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Stopped after prespecified interim analysis due to futility
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Non-arteritic, thromboembolic central retinal artery occlusion (CRAO) is an acute neurovascular-ophthalmological emergency which leads to severe and permanent vision loss; no evidence-based therapy does exist. Two recent meta-analyses indicate early intravenous thrombolysis to be beneficial in CRAO. Therefore, the REVISION randomized placebo-controlled interventional trial will investigate intravenous alteplase in CRAO as it is practiced in acute ischemic stroke, i.e. within 4.5 hours after symptom onset.
The REVISION observational study will evaluate retinal changes on optical coherence tomography (OCT) in patients within 12 hours of CRAO onset, and the REVISION substudy, which will be conducted adjunct to either the interventional or the observational study, will evaluate the value of the retrobulbar spot sign for prediction of outcome and treatment response.
Non-arteritic, thromboembolic central retinal artery occlusion (CRAO) is an acute neurovascular-ophthalmological emergency which leads to severe and permanent vision loss in the affected eye in ~ 95% of cases. Despite a variety of widely practiced "conservative standard treatments", such as hemodilution, ocular massage, and paracentesis, there is no evidence-based therapy for non-arteritic CRAO. Animal models have proven a limited ischemic tolerance of the retina with irreversible damage occurring within only four hours after disruption of blood flow. This is why rapid reperfusion represents THE logical therapeutic approach. Two recent meta-analyses indicate early intravenous thrombolysis to be beneficial in CRAO. Therefore, the REVISION trial will investigate intravenous alteplase in CRAO as it is practiced in acute ischemic stroke, i.e. within 4.5 hours after symptom onset.
Sequential evaluation by optical coherence tomography (OCT) will visualize dynamic ischemic changes of the retina during and after CRAO. The REVISION observational study will enroll patients within 12 hours of symptom onset and aims at comparing late time window retinal findings to early ischemic changes found in patients of the randomized REVISION interventional trial. Ultimately, OCT may become the preferred tool when it comes to assess retinal tissue viability in patients with an unknown CRAO onset (e.g. wake-up CRAO), and CRAO patients who present in an extended time window beyond 4.5 hours.
The REVISION substudy, which will be conducted adjunct to either the interventional or the observational study, will evaluate the value of the retrobulbar spot sign for prediction of outcome and treatment response.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Thrombolysis (interventional study) | Active Comparator | Tenecteplase (0.25 mg per kg body weight as bolus; until trial protocol V04: Alteplase [0.9 mg per kg body weight; 10% as bolus; remaining over one hour] will be administered intravenously within 4.5 hours of symptom onset |
|
| Placebo (interventional study) | Placebo Comparator | Placebo (0.25 mg per kg body weight as bolus; until trial protocol V04: 0.9 mg per kg body weight; 10% as bolus; remaining over one hour) will be administered intravenously within 4.5 hours of symptom onset |
|
| Observational study | No Intervention | The prospective REVISION observational study will enroll patients within 12 hours of symptom onset |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Tenecteplase (until trial protocol V04: Alteplase) | Drug | Intravenous thrombolysis within 4.5 hours of symptom onset |
|
| Measure | Description | Time Frame |
|---|---|---|
| Functional recovery at visit 3 | Functional recovery to best corrected visual acuity of logarithm of the minimum angle of resolution ≤ 0.5 in the affected eye, which corresponds to normal to mild vision impairment (intention-to-treat analysis). | 30 days |
