Clinical trial NCT04526951: TENecteplase in Central Retinal Artery Occlusion Stuy (TenCRAOS)
Official title: 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.
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Central Retinal Artery Occlusion
Keywords: thrombolysis tenecteplase
Lead sponsor: Oslo University Hospital
Sponsor class: OTHER
First posted: 2020-08-26
Enrollment: 78
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. Non-arteritic central retinal artery occlusion with ≥ 1.0 logMAR visual acuitiy and symptoms lasting less than 4.5 hours.
2. Ability to administer the Investigator Medicinal Product (IMP) within 4.5 hours of symptom onset.
3. Age ≥18 years.
4. Informed written consent of the patient.
5. 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:

1. No other active intervention targeting CRAO.
2. 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).
3. Systemic diseases; severe general diseases, systemic arterial hypertension (blood pressure \>185/110 mmHg), despite medical therapy, or clinical suspicion of acute systemic inflammation.
4. Presence of intracranial haemorrhage on brain MRI/CT.
5. 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.
6. No willingness and ability of the patient to participate in all follow-up examinations.
7. Pregnancy (if suspicion of pregnancy s-hCG or u-hCG must be negative).
8. Allergy or intolerance to any ingredients of IMP or placebo or gentamicin.
9. Other conditions / circumstances likely to lead to poor treatment adherence (eg, history of poor compliance, alcohol or drug dependency, no fixed abode).
10. Significant bleeding disorder either at present or within the past 6 months.
11. Effective oral anticoagulant treatment, eg, warfarin sodium (INR \>1.3).
12. Effective anticoagulant treatment with heparin or low molecular weight heparin the last 48 hours.
13. Any history of central nervous system damage (ie, neoplasm, aneurysm, intracranial or spinal surgery).
14. Known hemorrhagic diathesis.
15. Major surgery, biopsy of a parenchymal organ, or significant trauma within the past 2 months (this includes any trauma associated with acute myocardial infarction).
16. Recent non-compressible vessel puncture within 2 weeks.
17. Recent trauma to the head or cranium.
18. Prolonged cardiopulmonary resuscitation (\>2 minutes) within the past 2 weeks.
19. Acute pericarditis and/or subacute bacterial endocarditis.
20. Acute pancreatitis.
21. Severe hepatic dysfunction, including hepatic failure, cirrhosis, portal hypertension (oesophageal varices) and active hepatitis.
22. Active peptic ulceration.
23. Arterial aneurysm and known arterial/venous malformation.
24. Neoplasm with increased bleeding risk.
25. Any known history of hemorrhagic stroke or stroke of unknown origin.
26. Known history of ischemic stroke or transient ischemic attack in the preceding 3 months.
27. Dementia.

Primary outcomes:
measure: 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).
timeFrame: 30 (±5) days
Secondary outcomes:
measure: Proportion of patients with ≤ 0.5 logMAR visual acuity in the affected eye at 30 (±5) and 90 (±15) days.
timeFrame: 30 (±5) and 90 (±15) days
measure: Mean improvement in logMAR visual acuity in the affected eye from baseline to 30 (±5) and 90 (±15) days.
timeFrame: 30 (±5) and 90 (±15) days
measure: 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
timeFrame: 30 (±5) and 90 (±15) days
measure: Number of test points seen (of 100) on monocular Esterman perimetry at 30 (±5) and 90 (±15) days
timeFrame: 30 (±5) and 90 (±15) days
measure: Acute ischemic lesions on follow-up on diffusion-weighted (DWI) MRI or on brain CT at baseline and 24hrs.
timeFrame: 24 hours
measure: National Institutes of Health Stroke Scale score (NIHSS) at 24hrs and discharge.
timeFrame: 24 hours
measure: Modified Rankin Scale score (mRS) at discharge, 30 (±5) and 90 days (±15) days.
timeFrame: Discharge, 30 (±5) and 90 days (±15) days.
