RevaceptCS02: Revacept in Symptomatic Carotid Stenosis

• Sponsor: AdvanceCor GmbH (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01645306
• Collaborator: (none)
• Enrollment: 158
• Locations: 12
• Arms: 3
• Actual Duration (Months): 78.5
• Patients Per Site: 13.2
• Patients Per Site Per Month: 0.2

Study Details

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

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 Design

• Study Type: Interventional
• 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: Mar 8, 2013
• Actual Primary Completion Date: Oct 5, 2018
• Actual Study Completion Date: Sep 23, 2019

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. Major Bleedings [90 days after IMP application]

   patients with major bleedings occuring within 90 days after IMP application

3. 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.

4. 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.

5. 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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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.

1. 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)

1. 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

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

Sponsors and Collaborators

• 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

Study Documents (Full-Text)

• Study Protocol - Jun 22, 2015
• Statistical Analysis Plan - Jun 10, 2019

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.
• 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.
• 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.

• Responsible Party: AdvanceCor GmbH
• ClinicalTrials.gov Identifier: NCT01645306
• Other Study ID Numbers: Revacept/CS/02
• First Posted: Jul 20, 2012
• Last Update Posted: Jan 28, 2021
• Last Verified: Jan 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Ischemic Attack, Transient; Carotid Stenosis; Blindness; Amaurosis Fugax; Atherosclerosis; Constriction, Pathologic

Study Results

Participant Flow

Arm/Group Title	Placebo	40 mg Revacept	120 mg Revacept
Arm/Group Description	Phosphate buffered saline (PBS), 1% sucrose, 4% mannitol Placebo: single intravenous injection	40 mg Revacept in phosphate buffered saline (PBS), 1% sucrose, 4% mannitol Revacept: single intravenous injection	120 mg in phosphate buffered saline (PBS), 1% sucrose, 4% mannitol Revacept: single intravenous injection
Period Title: Overall Study
STARTED	51	54	53
COMPLETED	49	50	48
NOT COMPLETED	2	4	5

Baseline Characteristics

Arm/Group Title	Placebo	40 mg Revacept	120 mg Revacept	Total
Arm/Group Description	Phosphate buffered saline (PBS), 1% sucrose, 4% mannitol Placebo: single intravenous injection	40 mg Revacept in phosphate buffered saline (PBS), 1% sucrose, 4% mannitol Revacept: single intravenous injection	120 mg Revacept in phosphate buffered saline (PBS), 1% sucrose, 4% mannitol Revacept: single intravenous injection	Total of all reporting groups
Overall Participants	51	54	53	158
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	67.3 (10.25)	68.7 (10.45)	68.4 (9.82)	68.1 (10.13)
Sex: Female, Male (Count of Participants)
Female	8 15.7%	13 24.1%	17 32.1%	38 24.1%
Male	43 84.3%	41 75.9%	36 67.9%	120 75.9%
Race/Ethnicity, Customized (Count of Participants)
African	1 2%	0 0%	0 0%	1 0.6%
Asian	1 2%	2 3.7%	0 0%	3 1.9%
Caucasian	49 96.1%	52 96.3%	53 100%	154 97.5%
Region of Enrollment (participants) [Number]
United Kingdom	14 27.5%	18 33.3%	18 34%	50 31.6%
Germany	37 72.5%	36 66.7%	35 66%	108 68.4%

Outcome Measures

1. Primary Outcome

Title	New DWI Lesion(s)
Description	The number of new diffusion weighted imaging (DWI) lesion(s) reported. (1 day after intervention compared to baseline).
Time Frame	1 day post intervention

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	40 mg Revacept	120 mg Revacept
Arm/Group Description	Phosphate buffered saline (PBS), 1% sucrose, 4% mannitol Placebo: single intravenous injection	in phosphate buffered saline (PBS), 1% sucrose, 4% mannitol Revacept: single intravenous injection	in phosphate buffered saline (PBS), 1% sucrose, 4% mannitol Revacept: single intravenous injection
Measure Participants	51	54	53
Mean (Standard Deviation) [Number of new lesions]	1.2 (0.4)	1.0 (0.3)	0.6 (0.3)

