Revacept in Symptomatic Carotid Stenosis (RevaceptCS02)

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

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.

Study Overview

• Status: Completed
• Conditions: Stroke; Atherosclerosis; Carotid Stenosis; TIA; Transient-ischaemic Attack; Amaurosis Fugax
• Intervention / Treatment: Drug: Placebo; Drug: Revacept

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.

• Study Type: Interventional
• Enrollment (Actual): 158
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Essen, Germany, 45147
    • Site 08: Universitätsklinikum Essen, Klinik für Neurologie
  • Hamburg, Germany, 20246
    • Site 11: Universitätsklinikum Hamburg Eppendorf
  • Hannover, Germany, 30625
    • Site 07: Medizinische Hochschule Hannover, Klinik für Neurologie
  • Leipzig, Germany, 04103
    • Site 12: Universitätsklinikum Leipzig AöR
  • Mainz, Germany, 55131
    • Site 09: Universitätsmedizin Mainz, Klinik und Poliklinik für Neurologie
  • Tübingen, Germany, 72076
    • Site 04: Universitätsklinikum Tübingen, Klinik für Allgemeine Neurologie
  • Ulm, Germany, 89081
    • Site 06: Universitätsklinikum Ulm, Abteilung für Neurologie
  • Bavaria
    • Munich, Bavaria, Germany, 81675
      • Site 01: Department of Neurology, TU Munich
• United Kingdom
  • Coventry, United Kingdom, CV2 2DX
    • Site 23 - University Hospital Coventry NHS Trust
  • London, United Kingdom, NW1 2BU
    • Site 26 - University College London Hospital
  • London, United Kingdom, SE5 8AF
    • Site 28 - King's College London Hospital
  • London, United Kingdom, SW17 0QT
    • Site 20: St George's NHS Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Phosphate buffered saline (PBS), 1% sucrose, 4% mannitol; Placebo control with PBS, 1% sucrose and 4% mannitol	Drug: Placebo; single intravenous injection; Other Names: Control Group
Active Comparator: 40 mg Revacept; low dose Revacept 40mg in PBS, 1% sucrose, 4% mannitol	Drug: Revacept; single intravenous injection; Other Names: 40 mg or 120 mg
Active Comparator: 120 mg Revacept; high dose revacept 120mg in PBS, 1% sucrose, 4% mannitol	Drug: Revacept; single intravenous injection; Other Names: 40 mg or 120 mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
Major Bleedings	patients with major bleedings occuring within 90 days after IMP application	90 days after IMP application
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
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
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)

Collaborators and Investigators

• Sponsor: AdvanceCor GmbH
• Investigators: Principal Investigator: Holger Poppert, Prof. Dr., Department of Neurology, TU Munich; Principal Investigator: Ian M Loftus, MD, St George's NHS Trust

Publications and helpful links

General Publications

• 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. doi: 10.1161/01.CIR.0000163561.90680.1C. Epub 2005 Apr 25.
• Bultmann A, Li Z, Wagner S, Peluso M, Schonberger T, Weis C, Konrad I, Stellos K, Massberg S, Nieswandt B, Gawaz M, Ungerer M, Munch 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.
• 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. doi: 10.1161/01.str.30.1.66.
• Massberg S, Konrad I, Bultmann A, Schulz C, Munch G, Peluso M, Lorenz M, Schneider S, Besta F, Muller 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. doi: 10.1096/fj.03-0464fje. Epub 2003 Dec 4.
• Molloy J, Markus HS. Asymptomatic embolization predicts stroke and TIA risk in patients with carotid artery stenosis. Stroke. 1999 Jul;30(7):1440-3. doi: 10.1161/01.str.30.7.1440.
• Nieswandt B, Watson SP. Platelet-collagen interaction: is GPVI the central receptor? Blood. 2003 Jul 15;102(2):449-61. doi: 10.1182/blood-2002-12-3882. Epub 2003 Mar 20.
• 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. doi: 10.1161/01.str.29.3.725.
• Schonberger T, Siegel-Axel D, Bussl R, Richter S, Judenhofer MS, Haubner R, Reischl G, Klingel K, Munch 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.
• Ungerer M, Rosport K, Bultmann A, Piechatzek R, Uhland K, Schlieper P, Gawaz M, Munch 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.
• Jamasbi J, Megens RT, Bianchini M, Munch 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.
• 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. No abstract available.
• Uphaus T, Richards T, Weimar C, Neugebauer H, Poli S, Weissenborn K, Imray C, Michalski D, Rashid H, Loftus I, Rummey C, Ritter M, Hauser TK, Munch G, Groschel K, Poppert H. Revacept, an Inhibitor of Platelet Adhesion in Symptomatic Carotid Stenosis: A Multicenter Randomized Phase II Trial. Stroke. 2022 Sep;53(9):2718-2729. doi: 10.1161/STROKEAHA.121.037006. Epub 2022 Jun 13.

Study record dates

Study Major Dates

• Study Start (Actual): March 8, 2013
• Primary Completion (Actual): October 5, 2018
• Study Completion (Actual): September 23, 2019

Study Registration Dates

• First Submitted: July 16, 2012
• First Submitted That Met QC Criteria: July 19, 2012
• First Posted (Estimate): July 20, 2012

Study Record Updates

• Last Update Posted (Actual): January 28, 2021
• Last Update Submitted That Met QC Criteria: January 27, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Eye Diseases; Neurologic Manifestations; Pathological Conditions, Anatomical; Brain Ischemia; Carotid Artery Diseases; Sensation Disorders; Vision Disorders; Ischemic Attack, Transient; Carotid Stenosis; Constriction, Pathologic; Atherosclerosis; Blindness; Amaurosis Fugax
• Other Study ID Numbers: Revacept/CS/02

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No