A multicentre study evaluating the safety of reperfusion thrombolytic therapy with intravenous recombinant tissue plasminogen activator (rtPA) for ischaemic stroke in patients on the non-vitamin K antagonist oral anticoagulant after reversing anticoagulant activity with a specific antidote.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Medical University Of Gdansk

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

10 Jan 2022 → ongoing

Decision date (initial)

2024-12-09

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Medical Research Agency

External identifiers

EU CT number

2024-518509-17-00

EudraCT number

2020-004898-41

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Therapy

The STROACT study aims to evaluate the thromboembolic safety of intravenous thrombolysis with rtPA in patients with acute ischemic stroke on chronic DOAC treatment after neutralisation of the anticoagulant activity by administration of a specific reversal agent (antidote).
PRIMARY OBJECTIVE – INTERVENTIONAL PART OF THE STROACT STUDY:
a) The incidence of thrombotic events and all-cause mortality at 90 days: ischemic stroke, transient ischemic attack, myocardial infarction, deep-vein thrombosis, pulmonary embolism, arterial systemic embolism, and death.
PRIMARY OBJECTIVE – OBSERVATIONAL PART OF THE STROACT STUDY:
a) To assess the proportion of patients with AIS on active DOAC treatment without any intervention with excellent or good functional outcome in modified Rankin scale (mRS).

Secondary objectives 7

1. SECONDARY OBJECTIVES – ONLY INTERVENTIONAL PART OF THE STROACT STUDY: a) Efficacy: To assess the proportion of patients with acute ischemic stroke (AIS) who achieve excellent or good functional outcomes, as assessed by the modified Rankin Scale (mRS) score of 0-1 and 0-2, respectively, at 90 days (+/- 3 days) after admission.
2. Safety – only interventional part of the STROACT study: a)To assess the incidence of fatal events after the investigational therapy in patients with acute ischaemic stroke on the non-vitamin K antagonist oral anticoagulants.
3. Safety – only interventional part of the STROACT study: b)To assess the incidence of non-fatal events after the investigational therapy in patients with acute ischaemic stroke on the non-vitamin K antagonist oral anticoagulants.
4. Safety – only interventional part of the STROACT study: c) To evaluate safety of the investigational therapy in patients with acute ischaemic stroke on the non- vitamin K antagonist oral anticoagulants assessed with neuroimaging.
5. Safety – only interventional part of the STROACT study: d) To assess characteristics of major clinically significant extracranial bleedings after the investigational therapy in patients with acute ischaemic stroke on the non-vitamin K antagonist oral anticoagulants.
6. Safety – only interventional part of the STROACT study: e) To assess overall safety profile of the investigational therapy in patients with acute ischaemic stroke on the non-vitamin K antagonist oral anticoagulants.
7. SECONDARY OBJECTIVES – ONLY INTERVENTIONAL PART OF THE STROACT STUDY: b) Efficacy: To assess the efficacy of the investigational therapy in patients with acute ischaemic stroke on the non-vitamin K antagonist oral anticoagulants using NIHSS score.

Conditions and MedDRA coding

Acute ischemic stroke

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 2

1. INTERVENTIONAL PART OF THE STROACT STUDY: 1. Obtaining informed consent to participate in the trial. NOTE: Patients whose neurological deficit is severe enough to make it impossible to sign the consent form are allowed to give only their oral consent to participate in the study. However, this consent should be additionally certified by the signature of two independent witnesses (who are neither family members of the patient nor the STROACT study staff) or by the signature of his/her legal representative. Patients with aphasia and/or other speech disorders may be included into the study if following neurological assessment of the recruiting stroke physician, they are able to understand all important information about the study. 2. Age >18 years. 3. Clinical diagnosis of acute ischemic stroke (sharply defined onset of first symptoms) resulting in a disabling neurological deficit. 4. Therapy with an oral anticoagulant that is the non-vitamin K antagonist oral anticoagulant (apixaban or rivaroxaban) with laboratory confirmed therapeutic anti-Xa activity measured as a plasma concentration > 50 ng/mL. 5. Administration of study intervention (intravenous thrombolysis with alteplase) should be possible to start within 4.5 hours from AIS symptoms onset or the last time the patient was seen without symptoms, as per investigator’s judgment. NOTE: If a patient was enrolled and there was a clear clinical reason for delaying the start of the study intervention within the 4.5-hour window, the patient may still be included in the study if rtPA can be given within 6.0 hours of the onset of acute ischemic stroke. NOTE: In patients recruited to STROACT study, in addition to the inclusion / exclusion criteria, apply all standard clinical practice indications and contraindications for rtPA administration in acute ischemic stroke unless stated otherwise in this protocol.
2. OBSERVATIONAL PART OF THE STROACT STUDY: 1. Age ≥ 18 years. 2. Clinical diagnosis of acute ischemic stroke (with sharply defined onset of first symptoms or last known well within 24 hours with laboratory confirmed therapeutic anti-IIa/Xa activity measured as a plasma concentration >50 ng/mL). 3. Therapy with an oral anticoagulant that is the non-vitamin K antagonist oral anticoagulant (dabigatran, apixaban or rivaroxaban) with laboratory confirmed therapeutic anti-IIa/Xa activity measured as a plasma concentration >50 ng/mL. 4. The neurological deficit rapidly improved to the point of a non-disabling deficit before obtaining the ICF to participate in the interventional part of the STROACT study. 5. Obtaining the ICF to participate in the observational part of the STROACT study.