2. Other Pre-specified Outcome

Title	Patients With Any Stroke or Transient Ischemic Attack (TIA)
Description	patients with any stroke or TIA occuring within 90 days after IMP application.
Time Frame	90 days after IMP application

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	40 mg Revacept	120 mg Revacept
Arm/Group Description	Phosphate buffered saline (PBS), 1% sucrose, 4% mannitol Placebo: single intravenous injection	in phosphate buffered saline (PBS), 1% sucrose, 4% mannitol Revacept: single intravenous injection	in phosphate buffered saline (PBS), 1% sucrose, 4% mannitol Revacept: single intravenous injection
Measure Participants	51	54	53
Count of Participants [Participants]	6 11.8%	6 11.1%	4 7.5%

3. Other Pre-specified Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	40 mg Revacept	120 mg Revacept
Arm/Group Description	Phosphate buffered saline (PBS), 1% sucrose, 4% mannitol Placebo: single intravenous injection	in phosphate buffered saline (PBS), 1% sucrose, 4% mannitol Revacept: single intravenous injection	in phosphate buffered saline (PBS), 1% sucrose, 4% mannitol Revacept: single intravenous injection
Measure Participants	51	54	53
Count of Participants [Participants]	5 9.8%	6 11.1%	4 7.5%

4. Other Pre-specified Outcome

Title	Any Clinical Event
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	40 mg Revacept	120 mg Revacept
Arm/Group Description	Phosphate buffered saline (PBS), 1% sucrose, 4% mannitol Placebo: single intravenous injection	in phosphate buffered saline (PBS), 1% sucrose, 4% mannitol Revacept: single intravenous injection	in phosphate buffered saline (PBS), 1% sucrose, 4% mannitol Revacept: single intravenous injection
Measure Participants	51	54	53
Number [Number of Events]	19	15	10

5. Other Pre-specified Outcome

Title	Anti-Drug Antibodies
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	40 mg Revacept	120 mg Revacept
Arm/Group Description	Phosphate buffered saline (PBS), 1% sucrose, 4% mannitol Placebo: single intravenous injection	in phosphate buffered saline (PBS), 1% sucrose, 4% mannitol Revacept: single intravenous injection	in phosphate buffered saline (PBS), 1% sucrose, 4% mannitol Revacept: single intravenous injection
Measure Participants	51	54	53
Count of Participants [Participants]	0 0%	0 0%	0 0%

6. Other Pre-specified Outcome

Title	Participants With Adverse Events (AEs)
Description	All adverse events were assessed during complete study period (~ 1 year after IMP application).
Time Frame	~ 365 days after IMP application (whole study period)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	40 mg Revacept	120 mg Revacept
Arm/Group Description	Phosphate buffered saline (PBS), 1% sucrose, 4% mannitol Placebo: single intravenous injection	in phosphate buffered saline (PBS), 1% sucrose, 4% mannitol Revacept: single intravenous injection	in phosphate buffered saline (PBS), 1% sucrose, 4% mannitol Revacept: single intravenous injection
Measure Participants	51	54	53
patients with adverse events	35 68.6%	41 75.9%	32 60.4%
patients with drug related AEs	4 7.8%	10 18.5%	2 3.8%
patients with serious AEs	17 33.3%	17 31.5%	15 28.3%
patients with drug related serious AEs	1 2%	4 7.4%	0 0%
patients with AE with fatal outcome events	0 0%	0 0%	1 1.9%

