Revacept in Symptomatic Carotid Stenosis (Revacept/CS/02)

• Change in rate of MES per hour [ Time Frame: 24 hours after treatment ] [ Designated as safety issue: No ]
• Assessment of neurological status (NIH Stroke Scale) [ Time Frame: 3 months after treatment ] [ Designated as safety issue: Yes ]
• Cerebral lesion analysis by DWI-NMR and correlation to neurological status [ Time Frame: 1 day after CEA / intervention ] [ Designated as safety issue: Yes ]
• Clinical endpoint rate of all cause death [ Time Frame: up to 12 months after treatment ] [ Designated as safety issue: Yes ]
• Assessment of cardiovascular outcome [ Time Frame: 3 and 12 months ] [ Designated as safety issue: Yes ]
  myocardial infarction and re-intervention
• Change in vital signs [ Time Frame: up to 3 months after treatment ] [ Designated as safety issue: Yes ]
• Change in ECG parameters [ Time Frame: up to 3 months after treatment ] [ Designated as safety issue: Yes ]
• Assessment of anti-drug antibody titres [ Time Frame: up to 3 months after treatment ] [ Designated as safety issue: Yes ]
• Assessment of Adverse Events [ Time Frame: up to 3 months after treatment ] [ Designated as safety issue: Yes ]
  including wound healing complications, laboratory abnormalities and use of concomitant medication
• Where feasible: Assessment of Haemostasis Safety [ Time Frame: up to 3 months after treatment ] [ Designated as safety issue: Yes ]
  laboratory parameters indicating thrombocytopenia and bleeding according to the RE-LY study group criteria, in vitro platelet function, in vitro bleeding time by PFA-100 / PFA-200
• Clinical endpoint rate of stroke-related death [ Time Frame: up to 12 months after treatment ] [ Designated as safety issue: Yes ]
• Clinical endpoint TIA, amaurosis fugax or stroke including haemorrhagic stroke [ Time Frame: up to 12 months after treatment ] [ Designated as safety issue: Yes ]

• Change in rate of MES per hour [ Time Frame: 24 hours after treatment ] [ Designated as safety issue: No ]
• Assessment of neurological status (NIH Stroke Scale) [ Time Frame: 3 months after treatment ] [ Designated as safety issue: Yes ]
• Cerebral lesion analysis by DWI-NMR and correlation to neurological status [ Time Frame: 1 day after CEA ] [ Designated as safety issue: Yes ]
• Clinical endpoints [ Time Frame: up to 12 months after treatment ] [ Designated as safety issue: Yes ]
  • Rate of all cause death
  • Rate of stroke-related death
  • Any TIA or stroke including haemorrhagic stroke
• Assessment of cardiovascular outcome [ Time Frame: 3 and 12 months ] [ Designated as safety issue: Yes ]
  myocardial infarction and re-intervention
• Change in vital signs [ Time Frame: up to 3 months after treatment ] [ Designated as safety issue: Yes ]
• Change in ECG parameters [ Time Frame: up to 3 months after treatment ] [ Designated as safety issue: Yes ]
• Assessment of anti-drug antibody titres [ Time Frame: up to 3 months after treatment ] [ Designated as safety issue: Yes ]
• Assessment of Adverse Events [ Time Frame: up to 3 months after treatment ] [ Designated as safety issue: Yes ]
  including wound healing complications, laboratory abnormalities and use of concomitant medication
• Assessment of Haemostasis Safety [ Time Frame: up to 3 months after treatment ] [ Designated as safety issue: Yes ]
  laboratory parameters indicating thrombocytopenia and bleeding according to the RE-LY study group criteria, in vitro platelet function, in vitro bleeding time by PFA-100

Patients suffering from symptomatic carotid artery stenosis, transient ischemic attacks (TIAs), amaurosis fugax or stroke and presenting with microembolic signals (MES) receive either Revacept (single dose) plus antiplatelet monotherapy (Aspirin or Clopidogrel) or monotherapy alone with the aim of reducing MES.

Patients receive a single dose of trial medication by intravenous infusion for 20 minutes. The primary endpoint (MES 24 hours after treatment) is assessed. Patients are followed up one and three days after treatment, at 3 months and by a telephone interview at 12 months.

• Carotid Stenosis
• Atherosclerosis
• Stroke
• Transient-ischaemic Attack
• TIA
• Amaurosis Fugax

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

• Placebo Comparator: Phosphate buffered saline (PBS), 1% sucrose, 4% mannitol
  Intervention: Drug: Placebo
• Active Comparator: 40 mg Revacept
  in phosphate buffered saline (PBS), 1% sucrose, 4% mannitol
  Intervention: Drug: Revacept
• Active Comparator: 120 mg Revacept
  in phosphate buffered saline (PBS), 1% sucrose, 4% mannitol
  Intervention: Drug: Revacept

• 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. 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.
• 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.
• 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.
• Molloy J, Markus HS. Asymptomatic embolization predicts stroke and TIA risk in patients with carotid artery stenosis. Stroke. 1999 Jul;30(7):1440-3.
• 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.
• 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.
• 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. Epub 2008 Jun 19.
• 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. Epub 2011 Apr 18.

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
     • MES detected by TCD (greater than or equal to 1 MES per hour)
     • Ipsilateral 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

   • Ipsilateral siphon or middle cerebral artery stenosis (tandem stenosis)
   • 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 other anti-platelet therapy than aspirin or clopidogrel within the last 3 weeks (3 days for dipyridamole extended release; 8 hours for tirofiban/Aggrastat)
   • Sustained hypertension (systolic BP > 179 mmHg or diastolic BP >109 mmHg), hypertensive patients shall be treated in accordance with current guidelines for the management of arterial hypertension
   • 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)

4. Prohibited Treatments and/or therapies

   • Oral anticoagulation or dual antiplatelet therapy (aspirin combined with clopidogrel or other P2Y inhibitors) within the last 3 weeks; dipyridamole extended release within last 3 days; tirofiban/Aggrastat within the last 8 hours
   • Indication for oral anticoagulation