Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT04756310 |
| Other study ID # |
THEA_UNAV_1/14 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
November 2014 |
| Est. completion date |
April 2018 |
Study information
| Verified date |
February 2021 |
| Source |
Laboratorios Thea, Spain |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Retinal diseases are currently the leading cause of legal blindness in the developed world.
Among these disorders, age-related macular degeneration (AMD) is one of the most prevalent
conditions in individuals over 55 years of age. Late AMD, the most severe presentation of the
disease, clinically manifests as either geographic atrophy (dry form) or choroidal
neovascularization (CNV) (wet form). Although patients with wet AMD only represent 10% of the
total cases, CNV is the main and most serious cause of central vision loss. At present, the
treatment of wet AMD comprises intraocular injections of certain antiangiogenic agents which
act by blocking VEGF (vascular endothelial growth factor). No effective treatment is yet
available for dry AMD, though the AREDS (Age-Related Eye Disease Study) has shown that the
administration of antioxidant supplements is able to slow progression of the disease. Such
vitamin supplements are also indicated in patients who already have severe AMD (both
exudative and atrophic) in one eye, since the risk of progression in these cases is high.
Recent studies involving new antioxidant and antiangiogenic molecules such as resveratrol,
present in grapes and wine, have also revealed great efficacy in slowing the progression of
advanced AMD. Hydroxytyrosol is another polyphenol with important antioxidant and
antiinflammatory effects in the RPE.
Considering the above, the present randomized, multicenter interventional study involving
Spanish and Portuguese patients with unilateral wet AMD was designed to compare the effects
of two different nutritional supplements: one containing the antioxidants and minerals
recommended by the AREDS at doses that can be used in the European Union (Theavit), and the
other comprising these same substances plus omega-3 fatty acids (lipidic antioxidant), lutein
(pigment protecting against light-induced damage) and resveratrol (antioxidant and
antiangiogenic agent) (Retilut).
Description:
Retinal diseases are currently the leading cause of legal blindness in the developed world.
Among these disorders, age-related macular degeneration (AMD) is one of the most prevalent
conditions in individuals over 55 years of age. In the United States, the prevalence of AMD
varies from 0.5% at 55 years to 7% in people over 75 years. These data are clearly a cause
for concern, in view of the aging of the population in developed countries. In Spain, a
country with one of the greatest population aging problems, AMD affects 1.7% of all people
over 50 years, and the incidence increases with age, reaching 18.5% among those over 85
years. AMD is characterized by progressive destruction of the central region of the retina
(macula), resulting in central vision loss. While this does not lead to complete blindness,
the associated impairment of autonomy has a very strong impact upon patient quality of life.
AMD is a multifactorial disease - a fact that makes it difficult to establish the underlying
etiology. In this sense, although only age is accepted as the principal factor associated to
the development of AMD, other factors such as smoking, diet, oxidative stress, arterial
hypertension or obesity have been extensively investigated in the context of the disease.
Late AMD, the most severe presentation of the disease, clinically manifests as either
geographic atrophy (dry form) or choroidal neovascularization (CNV) (wet form). Although
patients with wet AMD only represent 10% of the total cases, CNV is the main and most serious
cause of central vision loss. At present, the treatment of wet AMD comprises intraocular
injections of certain antiangiogenic agents such as ranibizumab, bevacizumab, aflibercept,
etc., which act by blocking vascular endothelial growth factor (VEGF). No effective treatment
is yet available for dry AMD, though the Age-Related Eye Disease Study (AREDS) has shown that
the administration of antioxidant supplements is able to slow progression of the disease.
Such vitamin supplements are also indicated in patients who already have severe AMD (both
exudative and atrophic) in one eye, since the risk of progression in these cases is high.
The AREDS, sponsored by the National Eye Institute, was started in 1998 with the purpose of
evaluating the effect of high-dose antioxidants (vitamins C and E, and beta-carotene) and
minerals (zinc) upon the course of the disease. The results of the study showed that high
levels of antioxidants and zinc significantly reduced the risk of progression towards
advanced stages of AMD by 25%, and of vision loss by 19%. However, due to safety reasons, the
doses used in the AREDS cannot be administered in the European Union, since they exceed the
Recommended Daily Allowances (RDA). Therefore, the standard clinical practice is to use these
substances in patients with high risk AMD as nutritional supplements at the usual RDAs.
However, no interventional studies demonstrating the effects of these supplements have been
carried out.
