Trial of Aganirsen in iCRVO Patients at Risk of Developing NVG

Study Overview
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Brief Summary
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A prospective, randomised, placebo-controlled, double-masked, three-armed multi-centre phase II/III trial for the Study of a Topical Treatment of Ischaemic Central Retinal Vein Occlusion to Prevent Neovascular Glaucoma - the STRONG Study

Detailed Description
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The STRONG Study is a phase II/III prospective, randomised, placebo-controlled, double-masked, three-armed multi-centre study of aganirsen antisense oligonucleotide, a topical treatment for iCRVO intended to prevent Neovascular Glaucoma (NVG). The study will evaluate the efficacy of two different doses of aganirsen formulated in an eye emulsion in avoiding new vessel formation by blocking the Insulin Receptor Substrate (IRS)-1. Eligible patients will be treated with aganirsen or placebo for a period of 24 weeks. They will also be invited to participate in sub-studies working on the analysis of gonioscopic images, detection of biomarkers for neovascular glaucoma and risk factors for ischaemic central retinal vein occlusion.

Official Title
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Prospective, Randomised, Placebo-controlled, Double-masked, Three-armed Multi-centre Trial of Aganirsen Versus Vehicle in Patients After Ischaemic Central Retinal Vein Occlusion With a High Risk to Develop Neovascular Glaucoma

Conditions
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Ischaemic Central Retinal Vein Occlusion, Neovascular Glaucoma

Intervention / Treatment
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* Drug: aganirsen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects meeting all of the following criteria will be considered for enrolment to the trial: Male or female ≥ 18 years IOP in the study eye ≤ 21mmHg Primary ischaemic CRVO or conversion to ischaemic CRVO in the study eye for no longer than 4 weeks Best-corrected visual acuity (BCVA) ETDRS letter score < 35 (< 20/200 Snellen equivalent) in the study eye ≥ 10-disc area of retinal capillary obliteration on fluorescein fundus angiography in the study eye (central fundus: macular area as defined by the optic disc and the arcades, an approximate 6000 micron circle around the fovea) and/or large, confluent retinal haemorrhages in the study eye Must be accompanied by 4 or more out of 6 following criteria: A relative afferent pupillary defect (with a normal fellow eye) ≥ 10 cotton-wool-spots in the study eye Venous tortuosity in the study eye Peripheral visual field defects corresponding to ischaemia (Goldmann perimeter or other semi-automatic kinetic methods) in the study eye Engorged vessels on iris and/or in the chamber angle in the study eye Detectable anterior chamber flare in the study eye Exclusion Criteria: Subjects presenting 1 or more of the following criteria will not be enrolled in the trial: Ocular conditions with a poorer prognosis in the fellow eye than in the study eye Primary or secondary glaucoma in the study eye Prior or concomitant ocular treatment with anti-VEGF in the study eye (ranibizumab/bevacizumab is not allowed within the last 45 days, aflibercept within the last 90 days) before screening visit Use of anti-VEGF treatment in the fellow eye during the trial Previous use of intraocular corticosteroids at any time or use of periocular corticosteroids in the study eye within 90 days prior to screening visit History of idiopathic or autoimmune uveitis in either eye Presence of NVD, NVE or anterior segment neovascularisation (NVA or NVI) in the study eye Previous PRP in the study eye Intraocular surgery (other than intravitreal anti-VEGF treatment) or laser treatment in the study eye within the past 90 days before screening visit Patients with a history of breast cancer

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: aganirsen low-dose:<br>43µg daily, one drop of 0.86 mg/g emulsion (morning) + one drop of placebo (evening) daily | Drug: aganirsen<br>* aganirsen antisense oligonucleotide against Insulin Receptor Substrate (IRS-1)<br>* Other names: GS-101;|
| Experimental: aganirsen high-dose<br>86µg daily, one drop of 0.86 mg/g emulsion twice daily (morning and evening) | Drug: aganirsen<br>* aganirsen antisense oligonucleotide against Insulin Receptor Substrate (IRS-1)<br>* Other names: GS-101;|
| Placebo Comparator: aganirsen placebo (vehicle)<br>one drop of placebo emulsion (morning) + one drop of placebo emulsion (evening) daily | Drug: aganirsen<br>* aganirsen antisense oligonucleotide against Insulin Receptor Substrate (IRS-1)<br>* Other names: GS-101;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| NVG component | Co-primary I: NVG component scored dichotomously (NVG=yes/NVG=no) where yes is development of NVI, NVA, NVD, and/or NVE, or rescue treatment; no otherwise | Week 24 | 
| IOP component | Co-primary II: IOP component scored dichotomously (failure/success); failure is rise in IOP from baseline to week 24 of ≥ 20% to > 21 or rescue treatment; success otherwise | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Secondary NVG | The time to development of secondary NVG in the study eye up to week 24 (in case aganirsen does not totally inhibit but slows down the development of NVG). | 24 weeks | 
| Anterior segment neovascularisation | The time to development of anterior segment neovascularisation (NVI or NVA), NVD or NVE in the study eye, requiring PRP or cryotherapy up to week 24. | 24 weeks | 
| NVG Classification | NVG Classification at 24 weeks on a scale from 1 (non-NVG) to 6 (most advanced NVG) based on central reading of neovascularisation | 24 weeks | 
| Visual Acuity | The change from baseline in BCVA (EDTRS letter score) in the study eye to week 24. | 24 weeks | 
| Number of additional needed laser treatments and re-treatments in the study eye at up to week 24 | Number of additional needed laser treatments and re-treatments in the study eye at up to week 24 | 24 weeks | 
| Required intensity of laser spots of additional laser treatments and re-treatments in the study eye at up to week 24 | Required intensity of laser spots of additional laser treatments and re-treatments in the study eye at up to week 24 | 24 weeks | 
| Retinal non-perfusion area | The change from baseline in size of retinal non-perfusion areas in the study eye to week 24 | 24 weeks | 
| Retinal Thickness | Absolute change from baseline in retinal thickness in the study eye, assessed by spectral domain optical coherence tomography (SD-OCT) at week 24 | 24 weeks | 
| Quality of Life | The change from baseline in the NEI-VFQ-25 health questionnaire total score to week 24 | 24 weeks | 
| Quality of Life on EQ-5D | The change from baseline in the EQ-5D health questionnaire score to week 24 | 24 weeks | 
| Safety: Incidence of treatment-emergent Adverse Events | Incidence, causality and intensity of adverse events between the treatment arms | 24 weeks |