Age Related Macular Degeneration Clinical Trial
Official title:
A Phase I Study of the Inhibition of LFA-1 to Intercellular Adhesion Molecule-1 (ICAM-1) Using Subcutaneous Efalizumab Combined With Intravitreal Ranibizumab in the Treatment of Age-Related Macular Degeneration (SEIRA)
Efalizumab is an immunosuppressive recombinant humanized IgG1 monocolonal antibody (150 Kd)
that binds to human CD11a (1) and is used for the treatment of plaque psoriasis. Efalizumab
was derived from the humanization of the murine efalizuman monoclonal antibody MHM24, which
recognizes human and chimpanzee CD11a. Humanization of MHM24 was accomplished by grafting
the murine complementarity determining regions (hypervariable region) into consensus human
IgG1/ heavy and light chain sequences (Werther et al 1996). These same consensus human
immunoglobulin sequences have been successfully used in the humanization of other murine
antibodies, including those targeted to HER2 and IgE. Efalizumab inhibits the binding of
LFA-1 to intercellular adhesion molecule-1 (ICAM-1) thereby inhibiting the adhesion of
leukocytes to other cell types.
Ranibizumab is a recombinant, humanized, Fab fragment of a mouse monoclonal antibody
targeted against VEGF. As VEGF binds to cellular receptors, it stimulates angiogenesis and
vascular leakage. Blockade of VEGF by ranibizumab leads to reduced stimulation of cell
proliferation and permeability resulting in inhibition of angiogenesis and decreased
leakage. Ranibizumab intravitreal administration in neovascular AMD patients has been shown
to effectively reduce vascular leakage and growth of CNV and to stabilize or improve visual
function.
To further improve visual acuity, a combination therapy using efalizumab and ranibizumab is
proposed. Efalizumab could target the adhesion factors that precede angiogenesis and improve
the outcome for AMD patients in combination with the anti-VEGF agent, Ranibizumab.
This is an open-label, study of 0.5 mg intravitreal dose of Ranibizumab in combination with
1 mg/kg/wk subcutaneous dose of Efalizumab in in subjects with AMD. 10 subjects from 1 site
will be enrolled in this study. Subject accrual into the trial is expected to be completed
within 6 months.
All subjects will be evaluated monthly with a full ocular examination, visual acuity
measurement (ETDRS chart at distance of 4 meters), OCT, and adverse event monitoring.
Fluorescein Angiography (FA) and fundus photos will be done at BSL, Months 3, 6, 9 and 12.
Subjects will receive efalizumab 1mg/kg weekly subcutaneous injections for 24 weeks.
Subcutaneous Efalizumab injections can be self administered after an initial teaching
session in office on Day 0.
Subjects will receive six initial doses of 0.5 mg/eye intravitreous monthly injections of
ranibizumab (Day 0, Months 1, 2, 3, 4 and 5) with scheduled follow-up visits monthly for 12
months. Re-treatment after the first six injections will be on an as-needed basis, based on
predefined criteria.
3.2 RATIONALE FOR STUDY DESIGN
The rationale for the study is as follows:
- Phase III studies of patients with primary or recurrent choroidal neovascularization
(CNV) secondary to age-related macular degeneration (AMD) treated with repeated
intravitreal injections of 0.5 mg of ranibizumab showed evidence for bioactivity,
safety, and tolerability (Rosenfeld 2006);
- Phase III studies of patients with chronic moderate to severe plaque psoriasis treated
with weekly subcutaneous efalizumab injections of 1mg/kg showed evidence for
bioactivity, safety, and tolerability (Dubertret 2006);
- A Phase I study of patients with uveitis treated with subcutaneous efalizumab
injections of 1mg/kg in patients with uveitic macular edema is currently enrolling
(ClinicalTrials.gov Identifier: NCT00280826)
- Combination therapy of an iCAM-1 inhibitor and an anti-VEGF agent may offer increased
treatment benefit in the management of age-related macular degeneration.
;
Allocation: Non-Randomized, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
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