Review

. 2025 Apr;39(6):1031-1039.

doi: 10.1038/s41433-024-03568-2. Epub 2025 Feb 5.

Validating candidate endpoints for intermediate age-related macular degeneration trials in a multi-centre setting-lessons from the MACUSTAR study

Jan Henrik Terheyden¹, Hannah M P Dunbar^{2

3}, Steffen Schmitz-Valckenberg^{1

4

5}, Charlotte Behning⁶, Cecília Martinho⁷, Ulrich F O Luhmann⁸, Marlene Saßmannshausen¹, Anna Lüning¹, Alexandra Miliu¹, Inês Dinis Aires⁷, Pier Giorgio Basile⁷, Joana Batuca⁹, Matthias Schmid⁶, Klaus-Peter Moll¹⁰, Nadia Zakaria¹⁰, Adnan Tufail^{2

3}, Alison Binns¹¹, David P Crabb¹¹, Sergio Leal¹², Robert P Finger^{1

13}, Frank G Holz^{14

15}; MACUSTAR consortium

Collaborators, Affiliations

Collaborators

MACUSTAR consortium:
H Agostini, I D Aires, L Altay, R Atia, F Bandello, P G Basile, J Batuca, C Behning, M Belmouhand, M Berger, A Binns, C J F Boon, M Böttger, J E Brazier, C Carapezzi, J Carlton, A Carneiro, A Charil, R Coimbra, D Cosette, M Cozzi, D P Crabb, J Cunha-Vaz, C Dahlke, H Dunbar, R P Finger, E Fletcher, M Gutfleisch, F Hartgers, B Higgins, J Hildebrandt, E Höck, R Hogg, F G Holz, C B Hoyng, A Kilani, J Krätzschmar, L Kühlewein, M Larsen, S Leal, Y T E Lechanteur, D Lu, U F O Luhmann, A Lüning, N Manivannan, I Marques, C Martinho, A Miliu, K P Moll, Z Mulyukov, M Paques, B Parodi, M Parravano, S Penas, T Peters, T Peto, S Priglinger, R Ramamirtham, R Ribeiro, D Rowen, G S Rubin, J Sahel, C Sánchez, O Sander, M Saßmannshausen, M Schmid, S Schmitz-Valckenberg, J Siedlecki, R Silva, E Souied, G Staurenghi, J Tavares, D J Taylor, J H Terheyden, A Tufail, P Valmaggia, M Varano, A Wolf, N Zakaria

Affiliations

¹ Department of Ophthalmology, University Hospital Bonn, Bonn, Germany.
² UCL Institute of Ophthalmology, University College London, London, United Kingdom.
³ Moorfields Eye Hospital NHS Foundation Trust, London, UK.
⁴ GRADE Reading Center, Bonn, Germany.
⁵ John A. Moran Eye Center, Department of Ophthalmology and Visual Sciences, University of Utah, Salt Lake City, UT, USA.
⁶ Institute for Medical Biometry, Informatics and Epidemiology, Medical Faculty, University of Bonn, Bonn, Germany.
⁷ Association for Innovation and Biomedical Research on Light and Image, Coimbra, Portugal.
⁸ Roche Pharmaceutical Research and Early Development, Translational Medicine Ophthalmology, Roche Innovation Center Basel, Basel, Switzerland.
⁹ European Clinical Research Infrastructure Network, Paris, France.
¹⁰ Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
¹¹ Division of Optometry and Visual Science, School of Health Sciences, City, University of London, London, UK.
¹² Bayer Consumer Care AG, Basel, Switzerland.
¹³ Department of Ophthalmology, University Hospital Mannheim & Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
¹⁴ Department of Ophthalmology, University Hospital Bonn, Bonn, Germany. frank.holz@ukbonn.de.
¹⁵ GRADE Reading Center, Bonn, Germany. frank.holz@ukbonn.de.

PMID: 39910281
PMCID: PMC11978948
DOI: 10.1038/s41433-024-03568-2

Review

Validating candidate endpoints for intermediate age-related macular degeneration trials in a multi-centre setting-lessons from the MACUSTAR study

Jan Henrik Terheyden et al. Eye (Lond). 2025 Apr.

. 2025 Apr;39(6):1031-1039.

doi: 10.1038/s41433-024-03568-2. Epub 2025 Feb 5.