| Measure | Description | Time Frame |
|---|---|---|
| best corrected visual acuity (BCVA) at visits 2, 3, and 4 | Functional recovery to best corrected visual acuity of logarithm of the minimum angle of resolution ≤ 0.5 in the affected eye, which corresponds to normal to mild vision impairment (intention-to-treat and per-protocol analyses). | 90 days |
| Shift in visual outcome categories at visits 2, 3, and 4 |
| Measure | Description | Time Frame |
|---|---|---|
| Exploratory Outcomes of the REVISION Interventional Study | Optical coherence tomography/angiography (OCT/A) findings at screening, visit 2, 3, and 4 as prognostic biomarkers for prediction of time since CRAO onset, visual outcomes, and treatment response; to identify respective thresholds which are incompatible with a satisfactory IVT response and/or functional recovery | 90 days |
Inclusion Criteria:
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University Hospital Tuebingen | Tübingen | 72076 | Germany |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 38591748 | Background | Poli S, Grohmann C, Wenzel DA, Poli K, Tunnerhoff J, Nedelmann M, Fiehler J, Burghaus I, Lehmann M, Glauch M, Schadwinkel HM, Kalmbach P, Zeller J, Peters T, Eschenfelder C, Agostini H, Campbell BC, Fischer MD, Sykora M, Mac Grory B, Feltgen N, Kowarik M, Seiffge D, Strbian D, Albrecht M, Alzureiqi MS, Auffarth G, Bazner H, Behnke S, Berberich A, Bode F, Bohmann FO, Cheng B, Czihal M, Danyel LA, Dimopoulos S, Pinhal Ferreira de Pinho JD, Fries FN, Gamulescu MA, Gekeler F, Gomez-Exposito A, Gumbinger C, Guthoff R, Hattenbach LO, Kellert L, Khoramnia R, Kohnen T, Kurten D, Lackner B, Laible M, Lee JI, Leithner C, Liegl R, Lochner P, Mackert M, Mbroh J, Muller S, Nagel S, Prasuhn M, Purrucker J, Reich A, Mundiyanapurath S, Royl G, Salchow DJ, Schafer JH, Schlachetzki F, Schmack I, Thomalla G, Tieck Fernandez MP, Wakili P, Walter P, Wolf A, Wolf M, Bartz-Schmidt KU, Schultheiss M, Spitzer MS. Early REperfusion therapy with intravenous alteplase for recovery of VISION in acute central retinal artery occlusion (REVISION): Study protocol of a phase III trial. Int J Stroke. 2024 Aug;19(7):823-829. doi: 10.1177/17474930241248516. Epub 2024 Jun 25. | |
| 41805966 |
| Label | URL |
|---|---|
| Related Info | View source |
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Shift in visual outcome categories: normal vision (logarithm of the minimum angle of resolution (LogMAR) ≤ 0), mild vision impairment (LogMAR > 0 and ≤ 0.5), moderate vision impairment (LogMAR > 0.5 and ≤ 1.0), severe vision impairment (LogMAR > 1.0 and ≤ 1.3), counting fingers (LogMAR > 1.3 and ≤ counting fingers), hand motion or light perception, and no light perception. |
| 90 days |
| Dichotomized analysis of visual outcome at visits 2, 3, and 4 | Dichotomized analysis of visual outcome: 'normal vision to moderate vision impairment' vs. 'severe vision impairment or functional blindness' and 'normal vision to severe vision impairment' vs. 'functional blindness'. | 90 days |
| Visual field at visits 3 and 4 | Kinetic visual field using III4e mark | 90 days |
| Central retinal artery recanalization at visits 2, 3, and 4 | Central retinal artery recanalization assessed using optical coherence tomography angiography (OCTA) of the optic nerve head and the macula. | 90 days |
| Retinal arterial perfusion at visits 3 and 4 | Retinal arterial perfusion assessed using fluorescein angiography. | 90 days |
| National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) at visits 3 and 4 | NEI-VFQ-25 for assessment of relevant visual impairment | 90 days |
| National Institutes of Health Stroke Scale (NIHSS) score at visit 2 | NIHSS for assessment of neurological deficits due to ischemic stroke or intracranial hemorrhage | 72 hours |
