Evaluation of Wet Age-Related Macular Degeneration (AMD) Genetic Profile Interactions With Ranibizumab Treatment Outcomes

Age Related Macular Degeneration (AMD) is the leading cause of blindness in North America. This condition causes a progressive loss of central vision, the part of your vision that allows you to read, drive and see images in sharp detail directly in front of you. The wet form of AMD is characterized by the growth and leakage of small blood vessels into the choroid layer of the eye, or the back of the eye. These leaking blood vessels disrupt the structure and function of the eye, causing loss of vision, particularly the sharp vision created by the macula area of the eye.

Currently, the best treatment for wet AMD is a series of injections of an anti-vascular endothelial growth factor (anti-VEGF) drug, ranibizumab (Lucentis). The clinical response to treatment is varied. Approximately 70% of patients see a moderate vision gain (3-line gain on a visual acuity chart), but there are 30% who do not see a similar improvement in vision. There is no way to identify those patients who will respond with significant vision gain versus those who will not experience moderate vision gain. Recent research into AMD has demonstrated that genetic mutations are proving to be key risk factors for patients developing wet AMD, with up to 80% of wet AMD cases explained by inherited genetic variations. Scientists have theorized that there may be a genetic difference between those patients who see significant responses to treatment and those who do not. The investigators will be testing participant's genetic profile using the Macula Risk test and following their progress through the standard treatment for wet AMD over the course of this study. This study aims to demonstrate the association between known genetic variations and patient responses to treatment.

Study Overview

• Status: Completed
• Conditions: Age Related Macular Degeneration
• Intervention / Treatment: Drug: Ranibizumab

Detailed Description

Your ophthalmologist will determine your suitability for this study through a screening protocol. You will have measurements of your visual acuity and will undergo a series of imaging tests as described in the next paragraph to show presence of blood vessel growth in the back of your eye (the choroid). You cannot be included in this study if you have another significant eye disease that affects your vision, if you have blood vessel growth in the back of your eye (choroid) for reasons other than AMD, if you have medically uncontrolled glaucoma, if you have been treated for AMD in that past, if you have had intra-ocular surgery in the study eye in the past 3 months, if you have had any past retinal or vitreous surgery, or if you have physical or mental disabilities that would prevent accurate vision testing.

At the beginning of the study, we will take a sample of cells from the inside of your cheek, using a small swab. The sample will be sent to a genetic laboratory for analysis and storage. This information will be kept masked for the duration of the study, meaning that you, the study ophthalmologist and the data analyzer will not know the results of the genetic test until the study is completed.

You will be asked to come in for an initial assessment to determine your starting visual abilities and medical history. On your next appointment, you will receive your first treatment of intra-vitreal injections of Ranibizumab (Lucentis). You will be asked to come into the clinic every month for six (6) months total for treatment injections and testing. At each appointment, we will take 3-D images of your retina (the back of your eye) using an Optical Coherence Tomography (OCT) imaging device, test your eye pressure and determine if there are any signs of infection or inflammation from the injections. On months 1, 3, and 6 we will also test your vision, your contrast sensitivity using a standard contrast sensitivity chart (The Pelli-Robson chart) and take images of the blood vessel growth using a coloured dye (fluorescein) to help us see your vessels. Before every treatment, anesthetic eye drops (proparacaine) will be applied to your eye so you will not feel the injections. You will be given antibiotic eye drops (Zymar®) that you will be asked to use 4 times a day for a few days after the injection to prevent infection.

• Study Type: Interventional
• Enrollment (Actual): 70
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8G 5E4
      • St. Joseph's Healthcare Hamilton Regional Eye Centre
    • Toronto, Ontario, Canada, M5T 2S8
      • Toronto Western Hospital Eye Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients must be at least 18 years of age
• Choroidal neovascularization (CNV) secondary to age-related macular degeneration
• CNV under geometric center of the foveal avascular zone
• Evidence of activity on fundus fluorescein angiography
• Evidence of CNV activity as suggested by one of the following: sub-retinal hemorrhage, sub-retinal lipid, documented loss of 3 lines of vision within the last 3 months
• Visual acuity of between 20/40 and 20/300 in the study eye tested via Early treatment of Diabetic Retinopathy Study (ETDRS) eye chart score of 34 to 73 letters at 2 meters.

