The key work packages for this project are the following
WP 1 Project Management and Governance
WP 2 Trial Operational Set-up
WP 3 Trial Training and Data Harmonization
WP 4 Pharmaceutical Development and Manufacturing at appropriate lot size
WP 5 Central Reading
WP 6 Trial Performance and Monitoring
WP 7 Trial Analysis and Statistics
WP 8 Communication, Dissemination and Exploitation
WP 1 Project Management and Governance– Lead: UMC-Mainz
The coordinator will perform the administrative, financial and resource management activities and support as an advisor to the consortium as a whole in discharging their reporting requirements. The coordinator takes on full responsibility for overall consortium project management and controlling, contractual management, communication management and resource management.
Regular meetings and teleconferences will be held to ensure cohesiveness of all research and other activities with attendance as appropriate to the stage of the project by Work Package Leaders.
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WP 2 Trial Operational Set-up – Lead: Katrin Lorenz, Project Manager from UMC-Mainz
The WP sets the overall framework for the organisation of the clinical trial and the appropriate distribution of tasks. It includes the coordination and management of the selection and certification of the clinical sites, trial SOP development, development of core trial documentation (protocol, core regulatory and ethics submission packages), data collection methodologies, set up of a monitoring scheme of the involved clinical trial centers, contracting and indemnity. It also sets up the following entities:
Data and Safety Monitoring Board (DSMB)
DSMB ensures the on-going safety monitoring of the patient population during the STRONG clinical trial. The DSMB is an external and independent group tasked with ensuring safety of clinical trial participants with pre-planned interim un-blinding of data as well as on-going review of all Serious Adverse Events.
Scientific Advisory Board (SAB)
The Scientific Advisory Board (SAB) serves as an independent advisory group to the consortium. Prof. Norbert Pfeiffer will chair the General Assembly and the Scientific Advisory Board (SAB) and take all actions to enable proper decision making by these bodies.
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WP3 Trial Training and Data Harmonisation- Lead: Katrin Lorenz, Project Manager from UMC-Mainz
This WP works with the trial centres to assure that key clinical end points are administered in a harmonized fashion at all the clinical trial sites throughout the trial conduct.
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WP4 – Pharmaceutical Development and manufacturing at appropriate lot size – Lead: Amel Hadri, from AMATSI Pharma – Contract Manufacturing Organization (CMO)
AMATSI, a pharmaceutical Contract Development and Manufacturing Organization (CDMO) is responsible, on assignment from Gene Signal, to complete the development of the galenic formulation for NVG and stability studies thereof, to manufacture the required Aganirsen and relative placebo in compliance with the standards of Good Manufacturing Practice (GMP) & Good Clinical Practice (CGP). AMATSI will launch the formulation development as soon as the consortium enters into negotiation with the EC for the Grant Agreement in order to get positive feed-back from IMPD at Month 1 of the project, and the first batch of drugs delivered at Month 6.
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WP5 – Central Reading – Lead Professor Claus Cursiefen, “CORIC” Cologne Ophthalmological Reading and Image Analysis Centre.
This WP is important both for determining end-points and for the development of new techniques for image analysis and biomorphometry to better diagnose and grade Neovascular Glaucoma. Development of neovascularisation at the optic disc (NVD) and elsewhere in the fundus (NVE) are part of the endpoint definition. This reading of a well-established end-point will be performed as a state-of-the-art reading by an experienced and well-known central reading center (Moorfields Eye Hospital Reading Centre (MEHRC), London (Lead Dr. Tunde Peto). This reading is mandatory to ensure high quality grading of fundus photography and end-point determination. The diagnosis of Neovascular Glaucoma is also made by assessing neovascularisation of the chamber-angle and iris. Unfortunately however, so far there is no method available to quantitatively assess those changes. Thus, in a sub study new techniques for standardized anterior segment photographs on the level of the iris and gonioscopically at the chamber angle will be developed. They may serve as a quantitative measurement within this study for future studies. Moreover, SOPs for all participating centres will be described, built on those already implemented by the EVICR.net as well as quality standards for image taking and the adherence will be checked regularly and new objective tools developed for standardized image analysis and morphometry of pathological chamber-angle and iris neovascularisation will be implemented. New standards for clinical grading of anterior chamber neovascularisation will be developed based on these findings.