Exclusion criteria 2

1. INTERVENTIONAL PART OF THE STROACT STUDY: 1. Occlusion of a large intracranial vessel in CT/MR angiography (CTA/MRA), corresponding to the current acute neurological deficit being an indication for primary mechanical thrombectomy. 2. Significant disability prior to the current stroke event defined as >2 points on the modified Rankin Scale (mRS) and/or significant impairment of the cognitive function prior to AIS (the latter documented in patient’s medical records). 3. Mild and rapidly improving neurological deficit with high probability of complete recovery. 4. Clinically severe stroke with >18 points in NIHSS. 5. Neuroimaging findings that might be responsible for acute neurological deficit (“stroke mimics”) and/or are contraindications for standard thrombolytic treatment: such as intracranial and/or intracerebral bleeding, tumours, abscesses and other. 6. Treatment with the following anticoagulants: a. Oral vitamin K antagonist (warfarin, acenocumarol), b. Unfractionated heparin, c. Low molecular weight heparin, or d. Inhibitors of coagulation factor IIa (dabigatran) and Xa other than rivaroxaban or apixaban 7. Whole blood, and/or blood clotting factors (such as: prothrombin complex concentrate [PCC], recombinant factor VIIa [rVIIa], fresh frozen plasma [FFP]) administered within 7 days before study treatment initiation. 8. Anti-Xa activity (which is assumed to be directly proportional to the DOAC plasma concentration) is <50 ng/mL. 9. CT or MRI initial lesion volume >1/2 of the anatomical perfusion area of the middle cerebral artery (MCA), or anterior cerebral artery (ACA), or posterior cerebral artery (PCA). 10. Suspected subarachnoid haemorrhage based on specific symptomatology and/or physical examination (even if CT/MRI is normal). 11. Any history of subarachnoid or intracerebral haemorrhage, so not including previous (currently normal in neuroimaging) traumatic sub-or epidural hematomas > 6 months before the current acute stroke. 12. Any past (chronic) medical illnesses that significantly impair patient’s functional status down to mRS 3 points or more (thus not only related to CNS pathologies and including cognitive impairment), and/or with a poor prognosis (e.g., neoplasms individually assessed to be of poor prognosis). NOTE: Patients after treatment of intracranial aneurysm may be considered for recruitment into the STROACT trial if the procedure was performed > 3 months prior to enrollment. 13. History of major surgery / trauma within 2 months before the current acute stroke. 14. History of acute ischemic stroke or any other medical condition treated with intravenous thrombolysis, or ischemic stroke treated with mechanical thrombectomy, within the 72 hours preceding the current patient’s stroke symptoms. 15. Recent (within 10 preceding days) traumatic external heart massage, obstetrical delivery, lumbar puncture, any puncture of a non-compressible blood vessel. 16. Recent (within 4 preceding weeks) myocardial infarction. 17. Severe trauma at the onset of acute ischemic stroke (e.g., skull fracture, long bone fracture, pelvic fracture). 18. Expected need for major surgery within 72 hours after enrollment (e.g., laparotomy, hip femoral/pelvic fracture surgery, endarterectomy). 19.Cerebral venous sinus thrombosis (CVST). 20.Pulmonary embolism. 21.Suspected infective endocarditis and/or pericarditis. 22.Acute pancreatitis. 23.Systemic or suspected cerebral vasculitis.
2. OBSERVATIONAL PART OF THE STROACT STUDY: 1.Occlusion of a large intracranial vessel in CT/MR angiography (CTA/MRA), corresponding to the current acute neurological deficit being an indication for primary mechanical thrombectomy. NOTE 1: Patients who qualified to the mechanical thrombectomy cannot be enrolled to the observational part of the STROACT study. 2. Significant disability prior to the current stroke event defined as >2 points on the modified Rankin Scale (mRS) and/or significant impairment of the cognitive function prior to AIS (the latter documented in patient’s medical records). 3. Neuroimaging findings that might be responsible for acute neurological deficit (“stroke mimics”). 4. Treatment with the following anticoagulants: a. Oral vitamin K antagonist (warfarin, acenocumarol), b. Unfractionated heparin, c. Low molecular weight heparin, or d. Inhibitors of coagulation factor IIa/Xa other than dabigatran, rivaroxaban or apixaban 5. Whole blood, and/or blood clotting factors (such as: prothrombin complex concentrate [PCC], recombinant factor VIIa [rVIIa], fresh frozen plasma [FFP]) administered within 7 days before enrollment to the study. 6. Anti-IIa/Xa activity (which is assumed to be directly proportional to the DOAC plasma concentration) is <50 ng/. 7. Suspected subarachnoid haemorrhage based on specific symptomatology and/or physical examination (even if CT/MRI is normal). 8. Any past (chronic) medical illnesses that significantly impairs patient’s functional status down to mRS 3 points or more (thus not only related to CNS pathologies and including cognitive impairment), and/or with a poor prognosis (e.g., neoplasms individually assessed to be of poor prognosis). 9. Cerebral venous sinus thrombosis (CVST). 10. Pulmonary embolism. 11. Systemic or suspected cerebral vasculitis. 12. Congenital or acquired coagulopathy presenting with: a. Prolonged aPTT above 30% of the upper limit of normal (local laboratory reference range), b. Increased INR ≥1.7 13. Severe liver disease including acute hepatic failure, cirrhosis with/or without portal hypertension. 14. Pregnancy. 15. Predicted life expectancy <3 months. 16. Participation in another clinical trial at the time of enrollment or planned inclusion in another clinical trial within less than 90 days of enrollment, provided that protocols of these trials interfere pathophysiologicaly or formally and administratively with the STROACT study. 17. Previous participation in the current clinical trial. 18. Advanced renal failure (eGFR <30 mL/min/1.73m2). 19. Active infection with SARS-CoV-2 (up to 10 days from the first positive testing with any recommended assay or from the first symptoms of infection or severe “long” COVID-19 / severe Post-COVID Neurological Syndrome).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. PRIMARY ENDPOINTS – INTERVENTIONAL PART OF THE STROACT STUDY: 1. The occurrence of thrombotic events and death (1- yes, 0-no).
2. PRIMARY ENDPOINTS – OBSERVATIONAL PART OF THE STROACT STUDY: 1. Outcome in mRS at 90 days (the proportion of patients with AIS with excellent or good functional outcome assessed with modified Rankin scale (mRS), mRS 0-1 and 0-2 respectively) at 90 days (+/- 3 days) after the admission.

