Clinical trial NCT03349801: Development of Novel Clinical Endpoints in Intermediate AMD
Official title: Development of Novel Clinical Endpoints for Interventional Clinical Trials With a Regulatory and Patient Access Intention in Patients With Intermediate Age-related Macular Degeneration (AMD)
Study type: OBSERVATIONAL
Overall status: ACTIVE_NOT_RECRUITING
Conditions: Age Related Macular Degeneration (AMD)
Keywords: iAMD
biomarker
clinical endpoint
Lead sponsor: University Hospital, Bonn
Sponsor class: OTHER
Collaborators: name: Bayer
name: Moorfields Eye Hospital NHS Foundation Trust
name: Novartis Pharmaceuticals
name: Association for Innovation and Biomedical Research on Light and Image
name: City, University of London
name: European Clinical Research Infrastructure Network
name: La Fondation Voir et Entendre
name: Hoffmann-La Roche
name: Radboud University Medical Center
name: University of Sheffield
name: University College, London
name: Carl Zeiss Meditec AG
name: Innovative Medicines Initiative
First posted: 2017-11-22
Enrollment: 718
Sex: ALL
Minimum age (years): 55
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: The study will include subjects with no AMD or normal aging changes and subjects with AMD classified in accordance with the international Beckman Classification.

A total of 750 subjects will be recruited:

* 300 subjects will participate in the Cross-sectional part:

  * 50 with normal aging changes, no AMD
  * 50 with early AMD,
  * 50 with late AMD
  * 150 with iAMD
* 650 subjects will participate in the longitudinal part:

  * 600 iAMD
  * 50 early AMD

Brief summary: Development of novel clinical endpoints for interventional clinical trials with a regulatory and patient access intention in patients with intermediate age-related macular degeneration (AMD) - MACUSTAR

Detailed description: The purpose of the MACUSTAR clinical study is to develop novel clinical endpoints for clinical trials with a regulatory and patient access intention in patients with intermediate age-related macular degeneration (iAMD). Additional objectives are to characterize the visual impairment in iAMD and its progression, as well as identify risk factors for progression to late stage AMD.

Moreover, MACUSTAR aims to optimize and standardize most relevant existing and/or rapidly available clinical endpoints in:

* visual functional outcomes measures
* structural outcomes measures
* patient reported outcomes measures (PROMs)

The study will be composed by two parts:

* a cross-sectional part to technically evaluate the functional and structural outcome measures to support a biomarker qualification by regulatory authorities and payers; and
* a longitudinal part to assess the prognostic power of changes in retinal sensitivity (as measured by microperimetry) for progression from iAMD to late AMD (nAMD and GA).

Eligibility criteria: 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.
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.
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.
2. All general inclusion criteria.

No AMD

1. No signs of early, intermediate or late AMD in both eyes.
2. All general inclusion criteria only.

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 (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 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.

