Early Reperfusion Therapy With Intravenous Alteplase for Recovery of VISION in Acute Central Retinal Artery Occlusion (REVISION)

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.

Study Overview

• Status: Recruiting
• Conditions: Central Retinal Artery Occlusion
• Intervention / Treatment: Drug: Alteplase

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 422
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Sven Poli; Phone Number: 83349 +49-7071-29-0; Email: sven.poli@uni-tuebingen.de
• Study Contact Backup: Name: Julia Zeller; Phone Number: 68293 +49-7071-29-0; Email: julia.zeller@med.uni-tuebingen.de

Study Locations

• Germany
  • Tuebingen, Germany, 72076
    • Recruiting
    • University Hospital Tuebingen
    • Contact: Sven Poli, MD; Phone Number: 83349 +497071290; Email: sven.poli@uni-tuebingen.de
    • Contact: Julia Zeller; Phone Number: 68293 +497071290; Email: julia.zeller@med.uni-tuebingen.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Acute non-arteritic CRAO (i.e. sudden, painless monocular vision loss) ≤ 12 hours after symptom onset confirmed by an experienced ophthalmologist through assessment of: BCVA, intraocular pressure, swinging flash light test (relative afferent pupil defect), slit-lamp biomicroscopy, fundoscopy, and OCT of the macula of both eyes* (*within the 4.5-hour time window: to be skipped if not feasible ≤ 10 minutes; beyond the 4.5-hour time window: mandatory)
• BCVA of LogMAR ≥ 1.3 in the affected eye (functional blindness according to WHO ICD-11)
• Reading must have been possible with the affected eye before CRAO (LogMAR ≤ 0.5)
• Neurological examination performed by an experienced stroke neurologist
• Brain imaging as per local standard for acute retinal ischemia/stroke assessment, either cranial computed tomography (CT) or cranial magnetic resonance imaging (MRI)

Exclusion Criteria:

• Suspected giant cell arteritis
• Other-than-CRAO cause of acute visual loss (e.g., retinal detachment, vitreous hemorrhage, acute glaucoma, acute optic neuritis)
• BCVA of LogMAR < 1.3 or rapidly improving vision in the affected eye
• Acute ischemic stroke with indication for on-label intravenous thrombolysis (IVT)
• Any co-existing or terminal disease with anticipated life expectancy of < 3 months
• Prior participation in the REVISION trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Thrombolysis (interventional study); 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	Drug: Alteplase; Intravenous thrombolysis with alteplase within 4.5 hours of symptom onset
Placebo Comparator: Placebo (interventional study); Placebo (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	Drug: Alteplase; Intravenous thrombolysis with alteplase within 4.5 hours of symptom onset
No Intervention: Observational study; The prospective REVISION observational study will enroll patients within 12 hours of symptom onset

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Secondary Outcome Measures

Outcome Measure	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	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

Other Outcome Measures

Outcome Measure	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
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

Collaborators and Investigators

• Sponsor: University Hospital Tuebingen

Study record dates

Study Major Dates

• Study Start (Actual): October 10, 2022
• Primary Completion (Estimated): December 31, 2025
• Study Completion (Estimated): December 31, 2025

Study Registration Dates

• First Submitted: June 15, 2021
• First Submitted That Met QC Criteria: July 6, 2021
• First Posted (Actual): July 16, 2021

Study Record Updates

• Last Update Posted (Estimated): February 1, 2024
• Last Update Submitted That Met QC Criteria: January 31, 2024
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: Alteplase; Thrombolysis; Central Retinal Artery Occlusion
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Eye Diseases; Retinal Diseases; Arterial Occlusive Diseases; Retinal Artery Occlusion; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Tissue Plasminogen Activator
• Other Study ID Numbers: 2021-000183-29

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No