implantation	The total number of non eye-related adverse events reported from Day 1 post-implantation through study completion at Year 3.	Day 1, Week 1, Week 4, Week 12, Week 24, Week 52, Week 78, Week 156 post-implantation
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.	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.	Day 1, Week 1, Week 4, Week 12, Week 24, Week 52, Week 78, Week 156 post-implantation
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.	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.	Day 1, Week 1, Week 4, Week 12, Week 24, Week 52, Week 78, Week 156 post-implantation
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.	Full-field ERGs were recorded according to International Society of Clinical Electrophysiology of Vision Standards (ISCEV).	Day 1, Week 1, Week 4, Week 12, Week 24, Week 52, Week 78, Week 156 post-implantation
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.	Full-field ERGs were recorded according to International Society of Clinical Electrophysiology of Vision Standards (ISCEV).	Day 1, Week 1, Week 4, Week 12, Week 24, Week 52, Week 78, Week 156 post-implantation
Number of Participants Who Experienced an Improvement in Color Discrimination and/or Matching Post-Implantation in the Study Eye.	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.	Day 1, Week 1, Week 4, Week 12, Week 24, Week 52, Week 78, Week 156 post-implantation
Number of Participants Who Experienced an Improvement in Color Discrimination and/or Matching Post-Implantation in the Untreated Control Eye.	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.	Day 1, Week 1, Week 4, Week 12, Week 24, Week 52, Week 78, Week 156 post-implantation

Collaborators and Investigators

• Sponsor: National Eye Institute (NEI)
• Investigators: Principal Investigator: Paul A Sieving, MD, PhD, National Eye Institute (NEI)

Publications and helpful links

General Publications

• Kohl S, Baumann B, Broghammer M, Jagle H, Sieving P, Kellner U, Spegal R, Anastasi M, Zrenner E, Sharpe LT, Wissinger B. Mutations in the CNGB3 gene encoding the beta-subunit of the cone photoreceptor cGMP-gated channel are responsible for achromatopsia (ACHM3) linked to chromosome 8q21. Hum Mol Genet. 2000 Sep 1;9(14):2107-16. doi: 10.1093/hmg/9.14.2107.
• Wissinger B, Gamer D, Jagle H, Giorda R, Marx T, Mayer S, Tippmann S, Broghammer M, Jurklies B, Rosenberg T, Jacobson SG, Sener EC, Tatlipinar S, Hoyng CB, Castellan C, Bitoun P, Andreasson S, Rudolph G, Kellner U, Lorenz B, Wolff G, Verellen-Dumoulin C, Schwartz M, Cremers FP, Apfelstedt-Sylla E, Zrenner E, Salati R, Sharpe LT, Kohl S. CNGA3 mutations in hereditary cone photoreceptor disorders. Am J Hum Genet. 2001 Oct;69(4):722-37. doi: 10.1086/323613. Epub 2001 Aug 30.
• Kohl S, Baumann B, Rosenberg T, Kellner U, Lorenz B, Vadala M, Jacobson SG, Wissinger B. Mutations in the cone photoreceptor G-protein alpha-subunit gene GNAT2 in patients with achromatopsia. Am J Hum Genet. 2002 Aug;71(2):422-5. doi: 10.1086/341835. Epub 2002 Jun 20.
• Zein WM, Jeffrey BG, Wiley HE, Turriff AE, Tumminia SJ, Tao W, Bush RA, Marangoni D, Wen R, Wei LL, Sieving PA. CNGB3-achromatopsia clinical trial with CNTF: diminished rod pathway responses with no evidence of improvement in cone function. Invest Ophthalmol Vis Sci. 2014 Sep 9;55(10):6301-8. doi: 10.1167/iovs.14-14860.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start: July 1, 2012
• Primary Completion (Actual): March 1, 2013
• Study Completion (Actual): October 1, 2015

Study Registration Dates

• First Submitted: July 20, 2012
• First Submitted That Met QC Criteria: July 20, 2012
• First Posted (Estimate): July 24, 2012

Study Record Updates

• Last Update Posted (Estimate): November 21, 2016
• Last Update Submitted That Met QC Criteria: September 30, 2016
• Last Verified: September 1, 2016

More Information

Terms related to this study

• Keywords: Achromatopsia; Ciliary Neurotrophic Factor; CNTF
• Additional Relevant MeSH Terms: Nervous System Diseases; Neurologic Manifestations; Eye Diseases, Hereditary; Sensation Disorders; Vision Disorders; Cone Dystrophy; Eye Diseases; Color Vision Defects
• Other Study ID Numbers: 120167; 12-EI-0167

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No