Primary outcomes:
measure: Mean change from baseline in best corrected visual acuity (BCVA) using an early treatment diabetic retinopathy study (ETDRS) chart
timeFrame: 3 years from baseline
measure: Mean change from baseline in scotopic and mesopic microperimetry sensitivity
timeFrame: 3 years from baseline
measure: Mean change from baseline in low luminance visual acuity (LLVA)
timeFrame: 3 years from baseline
measure: Mean change from baseline in vanishing optotypes visual acuity (VA)
timeFrame: 3 years from baseline
measure: Mean change from baseline in low luminance deficit (LLD)
timeFrame: 3 years from baseline
measure: Mean change from baseline in absolute rod threshold of the dark adaptation test
timeFrame: 3 years from baseline
measure: Mean change from baseline in rod intercept time of the dark adaptation test
timeFrame: 3 years from baseline
measure: Proportion of subjects with progression in dark adaptation deficit beyond coefficient of repeatability structural
timeFrame: 3 years from baseline
measure: Mean change from baseline in the cube root of drusen volume by spectral-domain optical coherence tomography (SD-OCT)
timeFrame: 3 years from baseline
measure: Mean change from baseline in retinal thickness by spectral-domain optical coherence tomography (SD-OCT)
timeFrame: 3 years from baseline
measure: Focal pigmentary changes captured by colour fundus photography (CFP)
timeFrame: 3 years from baseline
measure: Presence of refractile deposits
timeFrame: 3 years from baseline
measure: Presence of intraretinal cystoid spaces
timeFrame: 3 years from baseline
measure: Presence of localized retinal pigment epithelium (RPE) hypertransmission
timeFrame: 3 years from baseline
measure: Presence of localized disruption of ellipsoid zone
timeFrame: 3 years from baseline
measure: Presence of localized subsidence of the outer plexiform layer and the inner nuclear layer
timeFrame: 3 years from baseline
measure: Presence of hyporeflective wedge-shaped bands
timeFrame: 3 years from baseline
measure: Presence of reticular drusen/subretinal drusenoid deposits and associated local changes as determined by multimodal imaging
timeFrame: 3 years from baseline
measure: Changes in localized fundus autofluorescence signal alterations
timeFrame: 3 years from baseline
measure: Proportion of subjects with reduction in drusen volume
timeFrame: 3 years from baseline
measure: Proportion of subjects with study eye that progressed to geogrphic atrophy (GA) and/or neovascular age-related macular degeneration (nAMD)
timeFrame: 3 years from baseline
measure: Proportion of subjects with conversions to late AMD detected with fluorescein angiography (FA) that could be detected with OCT-A (at equipped sites)
timeFrame: 3 years from baseline
measure: Presence of quiescent choroidal neovascularisation (CNV) as assessed by optical coherence tomography angiography (OCT-A) (at equipped sites)
timeFrame: 3 years from baseline
measure: OCT-A findings (at equipped sites)
timeFrame: 3 years from baseline
measure: Mean change from baseline in patient-reported low luminance visual functioning, as measured by the vision impairment in low luminance (VILL) questionnaire, including the domains of reading & accessing information
timeFrame: 3 years from baseline
measure: Mean change from baseline in patient-reported low luminance visual functioning, as measured by the VILL questionnaire, including the domains of Orientation & mobility (incl. driving)
timeFrame: 3 years from baseline
measure: Mean change from baseline in patient-reported low luminance visual functioning, as measured by the VILL questionnaire, including the domains of safety
timeFrame: 3 years from baseline
measure: Mean change from baseline in patient-reported low luminance visual functioning, as measured by the VILL questionnaire, including the domains of socio-emotional well-being
timeFrame: 3 years from baseline
measure: Change in utility index from baseline as measure by the patient-reported outcome measure (PROM) utility index
timeFrame: 3 years from baseline
measure: Mean change from baseline in patient-reported health status and utility using the EQ-5D-5L questionnaire (EuroQol Group)
timeFrame: 3 years from baseline
Secondary outcomes:
Other outcomes:
Locations:
city: Copenhagen
country: Denmark
facility: Righospitalet Copenhagen
city: Créteil
country: France
facility: Centre Hospitalier Intercommunal de Creteil
city: Paris
country: France
facility: Centre d'Investigation Clinique Centre National d'Ophtalmologie des Quinze-Vingts
city: Bonn
country: Germany
facility: University Hospital Bonn
city: Cologne
country: Germany
facility: University Hospital Cologne
city: Freiburg
country: Germany
facility: Department of Ophthalmology, University of Freiburg
city: Munich
country: Germany
facility: University Eye Hospital Munich
city: Münster
country: Germany
facility: St. Franziskus Hospital
city: Tübingen
country: Germany
facility: Universtiy Hospital Tuebingen
city: Ulm
country: Germany
facility: University Eye Hospital Ulm
city: Milan
country: Italy
facility: Luigi Sacco Hospital
city: Milan
country: Italy
facility: Ospedale San Raffaele
city: Rom
country: Italy
facility: G.B.Bietti Eye Foundation
city: Leiden
country: Netherlands
facility: Radboud University Medical Centre
city: Nijmegen
country: Netherlands
facility: Radboud University Medical Centre
city: Coimbra
country: Portugal
facility: Centre for Clinical Trials, AIBILI
city: Porto
country: Portugal
facility: Centro Hospitalar de São João, E.P.E.
city: Belfast
country: United Kingdom
facility: Queen's University Belfast
city: Gloucester
country: United Kingdom
facility: Gloucestershire Hospitals NHS Foundation Trust
city: London
country: United Kingdom
facility: Moorfields Eye Hospital
Study officials:
affiliation: University Hospital, Bonn
name: Frank Holz, Prof. Dr. med.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Terheyden JH, Pondorfer SG, Behning C, Berger M, Carlton J, Rowen D, Bouchet C, Poor S, Luhmann UFO, Leal S, Holz FG, Butt T, Brazier JE, Finger RP; MACUSTAR consortium. Disease-specific assessment of Vision Impairment in Low Luminance in age-related macular degeneration - a MACUSTAR study report. Br J Ophthalmol. 2023 Aug;107(8):1144-1150. doi: 10.1136/bjophthalmol-2021-320848. Epub 2022 Mar 30.
citation: Terheyden JH, Behning C, Luning A, Wintergerst L, Basile PG, Tavares D, Melicio BA, Leal S, Weissgerber G, Luhmann UFO, Crabb DP, Tufail A, Hoyng C, Berger M, Schmid M, Silva R, Martinho CV, Cunha-Vaz J, Holz FG, Finger RP; MACUSTAR consortium. Challenges, facilitators and barriers to screening study participants in early disease stages-experience from the MACUSTAR study. BMC Med Res Methodol. 2021 Mar 17;21(1):54. doi: 10.1186/s12874-021-01243-8.
citation: Terheyden JH, Holz FG, Schmitz-Valckenberg S, Luning A, Schmid M, Rubin GS, Dunbar H, Tufail A, Crabb DP, Binns A, Sanchez CI, Hoyng C, Margaron P, Zakaria N, Durbin M, Luhmann U, Zamiri P, Cunha-Vaz J, Martinho C, Leal S, Finger RP; MACUSTAR consortium. Clinical study protocol for a low-interventional study in intermediate age-related macular degeneration developing novel clinical endpoints for interventional clinical trials with a regulatory and patient access intention-MACUSTAR. Trials. 2020 Jul 18;21(1):659. doi: 10.1186/s13063-020-04595-6.