Diabetic Retinopathy Clinical Trial
Official title:
Phase 2 Ziv-aflibercept in Ocular Disease Short and Long-term Study
Background/aims: Aflibercept is an approved therapy for neovascular macular degeneration
(AMD), diabetic macular edema (DME), retinal vein occlusion and other retinal conditions.
Ziv-aflibercept is also approved by FDA and is extremely cost-effective relative to the
expensive same molecule aflibercept. In vitro and in vivo studies did not detect toxicity to
the retinal pigment epithelium cells using the approved cancer protein, ziv-aflibercept.
Ziv-aflibercept had no loss of anti-VEGF activity when kept at 4°C in polycarbonate syringes
over 4 weeks. Similar to bevacizumab, compounded ziv-aflibercept would yield a tremendous
saving compared to aflibercept or ranibizumab. Phase I studies and case reports did not
report any untoward toxic effects but attested to the clinical efficacy of the medication.
Our purpose is to ascertain the long-term safety and efficacy in various retinal diseases of
intravitreal ziv-aflibercept.
Methods: Prospectively, consecutive patients with retinal disease that require aflibercept
(AMD, DME, RVO, and others) will undergo instead the same molecule ziv-aflibercept
intravitreal injection of 0.05 ml of fresh filtered ziv-aflibercept (1.25mg). Monitoring of
best-corrected visual acuity, intraocular inflammation, cataract progression, and retinal
structure by spectral domain OCT to be done initially, one month, 6 months, 1 year, and 2
years after injections.
Anticipated Results: Analyze signs of retinal toxicity, intraocular inflammation, or change
in lens status, together with best corrected visual acuity and central foveal thickness at 1
month, 6 months, 1 year and 2 year. Anticipated Conclusions: Off label use of ziv-aflibercept
improves visual acuity without ocular toxicity and offers a cheaper alternative to the same
molecule aflibercept (or lucentis), especially in the third world similar to bevacizumab.
Ascertain the long term safety and efficacy of ziv-aflibercept in a large variety of ocular
diseases and over a long-term after its proven safety and efficacy in the laboratory, in
phase one study and in isolated case report.
Background and Significance:
Anti-VEGF therapy is currently one of the mainstay of therapy in a great number of diseases
of the eye with intravitreal injections of antiVEGF being the number one procedure done in
the office of an ophthalmology practice. The ophthalmic community has currently 2 very
expensive antiVEGF both approved by the FDA for ocular use: Ranibizumab and aflibercept.
However because of the prohibitive cost of these medications in the third world and the need
for repetitive use of these agents in the control of eye disease, the off-label use of
bevacizumab is currently the most common anti-VEGF used worldwide because of its equivalent
therapeutic efficacy and cost-effective superiority. Bevacizumab and ranibizumab have high
affinity to VEGF, aflibercept possess additional properties. Aflibercept (Eylea; Regeneron,
Tarrytown, New York, USA and Bayer Healthcare, Leverkusen, Germany) is a fusion protein
consisting of the Fc portion of human immunoglobulin IgG1 and the extracellular domains of
vascular endothelial growth factor receptors (VEGFR-2 and VEGFR-1), which binds to
circulating vascular endothelial growth factor (VEGF), thus acting as a decoy receptor.