The two reading centres have therefore separate and complementary capabilities.
CORIC is specialized in reading images of the anterior segment of the eye. Grading of the anterior segment includes not only evaluation of development of neovascularisations of the iris and the chamber angle but also development of a new semiautomatic method to quantify iris vessel dilation and degree of iris neovascularisation (imaging substudy). This expertise is based on the well-established semiautomatic analysis of corneal neovascularisations which has been developed in former trials with Aganirsen.
MEHRC has ample experience of reading OCT images, fundus photography and angiography for various retinal diseases such as central retinal vein occlusion, diabetic retinopathy, age-related macular degeneration and macular telangiectasia and is therefore the right reading center to evaluate the primary endpoint.
The sponsor, Gene Signal, is responsible for overall coherence and quality management of both reading centre activities. Gene Signal project management will coordinate the two reading centre activities, while the analysis of both data sets will be performed by the statisticians at TechnoSTAT. The scientific advisory board of the study will address any challenging and/special issues which may come up.
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WP6 – Trial Performance and Monitoring – Lead Antoine Ferry, MD, Gene Signal
This WP is to complete the clinical trial to the highest standards of quality on time and on budget: it delivers the final clinical study report of the clinical trial (Month 42). It includes coordination and implementation of the clinical trial, monitoring and on-going quality control, data management, periodic reports to regulatory authorities and interface with the trial governance and safety bodies on any issues arising during the trial conduct. This WP also includes the use of tools and techniques to assist patients with Aganirsen compliance (morning and evening application). If proven successful, the learnings developed for the STRONG trial may have positive implications for other Glaucoma patients, where compliance is a major challenge.
In addition, this WP will collect data on the natural course of CRVO and NVG within what will be one of the largest or even the largest cohort of patients world-wide. Biomarker-substudy: Patients will be analysed for known or suspected risk factor candidates such as thyroid hormones, growth hormone, IGF-1, prolactin, and parathormone. Furthermore, we aim to test the relevance of already suspected (e. g., Factor V-Leiden mutation, lipoprotein a, homocysteine) and novel thrombophilias (tissue factor, plasminogen-activator inhibitor) for the development of CRVO and/or NVG. It is expected that we will be able to identify hitherto unknown risk factors. Biobanking of blood samples will be performed for these and future analyses. The centre of excellence for the investigation and treatment of thrombosis and haemostasis, Mainz, will support evaluation.
Tear fluid has been shown to reflect in part the proteins and antibodies present in the eye. Thus, tear fluid will be sampled for laboratory analysis and risk factor determination and progression analysis of the effects of Aganirsen therapy on proteomic and antibody patterns and cytokines in the tear fluid of study participants.
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WP7 – Trial Analysis and Statistics – Lead – Yossi Tal, Ph.D. (TechnoStat)
This WP ensures trial design, data management, statistical methodology and that sample sizes are applicable to the trial end points. It interfaces with the DSMB, ensures oversight of data quality, conducts the interim and final data analysis and produces the statistical section of the clinical study report.
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WP8 Communication, Dissemination and Exploitation – UMC-Mainz
Dissemination activities and the relative publication plan targets key stakeholder communities. It will be undertaken to prepare for the conditional exploitation – results permitting. Medical publications and presentations/workshops and a dedicated web site will be organized to reach:
- The ophthalmic community and relevant research community
- Patient advocacy groups (existing or to be launched in view of preparing Phase III trials)
- Health public authorities
Gene Signal and Mainz will also collaborate to bring together a working group on NVG drawing expertise from members of the study scientific advisory board. The working group will condense learning on NVG and will include definitions of the unmet medical needs, the current approach to treatment and the design of future clinical studies. Gene Signal will lead dissemination of project results to public health authorities. This effort will also include an ongoing dialogue with the European Medicines Agency (EMA) and its scientific committees and working parties, including notably the Committees for Medicinal Products for Human Use (CHMP) and for Orphan Medicinal Products (COMP) as well as the Scientific Advice Working Party.
The coordinator will also participate in IRDirC meetings.
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