Adverse Events

Time Frame	Adverse Event Data was gathered at a 3 month follow up visit in the clinic and up to one year by a telephone interview.
Arm/Group Title	Placebo		40 mg Revacept		120 mg Revacept
Arm/Group Description	Phosphate buffered saline (PBS), 1% sucrose, 4% mannitol Placebo: single intravenous injection		in phosphate buffered saline (PBS), 1% sucrose, 4% mannitol Revacept: single intravenous injection		in phosphate buffered saline (PBS), 1% sucrose, 4% mannitol Revacept: single intravenous injection
All Cause Mortality
	Placebo		40 mg Revacept		120 mg Revacept
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/51 (0%)		0/54 (0%)		1/53 (1.9%)
Serious Adverse Events
	Placebo		40 mg Revacept		120 mg Revacept
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	17/51 (33.3%)		17/54 (31.5%)		15/53 (28.3%)
Blood and lymphatic system disorders
Anaemia	0/51 (0%)		1/54 (1.9%)		0/53 (0%)
Cardiac disorders
Acute myocardial infarction	2/51 (3.9%)		2/54 (3.7%)		2/53 (3.8%)
Angina pectoris	1/51 (2%)		0/54 (0%)		0/53 (0%)
Bradycardia	0/51 (0%)		0/54 (0%)		1/53 (1.9%)
Cardiac arrest	0/51 (0%)		0/54 (0%)		1/53 (1.9%)
Cardiac failure	0/51 (0%)		0/54 (0%)		1/53 (1.9%)
Cardiogenic shock	0/51 (0%)		0/54 (0%)		1/53 (1.9%)
Coronary artery disease	1/51 (2%)		0/54 (0%)		0/53 (0%)
Myocardial infarction	0/51 (0%)		1/54 (1.9%)		0/53 (0%)
Gastrointestinal disorders
Diverticulum intestinal haemorrhagic	0/51 (0%)		0/54 (0%)		1/53 (1.9%)
Mouth haemorrhage	0/51 (0%)		1/54 (1.9%)		0/53 (0%)
General disorders
Asthenia	1/51 (2%)		0/54 (0%)		0/53 (0%)
Chest discomfort	1/51 (2%)		0/54 (0%)		0/53 (0%)
Chest pain	1/51 (2%)		0/54 (0%)		0/53 (0%)
Infections and infestations
Lower respiratory tract infection	1/51 (2%)		0/54 (0%)		0/53 (0%)
Pneumonia	2/51 (3.9%)		0/54 (0%)		0/53 (0%)
Pyelonephritis	0/51 (0%)		0/54 (0%)		1/53 (1.9%)
Sepsis	0/51 (0%)		0/54 (0%)		1/53 (1.9%)
Urinary tract infection	0/51 (0%)		0/54 (0%)		1/53 (1.9%)
Injury, poisoning and procedural complications
Cerebral hyperperfusion syndrome	0/51 (0%)		1/54 (1.9%)		0/53 (0%)
Fall	2/51 (3.9%)		0/54 (0%)		1/53 (1.9%)
Post procedural haemorrhage	0/51 (0%)		1/54 (1.9%)		0/53 (0%)
Rib fracture	1/51 (2%)		0/54 (0%)		0/53 (0%)
Investigations
Angiocardiogram	0/51 (0%)		1/54 (1.9%)		0/53 (0%)
Biopsy larynx	0/51 (0%)		1/54 (1.9%)		0/53 (0%)
Cardiac clearance	1/51 (2%)		0/54 (0%)		0/53 (0%)
Diffusion-weighted brain MRI	0/51 (0%)		0/54 (0%)		1/53 (1.9%)
Weight decrease	1/51 (2%)		0/54 (0%)		0/53 (0%)
Metabolism and nutrition disorders
Dehydration	1/51 (2%)		0/54 (0%)		0/53 (0%)
Ketoacidosis	0/51 (0%)		0/54 (0%)		1/53 (1.9%)
Type 2 diabetes mellitus	0/51 (0%)		0/54 (0%)		1/53 (1.9%)
Musculoskeletal and connective tissue disorders
Back pain	0/51 (0%)		1/54 (1.9%)		0/53 (0%)
Intervertebral disc prorusion	0/51 (0%)		1/54 (1.9%)		0/53 (0%)
Muscular weakness	0/51 (0%)		1/54 (1.9%)		0/53 (0%)
