Periodic Reporting for period 6 - MACUSTAR (Develop and validate appropriate and acceptable outcome measures in intermediate age-related macular degeneration for future interventional clinical trials - Sofia ref.: 116076)
Okres sprawozdawczy: 2022-09-01 do 2024-05-31
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.
In order to reduce the significant patient and societal burden of late stage AMD, novel interventions should aim at stopping or delaying progression from 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).
Existing evidence indicates 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 quantified. It is also unknown whether there are specific risk factors in iAMD patients that are associated 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 are 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 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).
Existing evidence indicates 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 quantified. It is also unknown whether there are specific risk factors in iAMD patients that are associated 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 are assessed with regards to their measurement characteristics as well as their association with progression from iAMD to late stage AMD.
MACUSTAR clinical study was conceived as a cross-sectional and a longitudinal part. MACUSTAR was set up in seven European countries (Denmark, France, Germany, Italy, Portugal, Netherlands, United Kingdom).
The cross-sectional part: The main objective is to assess the discriminatory properties of each outcome measure, i.e. their ability to discriminate between the different disease stages. 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 goal 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.
The following study activities have been performed:
• Development of a clinical study protocol, of all test paradigms for functional testing, and related SOPs
• Regulatory authorities’ approvals obtained for all 20 participating clinical sites
• An elaborate Quality management system was developed, including the measurement-specific certification process for all technicians and study staff
• Extensive data quality checks of functional testing and imaging data
• Initiation of the clinical study: development of eCRF, legal documents, SOPs, technician certification, setup of the measurement devices for dark adaptation, microperimetry and OCT examinations, site initiation visits
• The study images of 948 patients were screened and graded, resulting in inclusion of 719 study patients by the end of recruitment
• Performance of 3555 follow up visits (291 V3, 520 V4, 474 V5, 440 V6, 430 V7, 413 V8, 425 V9, 315 V10, and 247 V11)
• 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 and of the 3-years longitudinal data of the study completed
• Statistical analysis of cross-sectional study data was completed according to the statistical analysis plan (SAP) for the cross-sectional study part
• Statistical analysis of the longitudinal study data is ongoing according the the SAP for the longitudinal study part
• Measures to mitigate COVID-19 effects on the study were successfully implemented
Advice was sought from the European Medicines Agency (EMA), U.S. FDA, and NICE to evaluate MACUSTAR protocols for regulatory acceptance at the project’s conclusion. Feedback was integrated into the clinical study protocol. The EMA issued a Letter of Support in February 2018 and a second letter in 2021, endorsing study continuation. In 2024, MACUSTAR requested the EMA´s advice on MACUSTAR 3-year longitudinal data. The third Letter of Support supported the relevance of structural and functional assessments in intermediate AMD, which could serve as enrichment criteria for future clinical trials. The EMA also endorsed use of the VILL questionnaire in future AMD studies: https://www.ema.europa.eu/en/documents/other/letter-support-intermediate-age-related-macular-degeneration-amd-biomarker-novel-clinical-endpoint-development_en.pdf(odnośnik otworzy się w nowym oknie)
To increase visibility, MACUSTAR conducted extensive communication efforts, including a project website (macustar.eu) social media (https://x.com/Macustar_EU(odnośnik otworzy się w nowym oknie)) bimonthly newsletters, and press releases. These efforts kept the public, patients, doctors, and study staff informed about the study’s objectives and eligibility criteria. MACUSTAR’s scientific findings have been presented at major ophthalmology conferences and published in high-impact scientific journals.
The cross-sectional part: The main objective is to assess the discriminatory properties of each outcome measure, i.e. their ability to discriminate between the different disease stages. 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 goal 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.
The following study activities have been performed:
• Development of a clinical study protocol, of all test paradigms for functional testing, and related SOPs
• Regulatory authorities’ approvals obtained for all 20 participating clinical sites
• An elaborate Quality management system was developed, including the measurement-specific certification process for all technicians and study staff
• Extensive data quality checks of functional testing and imaging data
• Initiation of the clinical study: development of eCRF, legal documents, SOPs, technician certification, setup of the measurement devices for dark adaptation, microperimetry and OCT examinations, site initiation visits
• The study images of 948 patients were screened and graded, resulting in inclusion of 719 study patients by the end of recruitment
• Performance of 3555 follow up visits (291 V3, 520 V4, 474 V5, 440 V6, 430 V7, 413 V8, 425 V9, 315 V10, and 247 V11)
• 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 and of the 3-years longitudinal data of the study completed
• Statistical analysis of cross-sectional study data was completed according to the statistical analysis plan (SAP) for the cross-sectional study part
• Statistical analysis of the longitudinal study data is ongoing according the the SAP for the longitudinal study part
• Measures to mitigate COVID-19 effects on the study were successfully implemented
Advice was sought from the European Medicines Agency (EMA), U.S. FDA, and NICE to evaluate MACUSTAR protocols for regulatory acceptance at the project’s conclusion. Feedback was integrated into the clinical study protocol. The EMA issued a Letter of Support in February 2018 and a second letter in 2021, endorsing study continuation. In 2024, MACUSTAR requested the EMA´s advice on MACUSTAR 3-year longitudinal data. The third Letter of Support supported the relevance of structural and functional assessments in intermediate AMD, which could serve as enrichment criteria for future clinical trials. The EMA also endorsed use of the VILL questionnaire in future AMD studies: https://www.ema.europa.eu/en/documents/other/letter-support-intermediate-age-related-macular-degeneration-amd-biomarker-novel-clinical-endpoint-development_en.pdf(odnośnik otworzy się w nowym oknie)
To increase visibility, MACUSTAR conducted extensive communication efforts, including a project website (macustar.eu) social media (https://x.com/Macustar_EU(odnośnik otworzy się w nowym oknie)) bimonthly newsletters, and press releases. These efforts kept the public, patients, doctors, and study staff informed about the study’s objectives and eligibility criteria. MACUSTAR’s scientific findings have been presented at major ophthalmology conferences and published in high-impact scientific journals.
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.
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.
In specific, the MACUSTAR study has achieved the following (among others):
• Development of a confirmatory AMD structure-function progression model guiding iAMD trial enrichment
• Algorithmic developments to detect innovative biomarkers
• Validation of a novel PROM (Vision impairment in low luminance questionnaire)
• Development of a preference-based measure and utility instrument based on the novel PROM
• Development of an iAMD subclassification
• Development of an AMD-specific performance based test
• Development of standard operating procedures for acquiring structural, functional and patient-reported data in iAMD
• Regulatory advice on newly developed enrichment factors and biomarkers
• Development of a clinical trial recruitment model
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.
In specific, the MACUSTAR study has achieved the following (among others):
• Development of a confirmatory AMD structure-function progression model guiding iAMD trial enrichment
• Algorithmic developments to detect innovative biomarkers
• Validation of a novel PROM (Vision impairment in low luminance questionnaire)
• Development of a preference-based measure and utility instrument based on the novel PROM
• Development of an iAMD subclassification
• Development of an AMD-specific performance based test
• Development of standard operating procedures for acquiring structural, functional and patient-reported data in iAMD
• Regulatory advice on newly developed enrichment factors and biomarkers
• Development of a clinical trial recruitment model