Revacept in Symptomatic Carotid Stenosis

Stroke Clinical Trial

— RevaceptCS02  

Official title:

Revacept, an Inhibitor of Platelet Adhesion in Symptomatic Carotid Stenosis: A Phase II, Multicentre; Randomised, Dose-finding, Double-blind and Placebo Controlled Superiority Study With Parallel Groups

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01645306
• Other study ID #: Revacept/CS/02
• Status: Completed
• Phase: Phase 2
• Start date: March 8, 2013
• Est. completion date: September 23, 2019

Study information

• Verified date: January 2021
• Source: AdvanceCor GmbH
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 158
• Est. completion date: September 23, 2019
• Est. primary completion date: October 5, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Amaurosis Fugax
• Atherosclerosis
• Blindness
• Carotid Stenosis
• Constriction, Pathologic
• Ischemic Attack, Transient
• Stroke
• TIA
• Transient-ischaemic Attack

Intervention

Drug:
• Revacept
single intravenous injection
• Placebo
single intravenous injection

Locations

Country	Name	City	State
Germany	Site 08: Universitätsklinikum Essen, Klinik für Neurologie	Essen
Germany	Site 11: Universitätsklinikum Hamburg Eppendorf	Hamburg
Germany	Site 07: Medizinische Hochschule Hannover, Klinik für Neurologie	Hannover
Germany	Site 12: Universitätsklinikum Leipzig AöR	Leipzig
Germany	Site 09: Universitätsmedizin Mainz, Klinik und Poliklinik für Neurologie	Mainz
Germany	Site 01: Department of Neurology, TU Munich	Munich	Bavaria
Germany	Site 04: Universitätsklinikum Tübingen, Klinik für Allgemeine Neurologie	Tübingen
Germany	Site 06: Universitätsklinikum Ulm, Abteilung für Neurologie	Ulm
United Kingdom	Site 23 - University Hospital Coventry NHS Trust	Coventry
United Kingdom	Site 20: St George's NHS Trust	London
United Kingdom	Site 26 - University College London Hospital	London
United Kingdom	Site 28 - King's College London Hospital	London

Sponsors (1)

Lead Sponsor	Collaborator
AdvanceCor GmbH

Countries where clinical trial is conducted

Germany,  United Kingdom, 

References & Publications (11)

Bültmann A, Li Z, Wagner S, Peluso M, Schönberger T, Weis C, Konrad I, Stellos K, Massberg S, Nieswandt B, Gawaz M, Ungerer M, Münch G. Impact of glycoprotein VI and platelet adhesion on atherosclerosis--a possible role of fibronectin. J Mol Cell Cardiol. 2010 Sep;49(3):532-42. doi: 10.1016/j.yjmcc.2010.04.009. Epub 2010 Apr 27. — View Citation

Goertler M, Baeumer M, Kross R, Blaser T, Lutze G, Jost S, Wallesch CW. Rapid decline of cerebral microemboli of arterial origin after intravenous acetylsalicylic acid. Stroke. 1999 Jan;30(1):66-9. — View Citation

Jamasbi J, Megens RT, Bianchini M, Münch G, Ungerer M, Faussner A, Sherman S, Walker A, Goyal P, Jung S, Brandl R, Weber C, Lorenz R, Farndale R, Elia N, Siess W. Differential Inhibition of Human Atherosclerotic Plaque-Induced Platelet Activation by Dimeric GPVI-Fc and Anti-GPVI Antibodies: Functional and Imaging Studies. J Am Coll Cardiol. 2015 Jun 9;65(22):2404-15. doi: 10.1016/j.jacc.2015.03.573. — View Citation

Kleiman NS, Kolandaivelu K. Expanding the Roster: Developing New Inhibitors of Intravascular Thrombosis. J Am Coll Cardiol. 2015 Jun 9;65(22):2416-9. doi: 10.1016/j.jacc.2015.03.576. — View Citation

Markus HS, Droste DW, Kaps M, Larrue V, Lees KR, Siebler M, Ringelstein EB. Dual antiplatelet therapy with clopidogrel and aspirin in symptomatic carotid stenosis evaluated using doppler embolic signal detection: the Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic Carotid Stenosis (CARESS) trial. Circulation. 2005 May 3;111(17):2233-40. Epub 2005 Apr 25. — View Citation

Massberg S, Konrad I, Bültmann A, Schulz C, Münch G, Peluso M, Lorenz M, Schneider S, Besta F, Müller I, Hu B, Langer H, Kremmer E, Rudelius M, Heinzmann U, Ungerer M, Gawaz M. Soluble glycoprotein VI dimer inhibits platelet adhesion and aggregation to the injured vessel wall in vivo. FASEB J. 2004 Feb;18(2):397-9. Epub 2003 Dec 4. — View Citation

Molloy J, Markus HS. Asymptomatic embolization predicts stroke and TIA risk in patients with carotid artery stenosis. Stroke. 1999 Jul;30(7):1440-3. — View Citation

Nieswandt B, Watson SP. Platelet-collagen interaction: is GPVI the central receptor? Blood. 2003 Jul 15;102(2):449-61. Epub 2003 Mar 20. Review. — View Citation

Ringelstein EB, Droste DW, Babikian VL, Evans DH, Grosset DG, Kaps M, Markus HS, Russell D, Siebler M. Consensus on microembolus detection by TCD. International Consensus Group on Microembolus Detection. Stroke. 1998 Mar;29(3):725-9. — View Citation

Schönberger T, Siegel-Axel D, Bussl R, Richter S, Judenhofer MS, Haubner R, Reischl G, Klingel K, Münch G, Seizer P, Pichler BJ, Gawaz M. The immunoadhesin glycoprotein VI-Fc regulates arterial remodelling after mechanical injury in ApoE-/- mice. Cardiovasc Res. 2008 Oct 1;80(1):131-7. doi: 10.1093/cvr/cvn169. Epub 2008 Jun 19. — View Citation

Ungerer M, Rosport K, Bültmann A, Piechatzek R, Uhland K, Schlieper P, Gawaz M, Münch G. Novel antiplatelet drug revacept (Dimeric Glycoprotein VI-Fc) specifically and efficiently inhibited collagen-induced platelet aggregation without affecting general hemostasis in humans. Circulation. 2011 May 3;123(17):1891-9. doi: 10.1161/CIRCULATIONAHA.110.980623. Epub 2011 Apr 18. — View Citation

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Patients With Any Stroke or Transient Ischemic Attack (TIA)	patients with any stroke or TIA occuring within 90 days after IMP application.	90 days after IMP application
Other	Major Bleedings	patients with major bleedings occuring within 90 days after IMP application	90 days after IMP application
Other	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.	365 days after IMP application
Other	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.	3 month (+/- 1 month) after IMP application
Other	Participants With Adverse Events (AEs)	All adverse events were assessed during complete study period (~ 1 year after IMP application).	~ 365 days after IMP application (whole study period)
Primary	New DWI Lesion(s)	The number of new diffusion weighted imaging (DWI) lesion(s) reported. (1 day after intervention compared to baseline).	1 day post intervention