2.1 Primary objectives2.1.1 Cross-sectional part• Technical evaluation of the functional and structural outcome measures to support a biomarker qualification by regulatory authorities and payers. 2.1.2 Longitudinal part • Assessment of prognostic…
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Brief title
Condition
- Retina, choroid and vitreous haemorrhages and vascular disorders
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Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The MACUSTAR clinical study will generate a large volume of data in relation to
functional, structural and patient reported outcome measures (PROMs).
3.1.1 Functional outcomes
• Mean change from baseline in best corrected visual acuity (BCVA) using an
Early Treatment Diabetic Retinopathy Study (ETDRS) chart (standard parameter,
tested for comparison) (reference variable)
• Mean change from baseline in scotopic and mesopic microperimetry sensitivity
• Mean change from baseline in LLVA
• Mean change from baseline in vanishing optotypes VA
• Mean change in low luminance deficit (LLD = BCVA-LLVA)
• Mean change in absolute threshold
• Proportion of subjects with progression in dark adaptation deficit beyond
coefficient of repeatability (as determined in the re-test assessment in the
cross-sectional part)
• Mean change from baseline in the rod intercept time of the dark adaptation
test
3.1.2 Structural outcomes
• Mean change from baseline in the cube root of drusen volume by SD-OCT
• Proportion of subjects with reduction in drusen volume (different cut offs at
>=15, 30, 50%; to baseline of cube root drusen volume estimated by SD-OCT
without progression to GA and/or nAMD)
• Mean change from baseline of retinal thickness (total, inner retina, outer
nuclear layer, photoreceptor layer and Retinal Pigment Epithelium (RPE) layer)
by SD-OCT
• Focal pigmentary changes captured by colour fundus photography (CFP)
• Presence of refractile deposits
• Presence of intraretinal cystoid spaces
• Presence of localized RPE hypertransmission
• Presence of localized disruption of ellipsoid zone
• Presence of localized subsidence of the outer plexiform layer and the inner
nuclear layer
• Presence of hyporeflective wedge-shaped bands
• Changes in localized fundus autofluorescence signal alterations
• Presence of reticular drusen/subretinal drusenoid deposits and associated
local changes as determined by multimodal imaging
• Proportion of subjects with study eye that progressed to GA and/or nAMD
• Presence of quiescent choroidal neovascularization (CNV) as assessed by OCT
angiography (OCT-A) (at equipped sites)
• OCT-A findings (at equipped sites)
• Proportion of conversions to late AMD detected with fluorescein angiography
(FA) that could be detected with OCT-A (at equipped sites)
3.1.3 Patient reported outcomes
• Mean change from baseline in patient-reported low luminance visual
functioning, as measured by the VILL questionnaire, including the domains of:
o Reading & accessing information
o Orientation & mobility (incl. driving)
o Safety
o Socio-emotional well-being
• Change in utility index from baseline as measure by the PROM utility index
• Mean change from baseline in patient-reported health status and utility using
the EQ-5D-5L (https://euroqol.org/eq-5d-instruments/eq-5d-5l-about/)
3.1.3 Door de patiënt gerapporteerde uitkomsten
• Gemiddelde verandering ten opzichte van de uitgangswaarde bij door de patiënt
gerapporteerd visueel functioneren met lage luminantie, zoals gemeten met de
VILL-vragenlijst, inclusief de domeinen van:
o Lezen en toegang tot informatie
o Oriëntatie en mobiliteit (incl. rijden)
o Veiligheid
o Sociaal emotioneel welbevinden
• Verandering in de gebruiksindex van de basislijn als maatstaf door de
PROM-hulpprogramma-index
• Gemiddelde verandering ten opzichte van baseline in door de patiënt
gerapporteerde gezondheidsstatus en het nut met behulp van de EQ-5D-5L
(https://euroqol.org/eq-5d-instruments/eq-5d-5l-about/)
Secondary outcome
not applicable
Background summary
Age-related macular degeneration (AMD) affects almost 30% of the older
population and progresses slowly from early AMD to intermediate AMD (iAMD) and
ultimately late-stage AMD with severe and frequently irreversible visual loss
over a decade.1 Population aging will lead to a considerable increase in AMD
prevalence. Today, late stage AMD is the leading cause of blindness among the
elderly in industrialized countries and affects more than 2.5 million patients
in the European Union (EU)2, 3 resulting in direct annual costs of over 2
billion Euros.4
In order to reduce the significant burden of late AMD, novel interventions that
stop or delay progression from iAMD to late AMD will need to be developed.5 In
order to do this, clinical endpoints validated and accepted by regulatory
agencies, health technology assessment (HTA) bodies, and payers are needed
since currently these do not exist for iAMD clinical trials (CTs). In fact, at
the moment, effective treatment options are only available for neovascular AMD
(nAMD), and even then, it still remains a vision threatening disease as
justified by the risk of sub-retinal hemorrhages or atrophy and long-term
fibrosis development.
