Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT04241536 |
| Other study ID # |
CEC/010/20 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
June 1, 2021 |
| Est. completion date |
November 29, 2022 |
Study information
| Verified date |
January 2023 |
| Source |
Association for Innovation and Biomedical Research on Light and Image |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
The global aim of this project is to expand the knowledge on the multifactorial pathogenesis
of AMD. In addition to age, the multifactorial pathogenesis of AMD includes environmental and
genetic risk factors. However, how these interact to promote progression remains largely
unknown. AMD is a progressive retinal disease characterized by mostly asymptomatic early
phases and progression to potentially blinding late forms (choroidal neovascularization or
geographic atrophy). Individuals vary in their rate of progression, with some remaining
stable for years. The reasons behind this variability, as well as the triggers and mechanisms
of AMD progression, are not well understood. Currently, the standard of care for assessment
of the risk of progression is solely based on fundus appearance, and is limited in its
prediction ability. Our previous work showed that metabolomics enables the identification of
specific plasma metabolomic profiles in AMD, which vary with the severity stages. The
investigators hypothesize that the plasma and urinary metabolomic profile of subjects who
progress over a five-year period (progressors) is distinct from those who remain at the same
AMD severity stage (non-progressors). In this proposal, the investigators will follow our
existing cohort over five years, comparing the metabolomic profiles of progressors to
non-progressors.
Description:
Age-related macular degeneration (AMD) is the leading cause of adult blindness in developed
countries and the third cause of global blindness. It is an eye-ageing disease with
tremendous impact in daily quality of life. Clinically, AMD is a progressive disease, which
evolves from early to late stages - geographic atrophy (GA) or choroidal neovascularization
(CNV). GA has currently no treatment and CNV requires several costly intravitreal injections.
Patients with late stages of AMD represent a huge economic burden to society, with enormous
medical and non-medical costs.
Predicting progression is therefore of utmost importance. It is established that AMD
progression has a multifactorial nature, combining phenotypic and several environmental and
genetic risk factors. Attempts have been made to include the different risk-factors in
theoretical predicting models, however they are not practical on the clinical setting and
fail to explain biological interactions. Thus, in the current clinical practice, risk
prediction is still being assessed on a phenotypic basis, not considering AMD multifactorial
nature.
A new approach that may allow the integration of all AMD interacting factors is metabolomics,
the simultaneous multiparametric measurement of metabolic changes in living organisms as a
response to perturbation (disease, diet, environment, others). The value of metabolomics in
medical research has become clear through several studies on cancer, cardiovascular disease,
and Alzheimer disease (AD), the latter sharing common pathways with AMD, as well as by
increasing investments in this area. The metabolome reflects the occurring biochemical
processes, therefore forming a fingerprint of the organism's health status, at a given time,
which can be measured through nuclear magnetic resonance (NMR) spectroscopy and/or mass
spectrometry (MS). The research team's previous work showed that metabolomics can be a
powerful tool to study AMD as well, enabling the identification of specific plasma
metabolomic profiles in AMD, which vary with the severity stages, and are primarily lipid
metabolites linked to glycerophospholipid and sphingolipid pathways, as well as purines The
current study will further elucidate the role of metabolomics in the understanding of AMD,
and will also identify potential biologically robust biomarkers that can address the problem
of predicting progression. The investigators hypothesize that the plasma and urinary
metabolomic profile of subjects who progress over a five-year period (progressors) is
distinct from those who remain at the same AMD severity stage (non-progressors). Based on our
preliminary data, The investigators hypothesize that a panel of metabolites will distinguish
these two groups (progressors vs non-progressors), and that this will mostly consist of
lipids and amino acids.
To achieve these purposes, subjects who participated in our group's previous prospective
study on AMD metabolomics will be recruited. Eligible subjects will be all that participated
in the the IN654 study (between January 2015 and July 2016). These will be recalled and
progression will be phenotypically assessed, thus defining the AMD-progressors and
non-progressors groups.
Metabolomic signatures of AMD progression and disease will lay the path for the future
definition of progression metabolic biomarkers, which can represent a rapid, reliable and
potentially affordable methodology for progression prediction. Overall, this approach should
offer an opportunity to identify new valuable supplemental tools for routine clinical
evaluation. This will allow medical interventions based on preventive strategies to reduce
progression to blindness stages, which will, ultimately, also reduce societal costs of AMD.
Preliminary data The researh team pioneered the application of metabolomics to the study of
AMD across all stages, and, in 2015, the AIBILI team recruited and collected baseline data on
a total of 295 subjects (242 AMD patients and 53 controls). This study cohort will be derived
from that study population.
The investigators have published extensively on the hypothesis that metabolomic profiles
differ across AMD stages. The latest paper, which includes the entire study population,
meta-analyses to combine data from different cohorts was used. This paper provides additional
evidence that patients with AMD present an altered plasma metabolomic profile as compared to
controls, and that these profiles vary with disease severity. Results revealed that 28
metabolites differed significantly between AMD patients versus controls (false discovery rate
(FDR) q-value: 4.1 x 10-2 - 1.8 x 10-5), and 67 across disease stages (FDR q-value: 4.5 x
10-2 - 1.7 x 10-4). Pathway analysis showed significant enrichment of glycerophospholipid,
purine, taurine and hypotaurine, and nitrogen metabolism (p-value < 0.04).
To assess the performance of models considering metabolite information, receiving operating
curve (ROC) assessments were made. Both a model considering metabolite changes across disease
stages (AUC = 0.815; 95% CI:0.771-0.860) and a model comparing patients with AMD versus
controls (AUC = 0.789; 95% CI: 0.738-0.840) outperformed (p-value = 3.74 x 10-6 and p-value =
2.07 x 10-4, respectively) a more classical model considering demographic covariates alone
(AUC = 0.725; 95% CI: 0.671-0.779) This is evidence that metabolomics can be a useful tool
for longitudinal study of AMD progression.
General research design Five-years after the first AMD metabolomic study, all participants
will be invited to participate in this study.
All participants will be invited to come to AIBILI to perform the study procedures, which
include color fundus photographs (CFP), SD-OCT and swept source OCT (SS-OCT). Additionally,
they will also be invited to answer a validated food frequency questionnaire (FFQ)19 and a
questionnaire about their regular physical activity. Systemic comorbidities and current
medication will be registered. Blood and urine samples will be collected for metabolomic
profiling. Functional testing with microperimetry and dark adaptation will be offered as an
additional optional study procedure.
Afterwards, the obtained CFP will be graded. According to the procedures for IN654 study
classification, all CFP will be standardized using software developed by our group. Two
independent graders, masked to any other data, will assess AMD staging of all eyes, according
to the AREDS classification.21 Each eye of patients will be assessed separately, and if
different, the most advanced eye will be considered as the classification for that subject.
Previously performed IN654 study classification will be compared. Progressors will be defined
as patients who: (i) had originally been classified as early AMD, and at five years have
intermediate or late AMD; (ii) had originally been classified as intermediate AMD and have at
five years late AMD. Non-progressors will be defined as those who remain within the same AMD
stage at the five-year visit.
