Study Design

A total of 65 and 68 patients were enrolled at 13 sites in the United States for the CNTF3 and CNTF4 studies, respectively ( Table 1 ). Approvals were received from the National Institutes of Health Recombinant DNA Advisory Committee, from the Food and Drug Administration (FDA), and from the Institutional Review Board and Institutional Biosafety Committee at each site prior to enrollment. The Institutional Review Boards responsible for these studies are listed in the acknowledgment at the end of this article. Subjects signed written informed consent before determination of their full eligibility.

Each participant’s clinical diagnosis was consistent with retinitis pigmentosa.

The CNTF3 study–specific inclusion criteria included: age 18-68 years, BCVA of 20/63-20/320 (Snellen equivalent determined with the use of an Early Treatment Diabetic Retinopathy Study [ETDRS] chart), and absence of cystoid macula edema (CME) as judged by time-domain optical coherence tomography (OCT). The CNTF4 study–specific inclusion criteria were as follows: age 18-65 years with BCVA of 20/63 or better. Patients with CME were permitted. Each eye had a mean sensitivity deviation of at least 6 dB loss of static perimetric sensitivity, on average, throughout the central 60-degree-diameter field (including non-zero points). Each eye sensitivity was to have a non-zero value for at least 30 locations, and the horizontal field extent was to be 20 degrees or greater as tested on a Humphrey field analyzer (HFAII) 30-2 test with a Goldmann V target size. The eligibility of subjects was confirmed by an independent central reading center according to standardized criteria with trained fundus photograph and OCT graders who were masked to subjects’ treatment assignment.

Safety visits were conducted at 1 day, 1 week, and 1, 3, 6, and 12 months. Blood draws for laboratory safety studies, including serum antibodies, were obtained on each visit. The primary efficacy endpoints, change in BCVA and change in visual field sensitivity, were prespecified at 12 months post implant for CNTF3 and CNTF4, respectively. Patients received either high- or low-dose NT-501 implants in 2:1 ratio in 1 eye, and a sham treatment in the fellow eye. The high dose was selected based on the dose-response effect of ciliary neurotrophic factor in the rcd1 model of retinal degeneration and was the maximum effective dose. The low dose was 50% of the minimum effective dose in the rcd1 dog model.

The original trial design approved by the FDA specified that implants be removed at 12 months (CNTF3) or 24 months (CNTF4). After the initiation of the trial, the FDA recommended that patients retain the implants at the end of the study (avoiding a second surgery). Since all patients had consented to have their implants removed at the end of the study, they were offered a choice either to keep the implant in place or to have the implant removed. For each study, patients were followed for an additional 6 months (a total of 18 months follow-up for CNTF3 and 30 months for CNTF4). At the conclusion of the trial, 16 patients in the high-dose CNTF4 study (10 with the implant in place and 6 with the implant removed) consented to a registry study with an additional year of follow-up (42 months). Those with the implant removed were also tested at 54 months.

BCVA was measured by an electronic visual acuity tester (EVA) using the ETDRS protocol. BCVA in CNTF3 was measured twice per eye on each of 3 baseline visits. Baseline 1 BCVA was used to qualify subjects and baseline 2 and 3 BCVA (average of 4 measures per eye) was used as baseline BCVA. Three BCVA measurements were taken for each subsequent visit and the average of the 3 BCVA values was used to assess the change from baseline.

Visual field sensitivity in CNTF4 was measured with the 30-2 grid using the Humphrey visual field analyzer. Visual field sensitivity was measured twice per eye on each of 3 baseline visits. Eligibility for enrollment was determined by the results of baseline 1. The average value of the 4 baseline 2 and baseline 3 examinations, each representing the sum of actual thresholds for all 76 locations, provided the baseline visual field sensitivity. Four visual field sensitivity measurements per eye were taken for each subsequent visit and the average of the 4 visual field sensitivity sums was used to assess the change from baseline. Pupil diameter was measured within the Humphrey visual field analyzer at the conclusion of each test session.

Full-field electroretinograms (ERGs) were measured at baseline and at 12 months. The procedure adhered to International Society of Clinical Electrophysiology of Vision standards, but was limited to light-adapted (30 Hz flicker and single-flash) responses.