Regarding atrophic late AMD (geographic atrophy, GA), a limited number of
agents are in ongoing phase III CTs with no confirmatory proof of efficacy so
far. Given that GA is an advanced stage of AMD with irreversible loss of
photoreceptors and severe loss of vision in cases of foveal involvement, a
recovery of visual function is not expected when the patients reach this stage
of the disease. Therefore, currently there is no therapeutic intervention to
delay or stop the progression to late stage AMD. Consequently, from a public
health perspective, two main objectives exist: 1) find a solution for the often
clinically relevant and generally progressive visual impairment of patients
with iAMD in low-luminance and low-contrast situations, and 2) identify the
iAMD patients who are at risk of progression to late stage AMD in order to
treat them prior to any irreversible vision damage and potentially legal
blindness.
Although there is good evidence that indicates patients with iAMD experience
impairment of visual function, it is unknown to what extend these impact the
patients* life nor can it be reliably measured and quantified. It is also
unknown whether there are specific risk factors in the population of iAMD
patients which identify those with more rapid progression to late stages of the
disease.
Therefore, the successful development of iAMD interventions requires validated
functional, morphological and patient-reported endpoints to be used in CTs,
which must be clinically meaningful and accepted by regulatory agencies. In
addition, functional decline in iAMD, as well as specific risk factors for iAMD
progression to late AMD need to be better characterized to inform and improve
conduct of future iAMD CTs.
Considering this context, MACUSTAR clinical study will focus on iAMD in order
to generate data on the visual impairment in iAMD and its impact on patients*
lives, as well as data on functional, structural and patient-reported outcomes
(PROs) with progression from iAMD to late AMD. These data will lead to
validated clinical endpoints for future iAMD CTs.
To achieve this, several different but complementary functional tests,
multimodal retinal imaging and tools to evaluate different relevant aspects of
patient-reported functioning will be employed in the study. This multi-modal
approach aims to develop clinical endpoints that either alone or in
combination, serve as surrogate outcomes for progression from iAMD to late
stage AMD. Furthermore, PROs will be tested in iAMD patients, and combining
these to the functional testing performed under low luminance, will ensure that
functional endpoints are patient-relevant and that also data on the tests*
minimally important differences will be available. Utility values will be
developed for the PROs, which will inform future innovative cost-effectiveness
models and will be essential for future health technology assessments.
In the MACUSTAR clinical study, structural changes over time in iAMD patients
and structural differences between the AMD stages will also be assessed using
advanced imaging technologies. Furthermore, structural data from AMD patients
and from subjects with no AMD or aging-changes only will be compared. This will
allow the characterization of the disease evolution, the establishment of
structural-functional correlations and the identification of points-of-no
return in the disease progression. Then, structural biomarkers can be
identified and validated as clinical endpoints for future clinical trials
assessing iAMD progression.
