Genetic Biomarkers for the Response to Anti-VEGF (Vascular Endothelial Growth Factor).Treatment in Wet Age-related Macular Degeneration (Wet ARMD)

Age-Related Macular Degeneration Clinical Trial

Official title:

Genetic Biomarkers for the Response to Anti-VEGF (Vascular Endothelial Growth Factor).Treatment in Wet Age-related Macular Degeneration (Wet ARMD)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02762188
• Other study ID #: CHUB-SAMBA
• Status: Completed
• Phase: N/A
• First received: April 25, 2016
• Last updated: January 18, 2018
• Start date: August 1, 2013
• Est. completion date: January 18, 2018

Study information

• Verified date: January 2018
• Source: Brugmann University Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Age-Related Macular Degeneration (ARMD) is the most common cause of blindness in the adult population of the Western World. It affects the macula - the region of the retina most rich in photoreceptors and responsible for central vision. The ethiology of ARMD remains poorly understood. Population-based studies have demonstrated a complex ethiology, with contributions from a combination of genetic and environmental factors.

Two major forms of ARMD are clinically distinguishable: the dry and wet form. The latter represents the more aggressive clinical subgroup, and is characterized by the abnormal growth of new blood vessels (neovascularization) under the macula, thus leading to the accumulation of fluid under the retina, bleeding, progression to fibrosis, and finally loss of central vision.

The pathogenesis of this neovascularization is not fully understood, although the VEGF pathway is well known to be involved in angiogenesis and was implicated in the development of the new vessels under the macula. The VEGFs are the most specific and potent stimulators of the angiogenesis.

Molecules that bind and inactivate the VEGF have been developed for the treatment of ARMD and they are applied in ARMD clinic through intra vitreal injections.The difference seen in response to anti VEGF treatment for ARMD between the patients is suggestive for the presence of factors influencing the effect of the drug. Some of these could be genetic variants within genes involved in ARMD pathogenesis or VEGF pathway. Few associations with markers within genes previously found to be related with the pathogenesis of ARMD have been found. It remains unknown whether variants involved in the anti VEGF treatment response could influence the therapeutic outcome.

The purpose of this trial is to evaluate the association between a panel of selected polymorphic markers in the VEGF pathway and the response to therapy with anti VEGF antibody for ARMD. The hypothesis is that the individual genotype influences the response to the anti VEGF. This can lead to identification of genetic biomarkers allowing treatment individualization and optimization of the visual outcomes.

Description:

Age-Related Macular Degeneration (ARMD) is the most common cause of blindness in the adult population of the Western World. It affects the macula - the region of the retina most rich in photoreceptors and responsible for central vision.

Despite this manifest importance, the ethiology of ARMD remains poorly understood. Population-based studies have demonstrated a complex ethiology, with contributions from a combination of genetic and environmental factors. Genome-wide association studies revealed the presence of loci associated with susceptibility in a wide range of genes, including genes involved in the complement system, cholesterol homeostasis, growth factor diffusion and angiogenesis. Smoking has been identified as a major environmental factor.

Two major forms of ARMD are clinically distinguishable: the dry and wet form. The latter represents the more aggressive clinical subgroup, and is characterized by the abnormal growth of new blood vessels (neovascularization) under the macula, thus leading to the accumulation of fluid under the retina, bleeding, progression to fibrosis, and finally loss of central vision.

The pathogenesis of this neovascularization is not fully understood, although the VEGF pathway is well known to be involved in angiogenesis and was implicated in the development of the new vessels under the macula. The VEGFs are the most specific and potent stimulators of the angiogenesis. VEGF-A is a 45kD glycoprotein binding to transmembrane tyrosine kinase receptors, VEGFRs, which activates a cascade of downstream factors. VEGF-A has the strongest pro-angiogenic effect in the retina by promoting proliferation, sprouting and tubing of the endothelial cells. It can bind to at least two receptors -VEGFR1 and VEGFR2, although the most of the proangiogenic activity appears to be mediated through VEGFR2. Expression of a VEGFR2 isoform that lacks both the intracellular signaling domain and the transmembrane domain, represents a soluble form of the receptor, inactivating VEGF extracellularly.

Similarly, molecules that bind and inactivate the VEGF have been developed for the treatment of ARMD and they are applied in ARMD clinic through intra vitreal injections. These include antibodies, a recombinant receptor fusion protein and a synthetic aptamer. The anti-VEGFA antibodies - ranibizumab and bevacizumab, off-label, have been associated with limited side-effects and significant therapeutic improvement, and became the standard in the treatment of the wet form of ARMD. Indeed, for example in the first clinical trials for ranibizumab, monthly injections of ranibizumab demonstrated an average gain in visual acuity of 6.6 and 10.7 ETDRS letters after 24 months. However, currently most clinical centres apply modified treatment protocols. Commonly used is an initial loading dose of three consecutive monthly injections and subsequent follow-up and administration of additional injections depending on the evolution of visual acuity, optical coherence tomography and fluorescein angiography data . 25% of the ARMD patients show significant improvement of the visual acuity, 70% maintain or show slightly increased visual acuity, and the remaining 5 percent of the patients fail to respond to the treatment and continue to loose vision.