| Modified Rankin Scale (mRS) score at visits 3 and 4 | Dichotomized analysis and shift analyses of mRS (categories 0 - 1 (excellent outcome) vs. 2 - 6, 0 - 2 (functional independence) vs. 3 - 6, 0 - 3 (walking) vs. 4 - 6, and 0 - 4 vs. 5 - 6 (bedridden or death), and shift analysis) | 90 days |
| Fresh ischemic lesions on cranial magnetic resonance imaging (MRI) at visit 2 | Fraction of patients with and number of acute ischemic lesions on follow-up diffusion-weighted cranial MRI | 72 hours |
| Death at visits 3 and 4 | All-cause and stroke-related death | 90 days |
| Any intracranial hemorrhage (ICH) at visit 2 | Any ICH (except microhemorrhages) on follow-up magnetic resonance imaging; in case of missing follow-up brain imaging due to premature death, ICH will be replaced by "ICH or death without repeat scan") | 72 hours |
| Symptomatic intracranial hemorrhage (ICH) until visit 2 | Symptomatic ICH (as per ECASS III and Heidelberg bleeding classification) until follow-up magnetic resonance imaging; in case of missing follow-up brain imaging due to premature death, symptomatic ICH will be replaced by "symptomatic ICH or death without repeat scan") | 72 hours |
| Intraocular hemorrhage in the affected eye at visit 2 | Intraocular hemorrhage in the affected eye | 72 hours |
| Major bleeding until visit 2 | Major bleeding, defined as clinically overt bleeding associated with at least one of the following features: decrease in hemoglobin levels of ≥ 2 g/dL over 24 hours, bleeding requiring transfusion of ≥ 2 units of packed red cells, bleeding at a critical site (i.e., intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, or retroperitoneal), or bleeding resulting in the death of the patient | 72 hours |
| Retinal neovascularization requiring therapy at visit 3 and 4 | Retinal neovascularization requiring therapy | 90 days |
| (Serious) adverse events ((S)AE) | AE until visit 2, serious AE and AE of special interest until visit 3 and 4 | 90 days |
| Exploratory Outcomes of the REVISION Observational Study | Optical coherence tomography/angiography (OCT/A) findings at screening as prognostic biomarker for prediction of time since CRAO onset and visual outcomes, and to compare extended time window results to those of interventional study participants. | 1 day |
| Exploratory Outcomes of the Retrobulbar Spot Sign Substudy | To investigate the retrobular spot sign on transorbital ultrasound at visits 2 and 3 as prognostic biomarker for prediction of treatment response and visual outcomes; to compare central retinal artery recanalization assessment with transorbital ultrasound with that using optical coherence tomography/angiography (OCT/A) of the optic nerve head and the macula, and fluorescein angiography | 30 days |
| Background |
| Mac Grory B, Preterre C, Lebranchu P, Ryan SJ, Jorstad OK, Moe MC, Tunnerhoff J, Spitzer MS, Grohmann C, Dumitrascu OM, Biousse V, Guillon B, Aamodt AH, Poli S, Schrag M; Central Retinal ArterY OcclusioN (CRAYON) Collaborators. Intravenous thrombolysis for acute central retinal artery occlusion: Protocol for a systematic review and individual participant data meta-analysis of randomized controlled trials. PLoS One. 2026 Mar 10;21(3):e0342739. doi: 10.1371/journal.pone.0342739. eCollection 2026. |
| ID | Term |
|---|---|
| D015356 | Retinal Artery Occlusion |
| ID | Term |
|---|---|
| D012164 | Retinal Diseases |
| D005128 | Eye Diseases |
| D001157 | Arterial Occlusive Diseases |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
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| ID | Term |
|---|---|
| D000077785 | Tenecteplase |
| ID | Term |
|---|---|
| D010959 | Tissue Plasminogen Activator |
| D012697 | Serine Endopeptidases |
| D010450 | Endopeptidases |
| D010447 | Peptide Hydrolases |
| D006867 | Hydrolases |
| D004798 | Enzymes |
| D045762 | Enzymes and Coenzymes |
| D057057 | Serine Proteases |
| D010960 | Plasminogen Activators |
| D001779 | Blood Coagulation Factors |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
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