measure: Mean score on National Eye Institute Visual Function Questionnaire (NEI-VFQ 25) at 30 (±5) and 90 (±15) days
timeFrame: 30 (±5) and 90 (±15) days
measure: Mean score on EQ-5D at 30 (±5) and 90 (±15) days
timeFrame: 30 (±5) and 90 (±15) days
measure: Presence of ocular neovascularisation at 30 (±5) and 90 (±15) days
timeFrame: 30 (±5) and 90 (±15) days
Other outcomes:
measure: All-cause and stroke-related death at discharge, 30 (±5) and 90 (±15) days.
timeFrame: Discharge assessed up to 7 days , 30 (±5) and 90 (±15) days
measure: Proportion of patients with any intracranial haemorrhage at 24 hrs
timeFrame: 24 hours
measure: Proportion of patients with symptomatic intracranial haemorrhage until discharge.
timeFrame: at discharge, assessed up to 7 days
measure: Proportion of patients with complications such as systemic bleeding at 24 hrs, discharge and 30 (±5) days
timeFrame: 24 hours, at discharge assessed up to 7 days and 30 (±5) days
measure: Other serious adverse events
timeFrame: 24 hours, at discharge, 30 (±5) days and 90 days (±15) days.
measure: Occurrence of adverse events
timeFrame: 24 hours, at discharge assessed up to 7 days, 30 (±5) days and 90 days (±15) days.
measure: Retrobulbar spot sign detection using Duplex/Doppler ultrasound at baseline, point-of-care ultrasound (POCUS)
timeFrame: 30 (±5) and 90 (±15) days
measure: Retrobulbar spot sign and central retinal artery recanalisation using Duplex/Doppler ultrasound at 24h and discharge
timeFrame: 24 hours and at discharge assessed up to 7 days
measure: Macular optical coherence tomography (OCT) volume scans and macular OCT angiography (OCT-A) at 30 and 90 days
timeFrame: 30 (±5) and 90 (±15) days
Locations:
city: Melbourne
country: Australia
facility: St Vincent's Hospital Melbourne
city: Anderlecht
country: Belgium
facility: ULB-Hôpital Erasme
city: Antwerp
country: Belgium
facility: University Hospital Antwerp
city: Brussel
country: Belgium
facility: UZ Brussel
city: Leuven
country: Belgium
facility: University Hospital Leuven
city: Aarhus
country: Denmark
facility: Aarhus University Hospital
city: Copenhagen
country: Denmark
facility: Bispebjerg University Hospital
city: Copenhagen
country: Denmark
facility: Rigshospitalet University Hospital
city: Helsinki
country: Finland
facility: Helsinki University Hospital
city: Turku
country: Finland
facility: Turku University Hospital
city: Dublin
country: Ireland
facility: Mater Misericordiae University Hospital
city: Kaunas
country: Lithuania
facility: Kauno Klinikos Kaunas
city: Vilnius
country: Lithuania
facility: Respublican Vilnius University Hospital
city: Vilnius
country: Lithuania
facility: Vilnius University Hospital
city: Arendal
country: Norway
facility: Sørlandet Hospital Trust
city: Bergen
country: Norway
facility: Haukeland University Hospital
city: Drammen
country: Norway
facility: Vestre Viken Hospital Trust Drammen
city: Grålum
country: Norway
facility: Østfold Hospital Trust Kalnes, Dept of Ophthalmology
city: Lillehammer
country: Norway
facility: Innlandet Hospital Trust
city: Molde
country: Norway
facility: Nordmøre and Romsdal Regional Hospital
city: Namsos
country: Norway
facility: Helse Nord Trøndelag Trust
city: Oslo
country: Norway
facility: Oslo University Hospital
city: Skien
country: Norway
facility: Telemark Hospital Trust
city: Stavanger
country: Norway
facility: Stavanger University Hospital
city: Tromsø
country: Norway
facility: University Hospital of North Norway, Tromsø
city: Trondheim
country: Norway
facility: St Olav University Hospital
city: Tønsberg
country: Norway
facility: Vestfold Hospital Trust
city: Stockholm
country: Sweden
facility: Karolinska University Hospital
city: Sundsvall
country: Sweden
facility: Sundsvall Hospital
Study officials:
References: