Periodic Reporting for period 5 - MACUSTAR (Develop and validate appropriate and acceptable outcome measures in intermediate age-related macular degeneration for future interventional clinical trials - Sofia ref.: 116076)
Reporting period: 2021-09-01 to 2022-08-31
Despite significant advances in the treatment and understanding of late stage age-related macular degeneration (AMD), it continues to be the main cause of irreversible severe visual loss in Europe and its prevalence and incidence will increase with current demographic trends of aging population.
In order to reduce the significant patient and societal burden of late stage AMD, novel interventions should aim at stopping or delaying progression from the preceding disease stage intermediate AMD (iAMD) to late stage AMD. As a prerequisite, validated clinical endpoints for iAMD are needed for development of new therapeutic interventions. The clinical endpoints should be acceptable to regulatory agencies, health technology assessment (HTA) bodies, and payers. Currently, such endpoints do not exist for iAMD clinical trials (CTs).
In addition, there is good evidence indicating that patients with iAMD experience some impairment of visual function yet it is unknown to what extent this impacts 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, to enable successful development of iAMD interventions validated functional, morphological and patient-reported endpoints for CTs, which are clinically meaningful and accepted by regulatory agencies, are required. In addition, functional decline in iAMD, as well as, specific risk factors for iAMD progression to late stage AMD need to be better characterized to inform and improve conduct of future iAMD CTs.
Against this background, the major objective of MACUSTAR is to develop novel clinical endpoints for CTs with a regulatory and patient access intention in patients with iAMD. Additional objectives are to characterize visual impairment in iAMD and its progression, as well as, identify risk factors for disease progression.
For clinical endpoint development, functional, structural and patient-reported outcome measures will be assessed with regards to their measurement characteristics as well as their association with progression from iAMD to late stage AMD.
In order to reduce the significant patient and societal burden of late stage AMD, novel interventions should aim at stopping or delaying progression from the preceding disease stage intermediate AMD (iAMD) to late stage AMD. As a prerequisite, validated clinical endpoints for iAMD are needed for development of new therapeutic interventions. The clinical endpoints should be acceptable to regulatory agencies, health technology assessment (HTA) bodies, and payers. Currently, such endpoints do not exist for iAMD clinical trials (CTs).
In addition, there is good evidence indicating that patients with iAMD experience some impairment of visual function yet it is unknown to what extent this impacts 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, to enable successful development of iAMD interventions validated functional, morphological and patient-reported endpoints for CTs, which are clinically meaningful and accepted by regulatory agencies, are required. In addition, functional decline in iAMD, as well as, specific risk factors for iAMD progression to late stage AMD need to be better characterized to inform and improve conduct of future iAMD CTs.
Against this background, the major objective of MACUSTAR is to develop novel clinical endpoints for CTs with a regulatory and patient access intention in patients with iAMD. Additional objectives are to characterize visual impairment in iAMD and its progression, as well as, identify risk factors for disease progression.
For clinical endpoint development, functional, structural and patient-reported outcome measures will be assessed with regards to their measurement characteristics as well as their association with progression from iAMD to late stage AMD.
In order to generate data required to support the qualification of outcome measures as endpoints a clinical study with two parts, a cross-sectional and a longitudinal part, was set up in seven European countries (Denmark, France, Germany, Italy, Portugal, The Netherlands, United Kingdom) at 20 participating clinical sites:
The cross-sectional part: The main objective is to assess the discriminatory properties of each outcome measure employed, i.e. their ability to discriminate between the different disease stages. It includes a repeat visit within a short time frame of two weeks to assess variability and test-retest reliability of all outcomes measures. 34 patients with early and 43 with late stage AMD, 56 age-matched controls with normal ocular health and 168 patients with iAMD were included.
The longitudinal part: The main objective is to assess the change in outcome measures in a large cohort of iAMD patients (719 total, including 168 iAMD and 34 early AMD patients from cross-sectional part) over a follow-up period of at least 4 years. At 6-monthly (iAMD) or annual (early AMD) visits changes in function, retinal structure and reported PROs will be assessed against progression to late stage AMD.
The following study activities have been performed in the last five project years:
• Development and finalisation of clinical study protocol, of all test paradigms for functional testing, and related SOPs.
• Regulatory authorities’ approvals obtained for all 20 participating clinical sites.
• Development of a certification process for technicians for functional tests and image data acquisition and Reading Center set-up for technician certification and study image evaluation and subsequent certification of staff at all clinical sites.
• Set-up and initiation of clinical study at all clinical sites including development of eCRF, provision of the required documents, study materials for functional testing and blood collection, technician certification and devices for dark adaptation, microperimetry and OCT examinations and site initiation visits.
• Screening and grading of study images of 948 study patients followed by inclusion of 719 study patients by the end of recruitment.
• Performance of 3008 follow up visits (297 V3, 513 V4, 468 V5, 432 V6, 420 V7, 403 V8, 333 V9, 128 V10, and 14 V11).
• Extensive data quality check of functional testing and imaging data performed.
• A patient retention plan was developed to ensure that the subjects included in the longitudinal part of the study completed the 4 years follow-up.
• Database cleaning, database lock and data transfer of the cross-sectional part of the study finished.
• Statistical analysis of cross-sectional study data was completed according to the statitstical analysis plan.
• Measures to mitigate COVID-19 effects on the study were successfully implemented.