Authors

Collaborators

MACUSTAR consortium:
H Agostini, I D Aires, L Altay, R Atia, F Bandello, P G Basile, J Batuca, C Behning, M Belmouhand, M Berger, A Binns, C J F Boon, M Böttger, J E Brazier, C Carapezzi, J Carlton, A Carneiro, A Charil, R Coimbra, D Cosette, M Cozzi, D P Crabb, J Cunha-Vaz, C Dahlke, H Dunbar, R P Finger, E Fletcher, M Gutfleisch, F Hartgers, B Higgins, J Hildebrandt, E Höck, R Hogg, F G Holz, C B Hoyng, A Kilani, J Krätzschmar, L Kühlewein, M Larsen, S Leal, Y T E Lechanteur, D Lu, U F O Luhmann, A Lüning, N Manivannan, I Marques, C Martinho, A Miliu, K P Moll, Z Mulyukov, M Paques, B Parodi, M Parravano, S Penas, T Peters, T Peto, S Priglinger, R Ramamirtham, R Ribeiro, D Rowen, G S Rubin, J Sahel, C Sánchez, O Sander, M Saßmannshausen, M Schmid, S Schmitz-Valckenberg, J Siedlecki, R Silva, E Souied, G Staurenghi, J Tavares, D J Taylor, J H Terheyden, A Tufail, P Valmaggia, M Varano, A Wolf, N Zakaria

Affiliations

¹ Department of Ophthalmology, University Hospital Bonn, Bonn, Germany.
² UCL Institute of Ophthalmology, University College London, London, United Kingdom.
³ Moorfields Eye Hospital NHS Foundation Trust, London, UK.
⁴ GRADE Reading Center, Bonn, Germany.
⁵ John A. Moran Eye Center, Department of Ophthalmology and Visual Sciences, University of Utah, Salt Lake City, UT, USA.
⁶ Institute for Medical Biometry, Informatics and Epidemiology, Medical Faculty, University of Bonn, Bonn, Germany.
⁷ Association for Innovation and Biomedical Research on Light and Image, Coimbra, Portugal.
⁸ Roche Pharmaceutical Research and Early Development, Translational Medicine Ophthalmology, Roche Innovation Center Basel, Basel, Switzerland.
⁹ European Clinical Research Infrastructure Network, Paris, France.
¹⁰ Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
¹¹ Division of Optometry and Visual Science, School of Health Sciences, City, University of London, London, UK.
¹² Bayer Consumer Care AG, Basel, Switzerland.
¹³ Department of Ophthalmology, University Hospital Mannheim & Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
¹⁴ Department of Ophthalmology, University Hospital Bonn, Bonn, Germany. frank.holz@ukbonn.de.
¹⁵ GRADE Reading Center, Bonn, Germany. frank.holz@ukbonn.de.

PMID: 39910281
PMCID: PMC11978948
DOI: 10.1038/s41433-024-03568-2

Abstract

For the conduct of future interventional age-related macular degeneration (AMD) trials, the availability of clinical study endpoints is key. However, no endpoints have been accepted by regulators for evaluation of treatment for intermediate (i) AMD, i.e. the AMD stage at highest risk of developing irreversible geographic atrophy or macular neovascularization. The European MACUSTAR consortium has recruited more than 700 individuals to develop and validate structural, functional and patient-reported endpoints, enabling future iAMD trials based on a prospective observational, multi-centre cohort study. Reliably assessing candidate endpoints in a setting that involves multiple clinical sites across countries comes with a plurality of challenges in the study set-up, quality of data, recruitment of participants and study conduct. Therefore, the MACUSTAR consortium has established a framework that successfully addresses these topics, provides relevant insights into the natural history of iAMD and its sub-phenotypes, and will open new regulatory pathways. The MACUSTAR study is registered on ClinicalTrials.gov under NCT03349801.