Secondary endpoints 7

1. SECONDARY END POINTS – ONLY INTERVENTIONAL PART OF THE STROACT STUDY: a) Efficacy: mRS at 90 days - the proportion of patients with AIS with excellent or good functional outcome assessed with modified Rankin scale (mRS).
2. SECONDARY END POINTS – ONLY INTERVENTIONAL PART OF THE STROACT STUDY: b) Efficacy: Change in NIHSS score from baseline assessed at 7 (+/-1 day) after investigational treatment administration.
3. Safety – only interventional part of the STROACT study: a) Incidence of deaths: - Deaths from any cause - Deaths subdivided by cause at 7 (+/-1 day), 30 (+/-2 days) and 90 days (+/ 3 days) after treatment administration.
4. Safety – only interventional part of the STROACT study: b) Incidence of non-fatal events defined as - Recurrent ischaemic stroke - Haemorrhagic stroke (ICH or SAH) - Neurological deterioration (NIHSS) at 7 (+/-1 day) and 90 days (+/- 3 days) after treatment administration.
5. Safety – only interventional part of the STROACT study: c) Rate and severity of early (symptomatic and asymptomatic) intracranial haemorrhage detected by neuroimaging: - CT or MRI at 24hrs (+/- 4hrs) after investigational treatment administration - CT or MRI at 7 days (+/- 1 day) after investigational treatment infusion and assessed according to European Cooperative Acute Stroke Study (ECASS II) classification.
6. Safety – only interventional part of the STROACT study: d) Incidence and severity of major extracranial haemorrhages defined as: - fatal - severe enough to require transfusion or surgery - an absolute decrease in haemoglobin > 5 g/dL - a decrease in haematocrit of > 15% - leading to in persistent or temporary serious disability.
7. Safety – only interventional part of the STROACT study: e) Incidence and category of AEs reported during the study.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Medical University Of Gdansk

Sponsor organisation

Medical University Of Gdansk

Address

Ul. Marii Sklodowskiej-Curie 3a

City

Gdansk

Postcode

80-210

Country

Poland

Scientific contact point

Organisation

Medical University Of Gdansk

Contact name

Chief Medical officer; Principal Investigator

Public contact point

Organisation

Medical University Of Gdansk

Contact name

Director of Clinical Reseacher Support Centre

Third parties 1

Locations

1 EU/EEA country · 5 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 9 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications