Amaurosis Fugax, Atherosclerosis, Carotid Stenosis, Stroke, TIA, Transient-ischaemic Attack
Conditions
Brief summary
Patients suffering from symptomatic carotid artery stenosis, transient ischemic attacks (TIAs), amaurosis fugax or stroke receive either Revacept (single dose) plus antiplatelet monotherapy or monotherapy alone. Patients receive a single dose of trial medication by intravenous infusion for 20 minutes. Patients are followed up one and three days after treatment, at 3 months and by a telephone interview at 12 months.
Detailed description
Patients had a more than 50% carotid artery stenosis according to ECST and suffered from ischemic stroke, transitory ischemic attack or intermittent blindness (amaurosis fugax) within the last 30 days. All patients were on standard medication with aspirin or clopidogrel and received heparin for thrombosis prophylaxis. Carotid endarterectomy (CEA), carotid stenting (CAS) or best medical therapy for treatment of the carotid stenosis and prevention of secondary thrombo-emboli was performed according to guidelines. Additional treatment with Revacept or placebo was done on top of the standard therapy. Therefore the control group receiving placebo was already on the standard medical therapy for patients with symptomatic carotid stenosis and received also the guideline conform interventions CEA, CAS or best medical therapy. Secondary prophylaxis of thrombo-embolic ischemic events by Revacept should be investigated. Therefore microemboli were detected by transcranial Doppler and ischemic brain lesions were investigated by diffusion weighted imaging magnetic resonance imaging (DWI-MRI) scan as exploratory endpoints. Moreover clinical endpoints such as stroke, TIA, myocardial infarction, coronary intervention and death were investigated at 1 week, 3 months and 12 months follow-up. Safety was closely monitored with emphasis on bleeding complications as bleeding is the most dreaded complication of anti-thrombotic agents especially in patients with cerebral strokes.
Interventions
DRUGRevacept
single intravenous injection
DRUGPlacebo
single intravenous injection
Sponsors
AdvanceCor GmbH
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Signed written informed consent 2. Target population * Diagnosis: * Extracranial carotid artery stenosis (diagnosed by vascular duplex ultrasound peak flow or angiography) * Lesions with ≥ 50 % stenosis according to the European Carotid Surgery Trial (ECST) criteria * TIA, amaurosis fugax or stroke within the last 30 days * Age and sex: Men and women aged \> 18 years Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 4 weeks after receiving investigational product in such a manner that the risk of pregnancy is minimised.
Exclusion criteria
1. Sex and reproductive Status: * WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for up to 4 weeks after receiving investigational product. * Women who are pregnant or breastfeeding * Women with a positive pregnancy test on enrollment or prior to investigational product administration. 2. Target disease exceptions * NIHSS score \> 18 * Recent intracerebral haemorrhage by X-ray computed tomography (CT) or nuclear magnetic resonance (NMR) * Cardiac cause of embolisation (atrial fibrillation or other cardiac source e.g. artificial heart valves) 3. Medical history and concurrent disease * History of hypersensitivity, contraindication or serious adverse reaction to inhibitors of platelet aggregation, hypersensitivity to related drugs (cross-allergy) or to any of the excipients in the study drug * History or evidence of thrombocytopenia (\<30.000/ul), bleeding diathesis or coagulopathy (pathological international normalised ratio (INR) or activated partial thromboplastin time (aPTT)) * Thrombolysis within the last 48 hours * Relevant haemorrhagic transformation as determined by CT, NMR or anamnesis * Oral anticoagulation or dual anti-platelet therapy with aspirin or clopidogrel and other P2Y inhibitors at screening (3 days for dipyridamole extended release; 8 hours for tirofiban/Aggrastat) * Sustained hypertension (systolic BP \> 179 mmHg or diastolic BP \>109 mmHg) * History of severe systemic disease such as terminal carcinoma, renal failure (or current creatinine \> 200 umol/l), cirrhosis, severe dementia, or psychosis * Current severe liver dysfunction (transaminase level greater than 5-fold over upper normal range limit) * Active autoimmune disorder such as systemic lupus erythematosus, rheumatoid arthritis, vasculitis or glomerulonephritis * Known atrial fibrillation or other clinically significant ECG abnormalities (at present)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| New DWI Lesion(s) | 1 day post intervention | The number of new diffusion weighted imaging (DWI) lesion(s) reported. (1 day after intervention compared to baseline). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Patients With Any Stroke or Transient Ischemic Attack (TIA) | 90 days after IMP application | patients with any stroke or TIA occuring within 90 days after IMP application. |
| Major Bleedings | 90 days after IMP application | patients with major bleedings occuring within 90 days after IMP application |
| Any Clinical Event | 365 days after IMP application | patients with any stroke & TIA, myocardial infarction & percutaneous coronary intervention (PCI), death or bleeding within one year (365 days) after IMP application. |
| Anti-Drug Antibodies | 3 month (+/- 1 month) after IMP application | Anti-drug antibodies were measured at baseline and 3 month after IMP application. Number of patients with positive anti-drug antibodies compared to baseline are counted. |
| Participants With Adverse Events (AEs) | ~ 365 days after IMP application (whole study period) | All adverse events were assessed during complete study period (\ 1 year after IMP application). |
Countries
Germany, United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Phosphate buffered saline (PBS), 1% sucrose, 4% mannitol
Placebo: single intravenous injection | 51 |
| 40 mg Revacept 40 mg Revacept in phosphate buffered saline (PBS), 1% sucrose, 4% mannitol
Revacept: single intravenous injection | 54 |
| 120 mg Revacept 120 mg Revacept in phosphate buffered saline (PBS), 1% sucrose, 4% mannitol
Revacept: single intravenous injection | 53 |
| Total | 158 |
Baseline characteristics
| Characteristic | Placebo | 40 mg Revacept | 120 mg Revacept | Total |
|---|---|---|---|---|
| Age, Continuous | 67.3 years STANDARD_DEVIATION 10.25 | 68.7 years STANDARD_DEVIATION 10.45 | 68.4 years STANDARD_DEVIATION 9.82 | 68.1 years STANDARD_DEVIATION 10.13 |
| Race/Ethnicity, Customized Ethnic Origin African | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Ethnic Origin Asian | 1 Participants | 2 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Ethnic Origin Caucasian | 49 Participants | 52 Participants | 53 Participants | 154 Participants |
| Region of Enrollment Germany | 37 participants | 36 participants | 35 participants | 108 participants |
| Region of Enrollment United Kingdom | 14 participants | 18 participants | 18 participants | 50 participants |
| Sex: Female, Male Female | 8 Participants | 13 Participants | 17 Participants | 38 Participants |
| Sex: Female, Male Male | 43 Participants | 41 Participants | 36 Participants | 120 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 51 | 0 / 54 | 1 / 53 |
| other Total, other adverse events | 18 / 51 | 24 / 54 | 17 / 53 |
| serious Total, serious adverse events | 17 / 51 | 17 / 54 | 15 / 53 |
Outcome results
Primary
New DWI Lesion(s)
The number of new diffusion weighted imaging (DWI) lesion(s) reported. (1 day after intervention compared to baseline).
