TENecteplase in Central Retinal Artery Occlusion Stuy (TenCRAOS)

Study Overview
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Brief Summary
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TENecteplase in Central Retinal Artery Occlusion (TenCRAOS): A Prospective, randomized-controlled, double-dummy, double-blind phase 3 multi-centre trial of TNK 0.25 mg/kg + placebo vs. ASA + placebo (2 arms with 1:1 block randomization). A Prospective, randomized-controlled, double-dummy, double-blind phase 3 multi-centre trial of TNK 0.25 mg/kg + placebo vs. ASA + placebo (2 arms with 1:1 block randomization). At all participating centers, ophthalmologists are involved in the diagnosis and visual outcome measurements using a standardized protocol. The patients will be promptly examined by the ophthalmologist. As soon as the CRAO is diagnosed by the ophthalmologist, the patients will be managed in the stroke unit during treatment, monitoring, and medical investigations. After treatment in the stroke unit, the patients will be re-examined by an ophthalmologist and a neurologist as an out-patient at (30 ±5) and 90 (±15) days

Detailed Description
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Central retinal artery occlusion (CRAO) is an ophthalmologic emergency that, without prompt revascularization, bears high risk of permanent blindness. The condition is typically the result of an artery-to-artery embolism from a carotid plaque or cardio embolism. A recent meta-analysis of observational data indicates that prompt revascularization with systemic thrombolysis might improve outcome. A randomized controlled trial of early systemic thrombolysis for CRAO is therefore warranted. The aim of this project is to assess the effect of systemic tissue plasminogen activator tenecteplase versus placebo administered within 4.5 hours of CRAO onset in patients admitted to the participating hospitals in Europe. The main endpoint is the proportion of patients with ≤ 0.7 logMAR visual acuity 30 (±5) days after treatment, representing an improvement in visual acuity of at least 0.3 logMAR, equal to at least 15 letters/three lines on a visual acuity chart. In addition, we will access differences in visual field parameters and patient reported outcome measures between the groups. This study is based on a broad collaboration and interaction between leading ophthalmologists and neurologists in European centres.

Official Title
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TENecteplase in Central Retinal Artery Occlusion Study (TenCRAOS): A Randomized Placebo-controlled Trial of Early Systemic Tenecteplase Treatment in Patients With Central Retinal Artery Occlusion.

Conditions
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Central Retinal Artery Occlusion

Intervention / Treatment
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* Drug: Intravenous injection of Tenecteplase and one dose of placebo tablet
* Drug: One tablet of Acetylsalicylic Acid and one dose of IV placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Non-arteritic central retinal artery occlusion with ≥ 1.0 logMAR visual acuitiy and symptoms lasting less than 4.5 hours. Ability to administer the Investigator Medicinal Product (IMP) within 4.5 hours of symptom onset. Age ≥18 years. Informed written consent of the patient. A woman of childbearing potential (WOCBP) must confirm that in her opinion, she cannot be pregnant, OR if there is a possibility that she is pregnant, a negative pregnancy test must be confirmed before any IMP is given. Exclusion Criteria: No other active intervention targeting CRAO. Branch retinal artery occlusion, cilioretinal artery supplying the macula, combined arterial-venous occlusion, proliferative diabetic retinopathy, elevated intraocular pressure (> 30 mmHg) or clinical suspicion of ophthalmic artery occlusion occlusion (e.g. choroidal nonperfusion, absence of cherry red spot, no light perception). Systemic diseases; severe general diseases, systemic arterial hypertension (blood pressure >185/110 mmHg), despite medical therapy, or clinical suspicion of acute systemic inflammation. Presence of intracranial haemorrhage on brain MRI/CT. Medical history: heart attack within the last 6 weeks, intracerebral bleeding or neurosurgical operation within the last 4 weeks, therapy with anticoagulation, allergic reaction to contrast agent, hemorrhagic diathesis, aneurysms, inflammatory vascular diseases (eg, giant cell arteritis, granulomatosis with polyangitis), endocarditis, or gastric ulcer. No willingness and ability of the patient to participate in all follow-up examinations. Pregnancy (if suspicion of pregnancy s-hCG or u-hCG must be negative). Allergy or intolerance to any ingredients of IMP or placebo or gentamicin. Other conditions / circumstances likely to lead to poor treatment adherence (eg, history of poor compliance, alcohol or drug dependency, no fixed abode). Significant bleeding disorder either at present or within the past 6 months. Effective oral anticoagulant treatment, eg, warfarin sodium (INR >1.3). Effective anticoagulant treatment with heparin or low molecular weight heparin the last 48 hours. Any history of central nervous system damage (ie, neoplasm, aneurysm, intracranial or spinal surgery). Known hemorrhagic diathesis. Major surgery, biopsy of a parenchymal organ, or significant trauma within the past 2 months (this includes any trauma associated with acute myocardial infarction). Recent non-compressible vessel puncture within 2 weeks. Recent trauma to the head or cranium. Prolonged cardiopulmonary resuscitation (>2 minutes) within the past 2 weeks. Acute pericarditis and/or subacute bacterial endocarditis. Acute pancreatitis. Severe hepatic dysfunction, including hepatic failure, cirrhosis, portal hypertension (oesophageal varices) and active hepatitis. Active peptic ulceration. Arterial aneurysm and known arterial/venous malformation. Neoplasm with increased bleeding risk. Any known history of hemorrhagic stroke or stroke of unknown origin. Known history of ischemic stroke or transient ischemic attack in the preceding 3 months. Dementia.

