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

• ClinicalTrials.gov Identifier: NCT01645306
• Recruitment Status: Completed
• First Posted: July 20, 2012
• Last Update Posted: December 19, 2019
• Sponsor: AdvanceCor GmbH
• Information provided by (Responsible Party): AdvanceCor GmbH

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Carotid Stenosis; Atherosclerosis; Stroke; Transient-ischaemic Attack; TIA; Amaurosis Fugax	Drug: Revacept; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 158 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: March 8, 2013
• Actual Primary Completion Date: October 5, 2018
• Actual Study Completion Date: September 23, 2019

Arms and Interventions

Arm	Intervention/treatment
Placebo Comparator: Phosphate buffered saline (PBS), 1% sucrose, 4% mannitol	Drug: Placebo; single intravenous injection
Active Comparator: 40 mg Revacept; in phosphate buffered saline (PBS), 1% sucrose, 4% mannitol	Drug: Revacept; single intravenous injection
Active Comparator: 120 mg Revacept; in phosphate buffered saline (PBS), 1% sucrose, 4% mannitol	Drug: Revacept; single intravenous injection

Outcome Measures

Primary Outcome Measures :

1. Assessment of incidence of microembolic signals (MES) [ Time Frame: 24 hours after treatment ]
   In patients with symptomatic carotid artery stenosis who have been treated with Revacept plus antiplatelet monotherapy versus antiplatelet monotherapy alone (placebo). MES will be assessed by transcranial Doppler (TCD) examination.

Secondary Outcome Measures :

1. Change in rate of MES per hour [ Time Frame: 24 hours after treatment ]
2. Assessment of neurological status (NIH Stroke Scale) [ Time Frame: 3 months after treatment ]
3. Cerebral lesion analysis by DWI-NMR [ Time Frame: 1 day after CEA / intervention ]
4. Clinical endpoint rate of all cause death [ Time Frame: up to 12 months after treatment ]
5. Assessment of cardiovascular outcome [ Time Frame: 3 and 12 months ]
   myocardial infarction and re-intervention
6. Change in vital signs [ Time Frame: up to 3 months after treatment ]
7. Change in ECG parameters [ Time Frame: up to 3 months after treatment ]
8. Assessment of anti-drug antibody titres [ Time Frame: up to 3 months after treatment ]
9. Assessment of Adverse Events [ Time Frame: up to 3 months after treatment ]
   including wound healing complications, laboratory abnormalities and use of concomitant medication
10. Where feasible: Assessment of Haemostasis Safety [ Time Frame: up to 3 months after treatment ]
    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
11. Clinical endpoint rate of stroke-related death [ Time Frame: up to 12 months after treatment ]
12. Clinical endpoint TIA, amaurosis fugax or stroke including haemorrhagic stroke [ Time Frame: up to 12 months after treatment ]

Eligibility Criteria

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

Criteria

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)

Contacts and Locations

Locations

Germany

Site 01: Department of Neurology, TU Munich

Munich, Bavaria, Germany, 81675

Site 08: Universitätsklinikum Essen, Klinik für Neurologie

Essen, Germany, 45147

Site 11: Universitätsklinikum Hamburg Eppendorf

Hamburg, Germany, 20246

Site 07: Medizinische Hochschule Hannover, Klinik für Neurologie

Hannover, Germany, 30625

Site 12: Universitätsklinikum Leipzig AöR

Leipzig, Germany, 04103

Site 09: Universitätsmedizin Mainz, Klinik und Poliklinik für Neurologie

Mainz, Germany, 55131

Site 04: Universitätsklinikum Tübingen, Klinik für Allgemeine Neurologie

Tübingen, Germany, 72076

Site 06: Universitätsklinikum Ulm, Abteilung für Neurologie

Ulm, Germany, 89081

United Kingdom

Site 23 - University Hospital Coventry NHS Trust

Coventry, United Kingdom, CV2 2DX

Site 26 - University College London Hospital

London, United Kingdom, NW1 2BU

Site 28 - King's College London Hospital

London, United Kingdom, SE5 8AF

Site 20: St George's NHS Trust

London, United Kingdom, SW17 0QT

Sponsors and Collaborators

AdvanceCor GmbH

Investigators

• Principal Investigator: Holger Poppert, PD Dr. med.; Department of Neurology, TU Munich
• Principal Investigator: Ian M Loftus, MD; St George's NHS Trust

More Information

Publications:

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.

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. doi: 10.1093/cvr/cvn169. 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. doi: 10.1161/CIRCULATIONAHA.110.980623. Epub 2011 Apr 18.

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.

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.

• Responsible Party: AdvanceCor GmbH
• ClinicalTrials.gov Identifier: NCT01645306
• Other Study ID Numbers: Revacept/CS/02
• First Posted: July 20, 2012
• Last Update Posted: December 19, 2019
• Last Verified: December 2019

Additional relevant MeSH terms:

Ischemic Attack, Transient; Carotid Stenosis; Blindness; Amaurosis Fugax; Atherosclerosis; Constriction, Pathologic; Pathological Conditions, Anatomical; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Cardiovascular Diseases; Brain Ischemia; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Carotid Artery Diseases; Vision Disorders; Sensation Disorders; Neurologic Manifestations; Eye Diseases; Signs and Symptoms; Mannitol; Diuretics, Osmotic; Diuretics; Natriuretic Agents; Physiological Effects of Drugs