The difference seen in response to anti VEGF treatment for ARMD between the patients is suggestive for the presence of factors influencing the effect of the drug. Some of these could be genetic variants within genes involved in ARMD pathogenesis or VEGF pathway. Few associations with markers within genes previously found to be related with the pathogenesis of ARMD have been found. It remains unknown whether variants involved in the anti VEGF treatment response could influence the therapeutic outcome.

A study demonstrated that the single nucleotide polymorphism (SNP) in VEGFR1 rs7993418 (TAC codon) form is associated to resistance to the anti VEGF therapy in carcinoma patients. This specific genotype leads to an increased expression of the VEGFR1 without changing the amino acid content of the protein. The increased VEGFR1 protein is most likely due to higher efficiency of messenger ribonucleic acid (mRNA) translation.

The purpose of this trial is to evaluate the association between a panel of selected polymorphic markers in the VEGF pathway and the response to therapy with anti VEGF antibody for ARMD. The hypothesis is that the individual genotype influences the response to the anti VEGF. This can lead to identification of genetic biomarkers allowing treatment individualization and optimization of the visual outcomes.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 501
• Est. completion date: January 18, 2018
• Est. primary completion date: January 18, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patients with the wet form of ARMD who receive or have received in the past anti VEGF intra vitreal injections

Exclusion Criteria:

• Patients whi had received treatments other than anti VEGF, before the use of anti-VEGF

• Patients without follow-up

• Patients receiving anti-VEGF because of another pathology than ARMD

Related Conditions & MeSH terms

• Age-Related Macular Degeneration
• Macular Degeneration

Intervention

Device:
• Genotype analysis
After signing informed consent, a blood sample is taken and DNA extracted according to standard procedures. The samples are genotyped with the Mass Array iPlex Gold. Processing of the data is done using the previously described protocol by Lambrechts and co. Statistical analysis will be done to evaluate the association between the different genetic variants and the clinical outcomes collected during the standard of care follow-up for ARMD.

Locations

Country	Name	City	State
Belgium	CHU Brugmann	Brussels

Sponsors (1)

Lead Sponsor	Collaborator
Brugmann University Hospital

Country where clinical trial is conducted

Belgium, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Snellen visual acuity test result	The visual acuity test is used to determine the smallest letters you can read on a standardized chart (Snellen chart).	Baseline
Primary	Snellen visual acuity test result	The visual acuity test is used to determine the smallest letters you can read on a standardized chart (Snellen chart).	3 months after treatment
Primary	Snellen visual acuity test result	The visual acuity test is used to determine the smallest letters you can read on a standardized chart (Snellen chart).	6 months after treatment
Primary	Snellen visual acuity test result	The visual acuity test is used to determine the smallest letters you can read on a standardized chart (Snellen chart).	12 months after treatment
Primary	Number of injections received per year		1 year
Primary	Central foveal thickness (µm)	Measured by optical coherence tomography (Heidelberg & Zeiss)	Baseline
Primary	Central foveal thickness (µm)	Measured by optical coherence tomography (Heidelberg & Zeiss)	3 months after treatment
Primary	Central foveal thickness (µm)	Measured by optical coherence tomography (Heidelberg & Zeiss)	6 months after treatment
Primary	Central foveal thickness (µm)	Measured by optical coherence tomography (Heidelberg & Zeiss)	12 months after treatment
Primary	Presence of Intra Retinal Cysts (yes/no)	Tested by optical coherence tomography (Heidelberg & Zeiss)	Baseline
Primary	Presence of Intra Retinal Cysts (yes/no)	Tested by optical coherence tomography (Heidelberg & Zeiss)	3 months after treatment
Primary	Presence of Intra Retinal Cysts (yes/no)	Tested by optical coherence tomography (Heidelberg & Zeiss)	4 months after treatment
Primary	Presence of Subretinal Fluid (yes/no)	Tested by optical coherence tomography (Heidelberg & Zeiss)	Baseline
Primary	Presence of Subretinal Fluid (yes/no)	Tested by optical coherence tomography (Heidelberg & Zeiss)	3 months after treatment
Primary	Presence of Subretinal Fluid (yes/no)	Tested by optical coherence tomography (Heidelberg & Zeiss)	4 months after treatment
Primary	Presence of Pigment Epithelial Detachment (yes/no)	Tested by optical coherence tomography (Heidelberg & Zeiss)	Baseline
Primary	Presence of Pigment Epithelial Detachment (yes/no)	Tested by optical coherence tomography (Heidelberg & Zeiss)	3 months after treatment
Primary	Presence of Pigment Epithelial Detachment (yes/no)	Tested by optical coherence tomography (Heidelberg & Zeiss)	4 months after treatment