Retinal thickness and morphology were evaluated by OCT. The fast macular thickness map protocol, a 7-mm horizontal line scan, and 6-mm vertical line scan were obtained with the Stratus OCT and software version 4.0 or higher (Carl Zeiss Meditec, Inc, Dublin, California, USA). OCT images were collected by certified technicians. The images were evaluated by masked readers at the Duke University OCT Reading Center and analyzed for average thickness at center point, total macular volume, and average thickness in 9 subfields. Pathologic findings, such as cysts, epiretinal membrane, vitreomacular traction, and choroidal neovascularization, were also recorded and analyzed.

A subset of all high-dose CNTF4 patients (n = 10) from a single center (Dallas, Texas, USA) were evaluated on the 12-month visit by spectral-domain OCT (Spectralis HRA + OCT; Heidelberg Engineering, Heidelberg, Germany). The images of horizontal midline scans were exported to data-analysis software (Igor Pro; WaveMetrics, Inc, Portland, Oregon, USA) and segmented to identify the Bruch membrane/choroid boundary, the ellipsoid zone (inner/outer segment border), and the inner nuclear layer/outer plexiform layer boundary. Using the locations of these boundaries, a masked reader defined the receptor outer segment plus retinal pigment epithelium (OS+) as the distance between the ellipsoid zone and Bruch membrane/choroid boundaries. The outer nuclear layer was the distance between the inner nuclear layer/outer plexiform layer and ellipsoid zone boundaries. In order to avoid possible complications from CME, segment thicknesses were determined 1.7 mm (6 degrees) nasal and temporal to the fovea and compared between high-dose ciliary neurotrophic factor–implanted and sham-treated eyes. Since spectral-domain OCT scans were not available at baseline, comparisons were between the implanted and sham eyes at 12 months.

Study Treatment

The ciliary neurotrophic factor–secreting, encapsulated cell implants, designated NT-501, are 6 mm long with 1 mm diameter and are constructed of a semi-permeable polymer outer membrane. The low-dose implants released 5 ng/day and the high-dose implant released 20 ng/day prior to implant.

Statistical Analysis

The efficacy analysis was performed on an intent-to-treat basis among all subjects. Since all subjects completed the study as planned, the last-observation-carried-forward method for missing data was not used. For change in BCVA, ERG, and visual field sensitivity, the within-group and between-group comparisons were based on a paired t test. Clinical response rates were compared between groups using a 2-sided Fisher exact test. For retinal thickness change as measured by OCT, the overall comparison among treatment medians was assessed using the Kruskal-Wallis test. Pair-wise differences between treatment medians were assessed using the Wilcoxon rank sum test.

Evaluation of Encapsulated Cell Implants After Removal

Immediately upon removal, the devices were placed into Endo-SFM conditioned medium (GIBCO BRL, Gaithersburg, Maryland, USA) at 37 C, 5% CO ₂ , 95% humidity for 24 hours. The rate of ciliary neurotrophic factor secretion was determined using a commercial enzyme-linked immunosorbent assay kit (R&D Systems, Minneapolis, Minnesota, USA).

Study Patients

Between January 8, 2007 and October 31, 2007, 65 patients and 68 patients were enrolled into the CNTF3 and CNTF4 studies, respectively, and were randomly assigned to study treatment. Groups were balanced for demographic and baseline ocular characteristics ( Table 1 ). All patients completed the 12-month primary endpoint follow-up and no patients dropped out of the study.

Safety Profile

Cumulative adverse events for the 12-month study period (CNTF3 and CNTF4) are summarized in Table 2 . The most frequent adverse event was miosis, measured on the Humphrey field analyzer in 25.6% of CNTF3 and 31.3% of CNTF4 patients assigned to receive the high-dose implant. Unequal pupil sizes were also reported by many of these patients. Although neither the field technicians nor the patients knew whether the implant was causing miosis or dilation, the unequal pupil sizes could possibly have interfered with masking. No serious adverse events related to the NT-501 implant or surgical procedures were reported during the 12-month study period. No treatment-related severe adverse effects, including retinal detachment, endophthalmitis, intraocular pressure (IOP) increase, or choroidal neovascularization (CNV), were reported. Neither ciliary neurotrophic factor nor antibodies against it was detected in the serum. Likewise, no antibodies against the encapsulated cells were detected.

Visual Acuity Changes

No significant changes in visual acuity were observed in ciliary neurotrophic factor–treated or sham-treated eyes in CNTF3 and CNTF4 patients ( Table 3 ).

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