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STRONG Report Summary

Project ID: 305321
Funded under: FP7-HEALTH
Country: Germany

Periodic Report Summary 3 - STRONG (European Consortium for the Study of a Topical Treatment of iCRVO to prevent Neovascular Glaucoma)

Project Context and Objectives:
Glaucoma is more than a single disease entity: it is a group of conditions characterized by progressive optic nerve degeneration (detectable by pathological cupping of the optic disc) and loss of visual function, ultimately resulting in total blindness. Secondary neovascular glaucoma (NVG), the major cause of which is ischaemic central retinal vein occlusion (iCRVO), is a very aggressive, rare form of glaucoma, responsible for 3.9% of glaucoma cases, but contributing disproportionately to blindness from all eye diseases. Also, NVG is the second most common cause for enucleations (removal of the eye ball) across all eye diseases, usually for intractable pain. Hypoxia associated with retinal vein occlusion is mostly (but not exclusively) responsible for the subsequent release of angiogenic factors. These also cause the growth of a fibrovascular membrane over the trabecular meshwork leading to an obstruction of the trabecular meshwork and/or associated peripheral anterior synechiae.
Today’s therapeutic approaches are insufficient and involve mainly lowering the elevated intraocular pressure, laser or cryo-therapy to destroy the affected retina, or off-label intravitreal injection of anti-Vascular Endothelial Growth Factor (VEGF) compounds, with unsolved issues in determining the correct timing, dosing and place of such interventions. There is, therefore, a need to widen the existing therapeutic options for NVG secondary to iCRVO. aganirsen is an antisense oligonucleotide which topical administration inhibits the production of VEGF, which plays a major role in the pathogenesis of NVG. The study is designed to test whether aganirsen is able to inhibit the formation of neovascularisation and fibrovascular membranes leading to the development of secondary NVG. This would be the first non-invasive treatment for this disease. At the same time, STRONG will provide important data on the natural course of iCRVO and NVG in a very large and well-investigated cohort. Substudies will evaluate known risk factors and biomarkers for the development and progression of iCRVO and NVG, and have a high potential to discover new ones. Finally, image analysis and biomorphometric methods will be developed and refined to better quantify and stage the disease.
The overarching goal of the phase II/III randomized, double- masked, 3 armed, placebo-controlled STRONG study is therefore:
- To assess whether at 24 weeks, topical aganirsen treatment can reduce the rate of anterior iris- and chamber-angle and posterior segment neovascularisation and NVG development after iCRVO, in a study with up to 333 patients in over 30 potential different sites
- To assess the natural course of iCRVO and NVG in the placebo-arm
- To evaluate known or suspected risk factors and biomarkers for iCRVO and NVG and to identify new ones for the development of NVG
- To improve the early diagnosis of NVG in iCRVO patients by image analysis and biomorphometric analysis
To achieve the above-mentioned goals the overall objectives for the trial are:
- To finalise the trial design (completed in month 18)
- To enlist sufficient trial centres (completed in month 18) to ensure recruitment of the statistically appropriate number of patients
- To manufacture sufficient trial supplies of aganirsen and its placebo in compliance with the Good Manufacturing Practices (GMP) (production ongoing)
- To provide central reading services to the STRONG trial for both established and novel methods for assessing neovascular glaucoma (reading services and procedures set up)
- To perform the STRONG trial, recruiting up to 333 patients while adhering to the highest GCP standards and protecting patient safety
- To analyse the collected trial data for NVG treatment, reducing if possible the trial sample size below 333 patients while meeting all requirements to file for conditional market authorisation
- To disseminate the test results to impacted communities in Europe and beyond.

Project Results:
At the beginning of the project, protocol assistance was sought from the EMA to ensure that the protocol is compliant with the European regulation with Orphan Drug Designation (ODD) of aganirsen for the treatment of NVG. The EMA Protocol Assistance was finished in 05/13. The trial protocol was adapted according to the EMA recommendations and was finalised in 03/14. The process of obtaining ODD from the Committee of Orphan Medicinal Products (COMP) was time consuming due to negative opinions on the prior applications. Therefore, the sponsor newly applied for the “Treatment of CRVO” (treatment of iCRVO to prevent NVG) which was submitted to the EMA in January 2014. The COMP published a Positive Opinion recommending aganirsen for ODD in the treatment of CRVO on 11 Apr 2014 (ref.: EMA/COMP/189040/2014).
On the basis of the finalized trial protocol, standard operating procedures (SOPs) for database development, data management, data validation for safety, pharmacovigilance, site monitoring, certification and technical SOPs were written by the partners. A feasibility questionnaire was sent to 56 experienced clinical sites in 8 countries during period 1. 56 answers were collected: 34 expressed interest in participating, 22 were not interested. 29 pre-study visits were performed in period 2 to finalise the list of participating sites. 28 sites were selected so far. In September 2015, 15 more clinical sites were provided with the feasibility questionnaire. Pre-study visits will follow for evaluation and selection. SOPs and all necessary study documents will be distributed to all clinical sites and are available on the project website The clinical sites will get SOP and GCP training at the initiation visit and the investigator meeting. The sites will be trained on EDC and reading centre certification as well. Before the trial can officially start, regulatory approval by the Ethics Committees and the Competent Authorities must be sought in all participating countries and trial sites. The Regulatory Committee submissions are ongoing in 5 out of 8 participating countries (Germany, France, Italy, Spain and Portugal) (status at the end of period 3). First ethic approvals are obtained in Germany and France; regulatory approval in Italy. The patient information and consent documentation for the main study and sub-studies were finalised in 03/14 and translated in the specific languages. The Investigator’s Brochure (IB) and Investigational Medical Product Dossier (IMPD) have to be updated after IMP manufacturing.
The design and programming of the trial-specific forms and Case Report Forms was performed. The Electronic Data Capture (EDC) system is developed and only needs final approval. Training material was prepared for on-line EDC training for all monitors, project managers and site representatives. The safety documentation will include procedures and communications relating to the notification of serious adverse events (SAE) and suspected unexpected serious adverse reactions (SUSAR) as well as all Data Safety and Monitoring Board (DSMB) decisions.
The manufacturing process of the study drug as emulsion was more complicated than expected and had to be improved. A manufacturer is now found which should enable the batch release in June 2018.
Potential Impact:
The STRONG study aims at assessing an innovative therapeutic approach for NVG secondary to iCRVO using aganirsen, an antisense oligonucleotide inhibiting insulin receptor substrate 1 (IRS-1), which has previously been shown to inhibit pathological angiogenesis and normalize the secretion of VEGF, both of which play a major role in the pathogenesis of NVG. If the trial is positive, the use of this topically active anti-angiogenic agent would lead to a non-invasive treatment for which conditional market authorization would be sought.
Today’s inadequate treatment options for iCRVO and NVG can leave the patient exposed to blindness, and in so much pain that enucleation (removal of the eyeball) is required. Blindness inflicts very significant individual suffering and leads to economic and social costs.

Therefore the potential results of the project contribute to several overarching objectives of EU policies:
- Improving the health of European citizens
- Increasing innovation and competitiveness of European health-related industries and services
- Concentrating on topics dedicated to small and medium enterprises (SMEs)
- Large pilot projects present excellent potential for innovation.

The STRONG study will also deliver new scientific insights into the natural course and risk factors of iCRVO and NVG. A list of potential markers that might discriminate between subjects with and without NVG will be created. This list will be identified based on biomarker analyses. The biomarker methodology should also allow for a novel classification of NVG secondary to iCRVO and evaluation of potential biomarkers able to differentiate between high- and low- drug responders.
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