Following publication of the AREDS I, certain dietary intake studies suggested the importance
of other molecules such as omega-3 fatty acids (DHA, EPA, DPA) and lutein / zeaxanthin. The
AREDS work group therefore decided to conduct a new study including both nutrients in
addition to those already evaluated (antioxidants and zinc). Lutein exerts an antioxidative
effect, can act as a blue light filter, and moreover has antiinflammatory properties. This
latter effect is especially important, considering that AMD is a disease secondary to a
low-grade chronic inflammatory process of the retinal pigment epithelium (RPE). In addition
to their antioxidant and antiinflammatory effects, the omega-3 fatty acids have important
antiangiogenic properties, as evidenced both by in vitro and in vivo studies.
Recent studies involving new antioxidant and antiangiogenic molecules such as resveratrol,
present in grapes and wine, have also revealed great efficacy in slowing the progression of
advanced AMD. Hydroxytyrosol is another polyphenol with important antioxidant and
antiinflammatory effects in the RPE.
Considering the above, the present randomized, multicenter interventional study involving
Spanish and Portuguese patients with unilateral wet AMD was designed to compare the effects
of two different nutritional supplements: one containing the antioxidants and minerals
recommended by the AREDS at doses that can be used in the European Union (Theavit), and the
other comprising these same substances plus omega-3 fatty acids (lipidic antioxidant), lutein
(pigment protecting against light-induced damage) and resveratrol (antioxidant and
antiangiogenic agent) (Retilut).
Study Design: A randomized, double-blind, multicenter interventional nutritional dose study
was designed. The patient follow-up period will last 24 months. The estimated patient
enrollment period will cover 9 months, and analysis of the results will be completed four
months after the end of the follow-up period. The estimated total duration of the project
will be between 52 months.
Study Subjects:
These patients from the different Spanish populations will be enrolled making use of the
infrastructure afforded by the RETICS network, "Eye disease related to aging, vision quality
and quality of life" (RD07/0062 subproject Retina). All patients will be 50 years old or
more, and written informed consent will be obtained in all cases, together with authorization
to enter their data in a database (data protection consent following the criteria of the
Ethics Committees of each of the participating centers).
On the baseline visit, the patients will undergo a complete ophthalmological evaluation, and
plasma will be collected for posterior analysis of several biochemical parameters.
Those patients who meet the inclusion criteria and none of the exclusion criteria will start
nutritional supplementation for two years (2 daily capsule, nutritional dose) with one of the
nutritional supplements. The study will be carried out on a simple-blind basis, even the
patient knows the origin of the treatment, the ophthalmologist conducting follow-up will not
know the composition of the provided supplement. Accordingly, the boxes and capsules will be
adequately masked. The blisters with the nutritional supplements will be delivered to each
patient at the inclusión visit (Day 0), and the empty blisters are to be returned as an
initial measure of treatment compliance. Patient follow-up will take place every 6 months
(Day 0, Month 6, Month 12, Month 18, Month 24), and will comprise a complete ophthalmological
evaluation, with the registry of any ophthalmological adverse events. The appearance of such
adverse events will be a secondary study endpoint, and is defined as the appearance of
choroidal neovascularization in the fellow eye. First objective will be the measure of the
change in the best corrected visual acuity (BCVA) in the study eye. Blood samples will be
collected at Day 0, Month 12 and Month 24 for biochemical analysis (Luminex® markers, omega
3, lutein and zeaxanthin profile and plasma REDOX status) representing also a secondary study
endpoints.
Ophthalmological examination:
- Visual acuity will be determined with the ETDRS system at a distance of four meters with
the best optic correction.
- Anterior segment biomicroscopy study to discard opacification of the media.
-Biomicroscopic funduscopy with +78/+90D lens.
- Digital retinography of the ocular fundus, red-free light photography of the fundus, and
autofluorescence photography of the fundus under maximum pharmacologic mydriasis to
ensure maximum image quality; a minimum of three examinations with photographs at 30/35°
will be obtained.
- The follow-up of neovascularization will be carried out by fluorescein angiography and
optical coherence tomography (OCT). The presence of subretinal and/or intraretinal fluid
will be taken as a sign of wet AMD in OCT.
Biochemical analysis:
The plasma of the patients both on Day 0 and at the end of the study will be subjected to the
following determinations:
- Analysis of the lipid profile (omega 3).
- Evaluation of the systemic oxidative condition based on total antioxidant capacity
assay.
- Determination of lutein levels by HPLC.
- Detection of the main inflammatory and oxidative stress markers and/or vascular factors
in plasma, based on Luminex® technology (affymetrix): VEGF-A, IL-1 beta, IL-6, IL-8,
Eotaxin-2 (CCL24), HGF, PDGF, MCP-1, TNF-alpha and FGF.
