Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT02645266 |
| Other study ID # |
BHC-RD-SOP-038 |
| Secondary ID |
|
| Status |
Active, not recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
May 1, 2018 |
| Est. completion date |
December 2024 |
Study information
| Verified date |
March 2024 |
| Source |
McMaster University |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Diabetic Macular Edema is a serious ocular consequence of poorly controlled diabetes. Even
though significant research has been done to clarify the pathogenesis of DME, a clear causal
pathway of the complication is of yet undetermined. However, there is some consensus among
researchers that a cascade of inflammatory markers plays an important role in the disease
process. The study hopes to better delineate the role these inflammatory markers play by
investigating whether basal levels predict response or lack thereof to Aflibercept.
Description:
Diabetic macular edema (DME) is a common and serious complication of diabetic retinopathy and
is one of the leading causes of vision loss in the developed world. Traditionally, DME was
treated with focal grid laser which was not very efficacious. More recently, over the last
decade, the development of intravitreal steroids such as Triamcinolone acetonide and anti-
vascular endothelial growth factor antibodies such as Bevacizumab (off label usage),
Ranibizumab and Aflibercept have proven to be promising. In fact, Aflibercept, being the
latest anti-VEGF entering the market, was found superior to traditional treatment in DA
VINCI, VIVID DME and VISTA DME studies and there are more trials ongoing. Also, several
trials have shown steroids to be superior to laser treatments. The steroids continue to have
a role in management of patient refractory to other treatments. This is thought to be due to
the inflammatory nature of diabetic macular edema.
Much of the recent success in treatment of DME is owed to the recent developments in our
understanding of the inflammatory cascade in a diabetic eye specially the discovery and
therapeutic targeting of VEGF. The pathophysiology of DME is thought to be complex and is yet
to be fully elucidated; however, a review of literature reveals that there is consensus
amongst researchers and clinicians with regards to the importance of disruption of blood
retinal barrier involving numerous inflammatory mediators and cytokines in this process. It
has been shown that the interruption in BRB is not merely a direct consequence of
hyperglycemia but the outcome of inflammatory cascade initiated by chronic hyperglycemia.
Chronic hyperglycemia leads to increased production of pro-inflammatory molecules such as
advanced glycation end products (AGEs) which are molecules that promote formation of abnormal
cross-links in between proteins. These compounds in turn lead to disruptions of the
functioning BRB through the up regulation of several inflammatory pathways. Currently the
best method to battle AGEs is to prevent their formation through tight glycemic control and
the development of therapies has been focused on targeting downstream inflammatory and
angiogenic mediators such as VEGFs. It has been shown that VEGFs( VEGF A, B, C, D, E and
PLGF) play a major role in neovascularization, formation of new highly friable blood vessels,
increased permeability and disruption of BRB with VEGF-A being the most potent promoter of
neovascularization. Other factors involved include pigment epithelial derived factor (PEDF),
Interleukin-6 and 8( IL-6 and 8), monocyte chemotactic protein-1 (MCP-1), Interferon gamma
protein 10(IP-10) etc. It is theorized that some factors play a protective role against the
pathogenesis of DME, including PEDF, FLT3L, GM-CSF, IP-10, IFN alpha. It is therefore the
lack of balance of these factors that is thought to play a major role in diabetic eye
disease.
Since, not all patients respond to anti-VEGF therapies injections; researchers have been
pursuing other cytokines and inflammatory mediators as the culprit in the non-responsive
group. Up-to-date there have been numerous studies investigating the levels of cytokines in
the eyes of diabetic patients and based on our extensive review of the literature this/these
mystery molecules can be any of the following cytokines: IL-1, IL-6, IL-7, IL-8, IL-10,
IL-12, MCP-1, MCP-3, IP-10,VEGF, PLGF, PEDF, ICAM-1, VCAM-1, GM-CSF, GRO(CXCL-1), TNF-alpha,
TGF- beta, Eotaxin, FGF-2, FLT3L,IFN alpha, MDC, MIG(CXCL 9), PKC, and MMP-9. These cytokines
may also present a novel path to monitor disease activity.
Until now, there has not been a study attempting to determine whether basal cytokine levels
are an indication to response to treatment or lack thereof. It is therefore, in our opinion,
essential to carry out such a study as a significant relationship between (an) elevated/
suppressed cytokine and letters gained on best corrected visual acuity or a relationship
between an elevated cytokine and not responding to our VEGF treatments could present a path
for deciding whether a patient is suited for the anti-VEGF treatment at hand. In addition, it
could pave the way for development of a new medication that could act complementary to our
current treatments. Above all, we hope to assist eye surgeons and physicians to help their
patients with the treatment that fits them the best.
