Development of Novel Clinical Endpoints in Intermediate AMD (MACUSTAR)

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)

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

Study Overview

• Status: Active, not recruiting
• Conditions: Age Related Macular Degeneration (AMD)
• Intervention / Treatment: Other: No intervention

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).

• Study Type: Observational
• Enrollment (Actual): 718

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen, Denmark
    • Righospitalet Copenhagen
• France
  • Créteil, France
    • Centre Hospitalier Intercommunal de Créteil
  • Paris, France
    • Centre d'Investigation Clinique Centre National d'Ophtalmologie des Quinze-Vingts
• Germany
  • Bonn, Germany
    • University Hospital Bonn
  • Cologne, Germany
    • University Hospital Cologne
  • Freiburg, Germany
    • Department of Ophthalmology, University of Freiburg
  • Munich, Germany
    • University Eye Hospital Munich
  • Münster, Germany
    • St. Franziskus Hospital
  • Tübingen, Germany
    • Universtiy Hospital Tuebingen
  • Ulm, Germany
    • University Eye Hospital Ulm
• Italy
  • Milan, Italy
    • Ospedale San Raffaele
  • Milan, Italy
    • Luigi Sacco Hospital
  • Rom, Italy
    • G.B.Bietti Eye Foundation
• Netherlands
  • Leiden, Netherlands
    • Radboud University Medical Centre
  • Nijmegen, Netherlands
    • Radboud University Medical Centre
• Portugal
  • Coimbra, Portugal
    • Centre for Clinical Trials, AIBILI
  • Porto, Portugal
    • Centro Hospitalar de São João, E.P.E.
• United Kingdom
  • Belfast, United Kingdom
    • Queen's University Belfast
  • Gloucester, United Kingdom
    • Gloucestershire Hospitals NHS Foundation Trust
  • London, United Kingdom
    • Moorfields Eye Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 55 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• 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

Description

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.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
no AMD; No interventions	Other: No intervention; According to clinical practice.
early AMD; No interventions.	Other: No intervention; According to clinical practice.
intermediate AMD; No interventions.	Other: No intervention; According to clinical practice.
late AMD; No interventions.	Other: No intervention; According to clinical practice.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	3 years from baseline
Mean change from baseline in scotopic and mesopic microperimetry sensitivity		3 years from baseline
Mean change from baseline in low luminance visual acuity (LLVA)		3 years from baseline
Mean change from baseline in vanishing optotypes visual acuity (VA)		3 years from baseline
Mean change from baseline in low luminance deficit (LLD)	LLD = BCVA-LLVA	3 years from baseline
Mean change from baseline in absolute rod threshold of the dark adaptation test		3 years from baseline
Mean change from baseline in rod intercept time of the dark adaptation test		3 years from baseline
Proportion of subjects with progression in dark adaptation deficit beyond coefficient of repeatability structural		3 years from baseline
Mean change from baseline in the cube root of drusen volume by spectral-domain optical coherence tomography (SD-OCT)		3 years from baseline
Mean change from baseline in retinal thickness by spectral-domain optical coherence tomography (SD-OCT)		3 years from baseline
Focal pigmentary changes captured by colour fundus photography (CFP)		3 years from baseline
Presence of refractile deposits		3 years from baseline
Presence of intraretinal cystoid spaces		3 years from baseline
Presence of localized retinal pigment epithelium (RPE) hypertransmission		3 years from baseline
Presence of localized disruption of ellipsoid zone		3 years from baseline
Presence of localized subsidence of the outer plexiform layer and the inner nuclear layer		3 years from baseline
Presence of hyporeflective wedge-shaped bands		3 years from baseline
Presence of reticular drusen/subretinal drusenoid deposits and associated local changes as determined by multimodal imaging		3 years from baseline
Changes in localized fundus autofluorescence signal alterations		3 years from baseline
Proportion of subjects with reduction in drusen volume		3 years from baseline
Proportion of subjects with study eye that progressed to geogrphic atrophy (GA) and/or neovascular age-related macular degeneration (nAMD)		3 years from baseline
Proportion of subjects with conversions to late AMD detected with fluorescein angiography (FA) that could be detected with OCT-A (at equipped sites)		3 years from baseline
Presence of quiescent choroidal neovascularisation (CNV) as assessed by optical coherence tomography angiography (OCT-A) (at equipped sites)		3 years from baseline
OCT-A findings (at equipped sites)		3 years from baseline
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		3 years from baseline
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)		3 years from baseline
Mean change from baseline in patient-reported low luminance visual functioning, as measured by the VILL questionnaire, including the domains of safety		3 years from baseline
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		3 years from baseline
Change in utility index from baseline as measure by the patient-reported outcome measure (PROM) utility index		3 years from baseline
Mean change from baseline in patient-reported health status and utility using the EQ-5D-5L questionnaire (EuroQol Group)		3 years from baseline

Collaborators and Investigators

• Sponsor: Frank G. Holz
• Collaborators: Radboud University Medical Center; Bayer; Hoffmann-La Roche; Novartis Pharmaceuticals; University College, London; University of Sheffield; Moorfields Eye Hospital NHS Foundation Trust; Carl Zeiss Meditec AG; City, University of London; Innovative Medicines Initiative; Association for Innovation and Biomedical Research on Light and Image; European Clinical Research Infrastructure Network; La Fondation Voir et Entendre
• Investigators: Principal Investigator: Frank Holz, Prof. Dr. med., University Hospital, Bonn

Publications and helpful links

General Publications

• 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. 2022 Mar 30:bjophthalmol-2021-320848. doi: 10.1136/bjophthalmol-2021-320848. Online ahead of print.
• 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.
• 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.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): March 26, 2018
• Primary Completion (Anticipated): November 30, 2022
• Study Completion (Anticipated): November 30, 2022

Study Registration Dates

• First Submitted: November 10, 2017
• First Submitted That Met QC Criteria: November 19, 2017
• First Posted (Actual): November 22, 2017

Study Record Updates

• Last Update Posted (Actual): May 24, 2022
• Last Update Submitted That Met QC Criteria: May 23, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Keywords: biomarker; iAMD; clinical endpoint
• Additional Relevant MeSH Terms: Eye Diseases; Retinal Degeneration; Retinal Diseases; Macular Degeneration
• Other Study ID Numbers: ECR-AMD-2017-13; MACUSTAR (Other Grant/Funding Number: Innovative Medicines Innitiative)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No