Finally, the functional, structural and PROs data will be combined with the
genetic and demographic data collected in the study, thus providing a wider
understanding of iAMD stage, relevant risk factors and better prediction of
disease progression.
Study objective
2.1 Primary objectives
2.1.1 Cross-sectional part
• Technical evaluation of the functional and structural outcome measures to
support a biomarker qualification by regulatory authorities and payers.
2.1.2 Longitudinal part
• Assessment of prognostic power of changes in retinal sensitivity (as measured
by microperimetry) for progression from iAMD to late AMD (nAMD and GA).
2.2 Secondary objectives
2.2.1 Cross-sectional part
• Analyses of correlation between structural and functional outcome measures
with the novel Visual Impairment in Low Luminance (VILL) and 5Q-5D-5L PROMs to
support patient-relevance of outcome measures.
• To evaluate the ability of outcome measures to differentiate between
different AMD stages and no AMD control subjects
• Establish a database with cross-sectional data of controls (no AMD), early,
intermediate and late AMD subjects with functional, structural and patient
reported outcome assessment data.
2.2.2 Longitudinal part
• Assessment of the association between functional and structural candidate
outcome measures with progression from iAMD to late stage AMD. Outcome measures
included in these assessments will be:
o Functional outcome measures: Low Luminance Visual Acuity (LLVA), vanishing
optotypes visual acuity, contrast sensitivity, absolute threshold, rate of rod
mediated dark adaptation, reading performance, and scotopic and mesopic
sensitivities by fundus controlled microperimetry.
o Structural outcome measures: based on multi-modal retinal imaging including
spectral domain optical coherence tomography (SD-OCT), confocal scanning laser
ophthalmoscopy (cSLO), fundus autofluorescence (FAF), on which generalized
retinal biomarkers such as change in drusen volume, or change in load of
reticular pseudodrusen as well as localized retinal biomarkers such as focal
changes in specific SD-OCT bands will be assessed.
• Establish a database with longitudinal data of iAMD subjects with functional,
structural and patient PROM outcome assessment data.
Study design
The study consists of two main parts: a cross-sectional part and a longitudinal
part.
Cross-sectional part: Four groups of subjects with different stages of AMD
(early, intermediate, late and no AMD) will be included.
Longitudinal part: a group of iAMD subjects will be followed-up for a 10-year
period.
Study burden and risks
The MACUSTAR clinical study is a low-interventional study, which will not test
therapeutic interventions. All devices used are already marketed in the study
countries or are market-ready. As almost all assessments and procedures (except
for FA and blood collection) are non-invasive, most Adverse Events (AE) may be
due to the spontaneous progression of the underlying disease or occurrence of
concomitant diseases.
Blood collection will be performed at the baseline visit and for subjects with
iAMD participating in the longitudinal study annually thereafter. The normal
minor risks associated with blood collection are: hematoma at the injection
site; a locally restricted inflammation; and, in very rare cases, a blood clot
(thrombosis).
The only invasive assessment planned in the context of the MACUSTAR clinical
study is FA. However, this diagnostic assessment will only be performed in a
limited number of subjects, in whom the investigator has the clinical suspicion
of progression of AMD to late stage and specifically to nAMD. FA is considered
to be needed as it is the current gold standard in clinical practice to
ascertain diagnosis of nAMD and is required to qualify for most currently
available publicly reimbursed treatments for nAMD in EU countries. In a
retrospective review of all adverse reactions to intravenous sodium fluorescein
injection (n=11 898) in subjects undergoing fluorescein angiography between
June 1998 and June 2004, a total of 132 adverse drug reactions (ADR) were
recorded, all classified as mild to moderate, with the most common ADRs being
nausea and vomiting. No serious ADRs or deaths were reported 7.