PubMed Disclaimer

Conflict of interest statement

Competing interests: Jan Henrik Terheyden: Heidelberg Engineering, Optos, Zeiss, CenterVue (now iCare), Novartis, Okko. Hannah M. P. Dunbar: Boehringer Ingelheim. Steffen Schmitz-Valckenberg: AlphaRET, Apellis, Bayer, Carl Zeiss Meditec, eyeDNA, Formycon, Galimedix, Heidelberg Engineering, Katairo, Kubota Vision, Novartis, Perceivve Therapeutics, Pixium, Roche, Sparing Vision. Charlotte Behning: None. Cecília Martinho: None. Ulrich F.O. Luhmann: Employee of and financial interest in F. Hoffmann-La Roche Ltd. Marlene Saßmannshausen: Heidelberg Engineering, Optos, Zeiss. Anna Lüning: None. Alexandra Miliu: None. Inês Aires: None. Pier Basile: None. Joana Batuca: None. Matthias Schmid: Pixum Vision. Klaus-Peter Moll: Employee of Novartis. Nadia Zakaria: Employee of Novartis. Adnan Tufail: Allergan, Bayer, Kanghong, Heidelberg Engineering, Novartis, Roche/Genentech, Iveric Bio, Apellis, Theá. Alison Binns: Apparatus and method for retinal measurement; Patent number 9492081; Boehringer-Ingelheim. David P. Crabb: Apellis, Santen, Allergan/Abbvie, Janssen; Thea. Sergio Leal: Employee of Bayer Pharma AG. Robert P. Finger: Alimera, Apellis, Bayer, Boehringer-Ingelheim, Novartis, ODOS, Oxford Innovation, ProGenerika, Roche/Genentech, Biogen, Icare, Heidelberg Engineering, Carl Zeiss Meditec. Frank G. Holz: Allergan, Annexon, Alzheon, Apellis, Astellas, Bayer, Boehringer-Ingelheim, Bioeq/Formycon, CenterVue (now iCare), Roche/Genentech, 4D Molecular Therapeuticcs, Geuder, Grayburg, Heidelberg Engineering, IvericBio/Astellas, Janssen, LinBiosciences, NightStarX, Novartis, Optos, Oxurion, Pixium Vision, Stealth BioTherapeutics, Carl Zeiss Meditec, Grade Reading Center.

Figures

**Fig. 1. Organizational flow chart. Early established data pathways and quality control mechanisms are enablers of the results generated by the MACUSTAR study.**
CRF case report form, CRO, clinical research organization (Association for Innovation and Biomedical Research on Light and Image), GCP good clinical practice, PM project management.

**Fig. 2. Inter-visit differences in visual function and patient-reported outcomes.**
Differences between baseline and validation visits across MACUSTAR study sites of exemplary visual function (A–C) and patient-reported outcome assessments (D) across MACUSTAR study sites in individuals with intermediate age-related macular degeneration that participated in the cross-sectional part. Two out of 20 sites did not contribute to the recruitment for the cross-sectional part and are not listed here; specific examination data (e.g. microperimetry, dark adaptometry) of individual sites had to be additionally excluded due to the availability and quality of data. BCVA best-corrected visual acuity, mesAT mesopic average threshold on microperimetry, PR-CS Pelli-Robson contrast sensitivity, VILL Vision Impairment in Low Luminance questionnaire.

**Fig. 3. Baseline prevalence of selected structural biomarkers.**
The prevalence of reticular pseudodrusen (A), pigmentary abnormalities (B), hyperreflective foci (C) and incomplete or complete retinal pigment epithelium and outer retinal atrophy (D) noticeably varied ross MACUSTAR study sites in all participants with intermediate age-related macular degeneration.

See this image and copyright information in PMC

References

1. Wong WL, Su X, Li X, Cheung CMG, Klein R, Cheng C-Y, et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob Health. 2014;2:e106–16. - PubMed
1. Wu Z, Ayton LN, Luu CD, Guymer RH. Longitudinal changes in microperimetry and low luminance visual acuity in age-related macular degeneration. JAMA Ophthalmol. 2015;133:442–8. - PubMed
1. Sassmannshausen M, Pfau M, Thiele S, Fimmers R, Steinberg JS, Fleckenstein M, et al. Longitudinal analysis of structural and functional changes in presence of reticular pseudodrusen associated with age-related macular degeneration. Investig Ophthalmol Vis Sci. 2020;61:19. - PMC - PubMed
1. Heier JS, Lad EM, Holz FG, Rosenfeld PJ, Guymer RH, Boyer D, et al. Pegcetacoplan for the treatment of geographic atrophy secondary to age-related macular degeneration (OAKS and DERBY): two multicentre, randomised, double-masked, sham-controlled, phase 3 trials. Lancet. 2023;402:1434–48. - PubMed
1. Khanani AM, Patel SS, Staurenghi G, Tadayoni R, Danzig CJ, Eichenbaum DA, et al. Efficacy and safety of avacincaptad pegol in patients with geographic atrophy (GATHER2): 12-month results from a randomised, double-masked, phase 3 trial. Lancet. 2023;402:1449–58. - PubMed

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions

Associated data

Actions
- Search in PubMed
- Search in ClinicalTrials.gov

Grants and funding

116076/Innovative Medicines Initiative (IMI)

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Validating candidate endpoints for intermediate age-related macular degeneration trials in a multi-centre setting-lessons from the MACUSTAR study

Collaborators

Affiliations

Validating candidate endpoints for intermediate age-related macular degeneration trials in a multi-centre setting-lessons from the MACUSTAR study

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Associated data

Grants and funding

LinkOut - more resources

Full Text Sources

Medical