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
Interventional Model Description: A prospective, randomized-controlled, double-dummy, double-blind phase 3 multi-centre trial of TNK 0.25 mg/kg + placebo vs. ASA + placebo (2 arms with 1:1 block randomisation). At all participating centers, ophthalmologists are involved in the diagnosis and visual outcome measurements using a standardized protocol. The patients will be promptly examined by the ophthalmologist. As soon as the CRAO is diagnosed by the ophthalmologist, the patients will be managed in the stroke unit during treatment, monitoring, and medical investigations. After treatment in the stroke unit, the patients will be re-examined by an ophthalmologist and a neurologist as an out-patient at (30 ±5) and 90 (±15) days.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Tenecteplase<br>The total dose of tenecteplase is 0.25 mg/kg body weight, maximum 25 mg. The total dose will be given as an intravenous bolus | Drug: Intravenous injection of Tenecteplase and one dose of placebo tablet<br>* Drug: Tenecteplase Tenecteplase administered as an intravenous injection (0.25 mg/kg body weigh; maximum 25 mg)<br>* Other names: Metalyse;|
| Active Comparator: acetylsalicylic acid<br>one tablet of aspirin 300 mg Other Name: Aspirin | Drug: One tablet of Acetylsalicylic Acid and one dose of IV placebo<br>* 300 mg Acetylsalisylic acid<br>* Other names: Aspirin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with ≤ 0.7 logMAR visual acuity in the affected eye at 30 (±5) days after treatment, representing an improvement in visual acuity of at least 0.3 logMAR (intention-to-treat (ITT) analysis). | logMAR | 30 (±5) days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with ≤ 0.5 logMAR visual acuity in the affected eye at 30 (±5) and 90 (±15) days. | logMAR | 30 (±5) and 90 (±15) days | 
| Mean improvement in logMAR visual acuity in the affected eye from baseline to 30 (±5) and 90 (±15) days. | logMAR | 30 (±5) and 90 (±15) days | 
| Proportion of patients with visual recovery (logMAR ≤ 0.7) and (logMAR ≤ 0.5) in the affected eye 30 (±5) and 90 (±15) days in patients who were treated with tenecteplase within 3 hours of onset | logMAR | 30 (±5) and 90 (±15) days | 
| Number of test points seen (of 100) on monocular Esterman perimetry at 30 (±5) and 90 (±15) days | Number of test points | 30 (±5) and 90 (±15) days | 
| Acute ischemic lesions on follow-up on diffusion-weighted (DWI) MRI or on brain CT at baseline and 24hrs. | DWI lesions | 24 hours | 
| National Institutes of Health Stroke Scale score (NIHSS) at 24hrs and discharge. | NIHSS score | 24 hours | 
| Modified Rankin Scale score (mRS) at discharge, 30 (±5) and 90 days (±15) days. | mRS score | Discharge, 30 (±5) and 90 days (±15) days. | 
| Mean score on National Eye Institute Visual Function Questionnaire (NEI-VFQ 25) at 30 (±5) and 90 (±15) days | Visual function related quality of life at 30 and 90 days. Measures the dimensions of self-reported vision-targeted health status that are most important for persons who have chronic eye diseases. 100 = best possible, 0 = worst possible | 30 (±5) and 90 (±15) days | 
| Mean score on EQ-5D at 30 (±5) and 90 (±15) days | Quality of life reported at 30 and 90 days. Health status is measured in terms of five dimensions (5D); mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. | 30 (±5) and 90 (±15) days | 
| Presence of ocular neovascularisation at 30 (±5) and 90 (±15) days | presence | 30 (±5) and 90 (±15) days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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thrombolysis tenecteplase