A dialogue with regulators including the European Medicine Agency (EMA), the U.S. Food and Drug Administration and the National Institute for Health and Care Excellence UK has been initiated on functional, structural and patient-reported outcomes testing protocols and respective data generated to achieve regulatory acceptance at the end of the project. The feedback was incorporated in the clinical study protocol. A “letter of support" was published by EMA in February 2018. A further interaction with EMA has been initiated in 2021. EMA highly supported the further conduct of the MACUSTAR study and published a second letter of support (https://www.ema.europa.eu/en/documents/other/letter-support-intermediate-agerelated-macular-degeneration-amd-biomarker-novel-clinical-endpoint_en-0.pdf). To support the achievement of important goals outlined above broad dissemination and communication actions were performed enhancing the visibility of MACUSTAR: The project website is accessible at www.macustar.eu and information materials about the main objectives and eligibility criteria of the MACUSTAR study have been shared with potential patients and doctors in all participating countries. In addition, several lectures were given at ophthalmological conferences and project results, as well as, guidelines and SOPs published in different journals:
o doi: 10.1007/s00347-019-0907-1
o doi: 10.1159/000496497
o doi: 10.1159/000491402
o doi: 10.1159/000478073
o doi:10.1186/s13063-020-04595-6
o doi: 10.1186/s12874-021-01243-8
o doi: 10.1159/000515148
o doi: 10.1159/000513591
o doi: 10.1038/s41598-021-86193-3
o https://doi.org/10.1167/tvst.9.13.43
o https://doi.org/10.1167/tvst.10.14.19
o doi:10.1001/jamaophthalmol.2022.2113
o doi: 10.1136/bjophthalmol-2021-320848
o doi: 10.1167/tvst.11.3.27
The cross-sectional part: The main objective is to assess the discriminatory properties of each outcome measure employed, i.e. their ability to discriminate between the different disease stages. It includes a repeat visit within a short time frame of two weeks to assess variability and test-retest reliability of all outcomes measures. 34 patients with early and 43 with late stage AMD, 56 age-matched controls with normal ocular health and 168 patients with iAMD were included.
The longitudinal part: The main objective is to assess the change in outcome measures in a large cohort of iAMD patients (719 total, including 168 iAMD and 34 early AMD patients from cross-sectional part) over a follow-up period of at least 4 years. At 6-monthly (iAMD) or annual (early AMD) visits changes in function, retinal structure and reported PROs will be assessed against progression to late stage AMD.
The following study activities have been performed in the last five project years:
• Development and finalisation of clinical study protocol, of all test paradigms for functional testing, and related SOPs.
• Regulatory authorities’ approvals obtained for all 20 participating clinical sites.
• Development of a certification process for technicians for functional tests and image data acquisition and Reading Center set-up for technician certification and study image evaluation and subsequent certification of staff at all clinical sites.
• Set-up and initiation of clinical study at all clinical sites including development of eCRF, provision of the required documents, study materials for functional testing and blood collection, technician certification and devices for dark adaptation, microperimetry and OCT examinations and site initiation visits.
• Screening and grading of study images of 948 study patients followed by inclusion of 719 study patients by the end of recruitment.
• Performance of 3008 follow up visits (297 V3, 513 V4, 468 V5, 432 V6, 420 V7, 403 V8, 333 V9, 128 V10, and 14 V11).
• Extensive data quality check of functional testing and imaging data performed.
• A patient retention plan was developed to ensure that the subjects included in the longitudinal part of the study completed the 4 years follow-up.
• Database cleaning, database lock and data transfer of the cross-sectional part of the study finished.
• Statistical analysis of cross-sectional study data was completed according to the statitstical analysis plan.
• Measures to mitigate COVID-19 effects on the study were successfully implemented.
A dialogue with regulators including the European Medicine Agency (EMA), the U.S. Food and Drug Administration and the National Institute for Health and Care Excellence UK has been initiated on functional, structural and patient-reported outcomes testing protocols and respective data generated to achieve regulatory acceptance at the end of the project. The feedback was incorporated in the clinical study protocol. A “letter of support" was published by EMA in February 2018. A further interaction with EMA has been initiated in 2021. EMA highly supported the further conduct of the MACUSTAR study and published a second letter of support (https://www.ema.europa.eu/en/documents/other/letter-support-intermediate-agerelated-macular-degeneration-amd-biomarker-novel-clinical-endpoint_en-0.pdf). To support the achievement of important goals outlined above broad dissemination and communication actions were performed enhancing the visibility of MACUSTAR: The project website is accessible at www.macustar.eu and information materials about the main objectives and eligibility criteria of the MACUSTAR study have been shared with potential patients and doctors in all participating countries. In addition, several lectures were given at ophthalmological conferences and project results, as well as, guidelines and SOPs published in different journals:
o doi: 10.1007/s00347-019-0907-1
o doi: 10.1159/000496497
o doi: 10.1159/000491402
o doi: 10.1159/000478073
o doi:10.1186/s13063-020-04595-6
o doi: 10.1186/s12874-021-01243-8
o doi: 10.1159/000515148
o doi: 10.1159/000513591
o doi: 10.1038/s41598-021-86193-3
o https://doi.org/10.1167/tvst.9.13.43
o https://doi.org/10.1167/tvst.10.14.19
o doi:10.1001/jamaophthalmol.2022.2113
o doi: 10.1136/bjophthalmol-2021-320848
o doi: 10.1167/tvst.11.3.27
MACUSTAR encompasses Europe’s most relevant academic and industry expertise to validate novel clinical endpoints for iAMD CTs, and assess novel approaches to outcome assessment such as combined endpoints based on changes in structure and function. MACUSTAR results targets shortening of future CTs and enabling of drug development in iAMD. The identification of surrogate biomarkers of functional outcomes will help design shorter trials and reduce development timelines.