Original article
Randomized Trial of Ciliary Neurotrophic Factor Delivered by Encapsulated Cell Intraocular Implants for Retinitis Pigmentosa

https://doi.org/10.1016/j.ajo.2013.03.021Get rights and content

Purpose

To evaluate the safety and effect on visual function of ciliary neurotrophic factor delivered via an intraocular encapsulated cell implant for the treatment of retinitis pigmentosa (RP).

Design

Ciliary neurotrophic factor for late-stage retinitis pigmentosa study 3 (CNTF3; n = 65) and ciliary neurotrophic factor for early-stage retinitis pigmentosa study 4 (CNTF4; n = 68) were multicenter, sham-controlled dose-ranging studies.

Methods

Patients were randomly assigned to receive a high- or low-dose implant in 1 eye and sham surgery in the fellow eye. The primary endpoints were change in best-corrected visual acuity (BCVA) at 12 months for CNTF3 and change in visual field sensitivity at 12 months for CNTF4. Patients had the choice of retaining or removing the implant at 12 months for CNTF3 and 24 months for CNTF4.

Results

There were no serious adverse events related to either the encapsulated cell implant or the surgical procedure. In CNTF3, there was no change in acuity in either ciliary neurotrophic factor– or sham-treated eyes at 1 year. In CNTF4, eyes treated with the high-dose implant showed a significant decrease in sensitivity while no change was seen in sham- and low dose–treated eyes at 12 months. The decrease in sensitivity was reversible upon implant removal. In both studies, ciliary neurotrophic factor treatment resulted in a dose-dependent increase in retinal thickness.

Conclusions

Long-term intraocular delivery of ciliary neurotrophic factor is achieved by the encapsulated cell implant. Neither study showed therapeutic benefit in the primary outcome variable.

Section snippets

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

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

Discussion

CNTF3 and CNTF4 studies were prospective, masked, randomized studies to evaluate the safety profile of the encapsulated cell–ciliary neurotrophic factor implant, to determine the effect of ciliary neurotrophic factor on retinal structure and visual function, and to explore the dose and primary endpoint for future studies in patients with RP. Neither study demonstrated a significant improvement in their respective endpoints: BCVA at 12 months for CNTF3 and visual field sensitivity at 12 months

Dr David G. Birch, PhD, takes a multidisciplinary approach to retinal degenerative diseases, utilizing electrophysiology, psychophysics and retinal imaging. He has served as principal investigator on several single site and multi-center clinical trials in retinal degenerative diseases, received an Achievement Award from the American Academy of Ophthalmology, is a Fellow of the Association for Research in Vision and Ophthalmology and is the author of over 250 scientific papers.

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      The cell-based system was implanted in the vitreous following scleral incision and was anchored in place with a single stitch [80,81]. The encapsulated cells were transfected with ciliary neurotrophic factor (CNTF) gene, and the implant was able to sustain the production and release of CNTF for at least two years [82]. Nevertheless, development was terminated as it failed to demonstrate long-term benefits (clinical trials: NCT00447980, NCT00447993) [82].

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