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Listed location countries
Age
Inclusion criteria
General Inclusion criteria (applicable to all groups)
1. Male and female subjects.
2. Aged 55 - 85 years at baseline.
3. Able and willing to provide written informed consent and to comply with the
study protocol visits and assessments.Intermediate AMD
1. Study eye must have iAMD and,
2. The fellow eye must have iAMD and/or, in addition, extrafoveal GA (no
atrophy within the central ETDRS subfield), maximum total GA size is 1.25 mm2.
Definition of iAMD: large drusen >125 µm and/or any AMD pigmentary
abnormalities, that are definite hyper- or hypopigmentary abnormalities
associated with medium or large drusen but not associated with other known
disease entities. (See table 4-1 for more specifications). If both eyes are
eligible for the study based on inclusion criteria, the eye with better visual
acuity (i.e. on BCVA) will be selected as the study eye as this will improve
reliability of functional testing and quality of image acquisition and thus
improve sensitivity to detect change over time. In cases in which both eyes
have the same visual acuity, the study eye will be selected at random by the
investigator.
3. ETDRS letter chart BCVA in the study eye not worse than 72 letters
(approximately 20/40 Snellen VA equivalent).
4. All general inclusion criteria.Late AMD
1. Subjects with bilateral GA, bilateral nAMD or nAMD in one eye and GA in the
other (See table 4-1 for more specifications).
2. BCVA between 20/80 and 20/200 in study eye.
3. All general inclusion criteria.Early AMD
1. Subjects with medium drusen > 63µm and <= 125µm and no AMD pigmentary
abnormalities in both eyes and not signs of intermediate or late AMD. (See
table 4-1 for more specifications).
2. All general inclusion criteria. No AMD
1. No signs of early, intermediate or late AMD in both eyes. (See table 4-1 for
more specifications).
2. All general inclusion criteria only.ãÞ*Öç*ÍRÚ
Exclusion criteria
General Exclusion criteria (applicable to all groups)
1. Media opacity or eye movement disorder (nystagmus) that interferes with
retinal imaging data quality in the opinion of the investigator.
2. Severe ptosis, extraocular motility restriction or head tremor preventing
adequate fundus visualization in the opinion of the investigator.
3. Any signs of nAMD or GA according to the criteria descried in table 4-1
(does not apply to the late AMD group).
4. Any concurrent intraocular condition in the study eye (e. g. glaucoma or
cataract) that, in the opinion of the investigator would either require
surgical intervention during the study to prevent or treat visual loss that
might result from that condition or affect interpretation of study results.
5. Severe non-proliferative diabetic retinopathy, or proliferative diabetic
retinopathy.
6. Any diabetic macular edema or macular disease
7. Ocular disorders in the study eye (i. e., pre-retinal membrane) at the time
of enrolment that may confound interpretation of study results and compromise
visual acuity.
8. Diagnosis of uncontrolled glaucoma with intraocular pressure of >30 mmHg
(despite current pharmacological or non-pharmacological treatment).
9. Known systemic illness which in the opinion of the investigator will prevent
from actively participating in the study.
10. Concomitant treatment for AMD in either eye (concomitant use of
vitamins/supplements is not excluded; does not apply to the late AMD group).
11. Any periocular or intravitreal injections (IVT) in either eye (does not
apply to the late AMD group).
12. Participation in any other interventional trial.
13. Obvious retinal changes due to causes other than AMD (e.g. evidenced by an
existing diagnosis of monogenetic macular dystrophies, Stargardt disease, cone
rod dystrophy, or toxic maculopathies).
14. Any history of allergies to fluorescein.Intermediate AMD
1. Any GA in the study eye
2. Any extrafoveal GA larger than 1.25 mm2 (as defined above) in the fellow eye.
3. All general exclusion criteria.Late AMD
1. All general exclusion criteria only.Early AMD
1. Intermediate or late AMD (following Beckman classification) in any eye.
2. All general exclusion criteria.No AMD
1. Early to late AMD (following Beckman classification) in any eye.
2. All general exclusion criteria.
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Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| ClinicalTrials.gov | NCT03349801 |
| CCMO | NL64026.091.17 |