Laboratory studies and clinical trials suggest that aflibercept's high binding affinity for
VEGF may impart greater durability of activity and similar efficacy compared to ranibizumab1
or bevacizumab. Aflibercept is approved by Food and Drug Administration (FDA) for the therapy
of wet age related macular degeneration (AMD) , macular edema from retinal vein occlusion or
diabetes.3 Ranibizumab is given monthly, while aflibercept is given bimonthly after 3 monthly
injections for eyes with wet AMD. Because of the high cost of ranibizumab and aflibercept, a
majority of ophthalmologists worldwide tend to treat patients with bevacizumab at a major
saving for the patient. Commercially, a much cheaper yet identical fusion protein to
aflibercept is ziv-aflibercept. Ziv-aflibercept (Zaltrap, Sanofi-Aventis US, LLC,
Bridgewater, NJ and Regeneron Pharmaceuticals, Inc, Tarrytown, NY) was approved by FDA in
August 2012 for the treatment of metastatic colorectal carcinoma resistant to an
oxiplatin-containing regimen. One may wonder if ziv-aflibercept can be used instead of
aflibercept in ophthalmic disorders. Hence the need to answer some major safety concerns:
first the difference in osmolarity, and second whether ziv-aflibercept could impair retinal
function and alter morphology6. A preliminary study was conducted on the use of
ziv-aflibercept in patients with exudative AMD or diabetic macular edema (DME) with poor
vision. In addition, the investigators tested the stability of ziv-aflibercept over a period
of 4 weeks and the economic implications of the use of compounded drug.
Ziv-aflibercept is supplied in single-use vials of 100 mg per 4 ml and 200 mg per 8 ml
formulated as 25 mg/mL ziv-aflibercept in polysorbate 20 (0.1%), sodium chloride (100 mM),
sodium citrate (5 mM), sodium phosphate (5 mM), and sucrose (20%), in Water for Injection
USP, at a pH of 6.2. Eylea is supplied as a single-use, glass vial designed to deliver 0.05
mL (2mg) of aflibercept (40 mg/mL in 10 mM sodium phosphate, 40 mM sodium chloride, 0.03%
polysorbate 20, and 5% sucrose, pH 6.2).
Design and Procedures:
Procedure: inject intravitreal ziv-aflibercept according to published protocols approved by
FDA (PROTOCOL A and PROTOCOL B, PROTOCOL C, PROTOCOL D, and other published aflibercept
protocols or protocols to be approved or under study for other diseases).
Design: Prospective nonrandomized open label long-term interventional clinical study in
patients with subfoveal CNV, extrafoveal CNV due to AMD or other diseases (myopia,
inflammatory, angioid streaks, traumatic, idiopathic), DME, BVO or CRVO-related macular
edema, diabetic vitreous hemorrhage, and any disease requiring anti-VEGF therapy. The
inclusion/exclusion criteria are summarized in tables 1 and 2.
All patients will have to sign a study consent form for the off-label use of intravitreal
ziv-aflibercept that is approved by FDA for oncology and the same molecule under different
osmolarity for eye disease.
Patients and Methods Patients All patients will have to sign a study consent form for the
off-label use of intravitreal ziv-aflibercept.
Pretreatment work up Initial work-up will include best-corrected visual acuity (BCVA) using
ETDRS acuity charts, slit-lamp examination of the anterior segment, dilated fundus
examination, and fluorescein angiography. Pretreatment macular thickness will be measured
with ocular coherence tomography (OCT) for all eyes.
Intravitreal injection of ziv-aflibercept The hospital pharmacy will divide 4cc vial of
ziv-aflibercept (ZALTRAP) purchased by the Ophthalmology Department, into twenty 1 cc
syringes using aseptic techniques. Therefore, each syringe will contain 0.2 ml of
ziv-aflibercept. The syringes will be stored at 4 degrees Celsius for no longer than 30 days.
The eye to be treated will be prepared with 5% povidone-iodine solution. Topical Anesthesia
will be administered. Using a 30-gauge needle, 0.05 ml ziv-aflibercept will be injected
intravitreally through the pars plana 3.5 mm from the limbus. If the intraocular pressure is
greater than 25 mmHg or the optic nerve head is not adequately perfused 20 minutes after the
injection (if patient reports poor vision of hand motion or less), then a paracentesis will
be performed. There is no need to either patch the eye or use topical antibiotics.
Post-injection follow-up Patients will be examined every month after the injection. At each
visit, BCVA will be measured along with slit-lamp examination of the anterior segment and
dilated fundus examination. OCT will be repeated at each follow-up. The patients will be
followed as per the standard approach delineated in the aflibercept trials for AMD or DME. In
case of unusually recurrent CNV or DME based on OCT, fluorescein angiography, clinical
examination or decrease in vision additional injections may be done depending on the
particular case above and beyond the standard protocols. The total follow-up period of the
extended study will be 24 months for each patient. Patients and data collection will span
over a period of 3 years.
Main outcome The main outcome measures will be improvement in visual acuity, decrease in
central retinal thickness, and stability of lesion size in AMD or retinopathy in DME. The
paired Student's t-test, Chi-square test, Pearson correlation and ANOVA will be used to
analyze the data.
Potential risks Potential risks due to the injection itself are minimal. However patients
have about 0.2% risk of eye infection. Retinal detachment and vitreous hemorrhage are
extremely rare potential risks. No untoward effects are expected from aflibercept itself.
From our experience and others, no signs of ocular toxicity were noted in already treated
eyes. But the investigators will again look at any sign of cataract or corneal toxicity. In
addition, intraocular inflammation is known to occur at a rate of 0.2% of any anti-VEGF
including aflibercept. Such cases will be recorded and treated with anti-inflammatory agents.
PROTOCOL A (AMD) adapted from VIEW 1 and VIEW 2 In eyes with wet AMD, involved eyes are
treated every 4 weeks for 3 initial monthly injections, then every 8 weeks till year 1.
Patients are evaluated monthly to determine the need for treatment and were treated at least
every 12 weeks (capped PRN regimen) 2.
PROTOCOL B (BVO) adapted from VIBRANT The recommended dosage for CRVO is monthly injection
till month 6 then monthly monitoring and PRN dosing PROTOCOL C (CRVO) adapted from COPERNICUS
and GALILEO The recommended dosage for CRVO is monthly injection till month 6 then monthly
monitoring and PRN dosing PROTOCOL D (DME) adapted from VISTA and VIVID The recommended
dosage for DME treatment is 5 initial monthly injections followed by one injection every 8
weeks
Subject identification, recruitment, and compensation:
Compensation for participation: None (Compensation relates to 25 times saving of the very
expensive drug). The department of ophthalmology would cover the cost of complication from
the study, i.e. like treating the patient with endophthalmitis with necessary antibiotics
intravitreal and systemic.
Subject identification:
Each collaborator will supply the data with the initials only of the patients to keep patient
anonymity under full protection.
Patient recruitment:
Any patient who is a candidate for anti-VEGF therapy for ocular disease is offered this form
of therapy such as: choroidal neovascularization of any kind (age-related macular
degeneration, myopia, inflammatory, angioid streak, trauma, laser induced, idiopathic) and
maculopathy or retinopathy from diabetes mellitus, branch or central retinal vein occlusion,
or other occlusive anterior or posterior pole disorders (neovascular glaucoma, rubeosis
iridis, corneal neovascularization, angry pterygium, surgical or traumatic fibrovascular
ingrowth), and tumor-associated new vessel formation.
Risk/benefit assessment:
There is a risk for endophthalmitis of 0.2% with any intraocular injection. Benefit is visual
restoration and avoidance of blindness outweigh the risks
Costs to the subject:
The patient will have a regular charge of the medication (100,000 LL or 66 USD) similar to
the off-label use of bevacizumab. Ranibizumab or aflibercept or dexamethasone implants cost
each 25 times more, knowing that ziv-aflibercept and aflibercept represent the same molecule
exactly. So the investigators are giving the patient the same active product at lower price.
This is a major difference between ranibizumab and bevacizumab (different molecule) with 25
times cheaper.
Privacy, Data Storage and Confidentiality:
Confidentiality of the files will be maintained using coded data under the supervision of Dr
AMM. Reference between subject code and identity, demographic data, and medical data entered
on study sheets will be maintained in a locked drawer in Dr AMM, and on a password-protected
computer.
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