Time frame: 1 day post intervention
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | New DWI Lesion(s) | 1.2 Number of new lesions | Standard Deviation 0.4 |
| 40 mg Revacept | New DWI Lesion(s) | 1.0 Number of new lesions | Standard Deviation 0.3 |
| 120 mg Revacept | New DWI Lesion(s) | 0.6 Number of new lesions | Standard Deviation 0.3 |
Other Pre-specified
Anti-Drug Antibodies
Anti-drug antibodies were measured at baseline and 3 month after IMP application. Number of patients with positive anti-drug antibodies compared to baseline are counted.
Time frame: 3 month (+/- 1 month) after IMP application
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Anti-Drug Antibodies | 0 Participants |
| 40 mg Revacept | Anti-Drug Antibodies | 0 Participants |
| 120 mg Revacept | Anti-Drug Antibodies | 0 Participants |
Other Pre-specified
Any Clinical Event
patients with any stroke & TIA, myocardial infarction & percutaneous coronary intervention (PCI), death or bleeding within one year (365 days) after IMP application.
Time frame: 365 days after IMP application
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Any Clinical Event | 19 Number of Events |
| 40 mg Revacept | Any Clinical Event | 15 Number of Events |
| 120 mg Revacept | Any Clinical Event | 10 Number of Events |
Other Pre-specified
Major Bleedings
patients with major bleedings occuring within 90 days after IMP application
Time frame: 90 days after IMP application
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Major Bleedings | 5 Participants |
| 40 mg Revacept | Major Bleedings | 6 Participants |
| 120 mg Revacept | Major Bleedings | 4 Participants |
Other Pre-specified
Participants With Adverse Events (AEs)
All adverse events were assessed during complete study period (\ 1 year after IMP application).
Time frame: ~ 365 days after IMP application (whole study period)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Participants With Adverse Events (AEs) | patients with drug related serious AEs | 1 participants |
| Placebo | Participants With Adverse Events (AEs) | patients with serious AEs | 17 participants |
| Placebo | Participants With Adverse Events (AEs) | patients with adverse events | 35 participants |
| Placebo | Participants With Adverse Events (AEs) | patients with drug related AEs | 4 participants |
| Placebo | Participants With Adverse Events (AEs) | patients with AE with fatal outcome events | 0 participants |
| 40 mg Revacept | Participants With Adverse Events (AEs) | patients with serious AEs | 17 participants |
| 40 mg Revacept | Participants With Adverse Events (AEs) | patients with adverse events | 41 participants |
| 40 mg Revacept | Participants With Adverse Events (AEs) | patients with drug related AEs | 10 participants |
| 40 mg Revacept | Participants With Adverse Events (AEs) | patients with drug related serious AEs | 4 participants |
| 40 mg Revacept | Participants With Adverse Events (AEs) | patients with AE with fatal outcome events | 0 participants |
| 120 mg Revacept | Participants With Adverse Events (AEs) | patients with AE with fatal outcome events | 1 participants |
| 120 mg Revacept | Participants With Adverse Events (AEs) | patients with drug related serious AEs | 0 participants |
| 120 mg Revacept | Participants With Adverse Events (AEs) | patients with adverse events | 32 participants |
| 120 mg Revacept | Participants With Adverse Events (AEs) | patients with serious AEs | 15 participants |
| 120 mg Revacept | Participants With Adverse Events (AEs) | patients with drug related AEs | 2 participants |
Other Pre-specified
Patients With Any Stroke or Transient Ischemic Attack (TIA)
patients with any stroke or TIA occuring within 90 days after IMP application.
Time frame: 90 days after IMP application
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Patients With Any Stroke or Transient Ischemic Attack (TIA) | 6 Participants |
| 40 mg Revacept | Patients With Any Stroke or Transient Ischemic Attack (TIA) | 6 Participants |
| 120 mg Revacept | Patients With Any Stroke or Transient Ischemic Attack (TIA) | 4 Participants |