Exclusion Criteria:

• Individuals with choroidal neovascularization from causes other than AMD
• Patients physically unable to tolerate intravenous fluorescein angiography
• Patients with medically uncontrolled glaucoma
• Any intraocular surgery within 3 months in the study eye
• Prior retinal or vitreous surgery including vitrectomy or scleral buckling
• Any significant ocular disease other than AMD that has compromised or could compromise vision in the study eye and confound analysis of the primary outcome
• Individuals with physical or mental disabilities that prevent accurate vision testing
• History of any laser treatment of CNV in study eye (laser photocoagulation or prior photodynamic therapy), or anti-VEGF (ranibizumab or bevacizumab) in the past 6 months in 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

Other: Ranibizumab; Ranibizumab is the current gold standard treatment for wet age-related macular degeneration. This intervention is approved by Health Canada, covered by OHIP (Ontario Health Insurance Plan) and used regularly by ophthalmologists in Canada. Participants will receive intravitreal injections of ranibizumab each month for up to 6 months, with ocular testing at each appointment as prescribed by the study protocol.

Drug: Ranibizumab; Intra-vitreal injections of 0.5mg/0.05 mL dosage, injected at months 0, 1, and 2. For those requiring additional injections, patients will receive monthly treatment up to a maximum of 6 months total.; Other Names: Lucentis

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Gains in visual acuity	Percent probability gains in visual acuity will be assessed by comparing best corrected visual acuity at each follow up appointment by the standardized vision testing, early treatment diabetic retinopathy study (ETDRS) test. The ETDRS visual acuity test was first developed to effectively evaluate visual changes following panretinal photocoagulation in patients with diabetic retinopathy. This method of measuring visual acuity was more accurate than previous methods, and thus has become the global standard, especially for clinical trials where it is essential to have utmost accuracy.	Baseline and months 1, 2, 3, 4, 5, and 6

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of cataract progression	Measured at each appointment with a slit lamp examination	Baseline and months 1, 2, 3, 4, 5, and 6
Changes in choroid vessel activity in lesion growth and activity at choroid	The changes in blood vessel lesion growth and activity will be measured by OCT (Ocular Coherence Tomography) and fundus fluoroscein angiography to assess choroidal neovascular leakage	Baseline and months 1, 2, 3, 4, 5 and 6
Resolution of macular edema	The speed at which macular edema resolves will be visually measured using optical coherence tomography	Baseline and months 1, 2, 3, 4, 5, 6
Mean change in visual acuity according to identified genetic mutations	Mean change in visual acuity according to individual mutations at the CFH haplotypes/C3 rs2230199 marker/ARMS2 rs10490924 marker and mt A4917G marker, calculated using the Macula Risk findings and visual acuity results as determined using ETDRS visual screening	Baseline and Months 1, 2, 3, 4, 5, 6
Mean change in visual acuity regardless of genetic profile results		Baseline and Months 1, 2, 3, 4, 5, 6
Interaction of smoking status and genetic profile on visual acuity changes		Baseline and Months 1, 2, 3, 4, 5, 6

Collaborators and Investigators

• Sponsor: McMaster University
• Collaborators: Canadian National Institute for the Blind
• Investigators: Principal Investigator: Varun Chaudhary, MD, FRCSC, St. Joseph's Healthcare Hamilton/McMaster University

Study record dates

Study Major Dates

• Study Start: January 1, 2012
• Primary Completion (Actual): October 1, 2014
• Study Completion (Actual): October 1, 2014

Study Registration Dates

• First Submitted: May 30, 2011
• First Submitted That Met QC Criteria: May 31, 2011
• First Posted (Estimate): June 1, 2011

Study Record Updates

• Last Update Posted (Estimate): March 17, 2016
• Last Update Submitted That Met QC Criteria: March 15, 2016
• Last Verified: March 1, 2016

More Information

Terms related to this study

• Keywords: Ranibizumab; Lucentis; Anti-inflammatory; Macular Degeneration; Vision loss; Age related macular degeneration; Anti-vascular endothelial growth factor (Anti-VEGF); Macula Risk; Genetic test
• Additional Relevant MeSH Terms: Eye Diseases; Retinal Degeneration; Retinal Diseases; Macular Degeneration; Physiological Effects of Drugs; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Ranibizumab
• Other Study ID Numbers: AMDgene12011