Osteonecrosis of jaw	0/51 (0%)		1/54 (1.9%)		0/53 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer	0/51 (0%)		0/54 (0%)		1/53 (1.9%)
Glottis carcinoma	0/51 (0%)		1/54 (1.9%)		0/53 (0%)
Laryngeal cancer	0/51 (0%)		1/54 (1.9%)		0/53 (0%)
Lung neoplasm malignant	1/51 (2%)		0/54 (0%)		0/53 (0%)
Malignant melanoma	0/51 (0%)		1/54 (1.9%)		0/53 (0%)
Sarcoma of skin	1/51 (2%)		0/54 (0%)		0/53 (0%)
Nervous system disorders
Aphasia	1/51 (2%)		1/54 (1.9%)		0/53 (0%)
Ataxia	0/51 (0%)		0/54 (0%)		1/53 (1.9%)
Carotid artery stenosis	0/51 (0%)		1/54 (1.9%)		0/53 (0%)
Cerebellar infarction	1/51 (2%)		0/54 (0%)		0/53 (0%)
Cerebral haemorrhage	1/51 (2%)		1/54 (1.9%)		0/53 (0%)
Cerebral infarction	1/51 (2%)		2/54 (3.7%)		1/53 (1.9%)
Cerebral ischemia	2/51 (3.9%)		1/54 (1.9%)		0/53 (0%)
Cerebrovascular accident	0/51 (0%)		1/54 (1.9%)		1/53 (1.9%)
Clumsiness	1/51 (2%)		0/54 (0%)		0/53 (0%)
Dizziness	1/51 (2%)		0/54 (0%)		0/53 (0%)
Epilepsy	0/51 (0%)		1/54 (1.9%)		0/53 (0%)
Headache	0/51 (0%)		1/54 (1.9%)		0/53 (0%)
Hypoaesthesia	1/51 (2%)		0/54 (0%)		0/53 (0%)
Intracranial aneurysm	0/51 (0%)		0/54 (0%)		1/53 (1.9%)
Ischaemic stroke	1/51 (2%)		0/54 (0%)		0/53 (0%)
Loss of consciousness	0/51 (0%)		0/54 (0%)		1/53 (1.9%)
Parkinsonism	1/51 (2%)		0/54 (0%)		0/53 (0%)
Postictal paralysis	1/51 (2%)		0/54 (0%)		0/53 (0%)
Seizure	1/51 (2%)		0/54 (0%)		1/53 (1.9%)
Status epilepticus	0/51 (0%)		1/54 (1.9%)		0/53 (0%)
Stroke in evolution	0/51 (0%)		1/54 (1.9%)		0/53 (0%)
Subarachnoid haemorrhage	1/51 (2%)		0/54 (0%)		0/53 (0%)
Syncope	0/51 (0%)		1/54 (1.9%)		0/53 (0%)
Transient ischaemic attack	2/51 (3.9%)		1/54 (1.9%)		4/53 (7.5%)
Psychiatric disorders
Panic attack	1/51 (2%)		0/54 (0%)		0/53 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/51 (2%)		0/54 (0%)		0/53 (0%)
Pneumonia aspiration	1/51 (2%)		0/54 (0%)		0/53 (0%)
Pulmonary embolism	1/51 (2%)		0/54 (0%)		0/53 (0%)
Surgical and medical procedures
Carotid Endarterectomy	0/51 (0%)		1/54 (1.9%)		1/53 (1.9%)
Chemotherapy	1/51 (2%)		0/54 (0%)		0/53 (0%)
Coronary angioplasty	0/51 (0%)		0/54 (0%)		1/53 (1.9%)
Coronary arterial stent insertion	0/51 (0%)		1/54 (1.9%)		0/53 (0%)
Skin lesion removal	0/51 (0%)		1/54 (1.9%)		0/53 (0%)
Vocal cordectomy	0/51 (0%)		1/54 (1.9%)		0/53 (0%)
Vascular disorders
Circulatory collapse	1/51 (2%)		0/54 (0%)		0/53 (0%)
Hypertensive crisis	0/51 (0%)		0/54 (0%)		1/53 (1.9%)
Hypotension	1/51 (2%)		1/54 (1.9%)		0/53 (0%)
Ischemia	0/51 (0%)		0/54 (0%)		1/53 (1.9%)
Other (Not Including Serious) Adverse Events
	Placebo		40 mg Revacept		120 mg Revacept
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	18/51 (35.3%)		24/54 (44.4%)		17/53 (32.1%)
Gastrointestinal disorders
Nausea	1/51 (2%)		3/54 (5.6%)		1/53 (1.9%)
Vomiting	0/51 (0%)		3/54 (5.6%)		0/53 (0%)
General disorders
Oedama peripheral	2/51 (3.9%)		5/54 (9.3%)		2/53 (3.8%)
Infections and infestations
Pneumonia	4/51 (7.8%)		0/54 (0%)		0/53 (0%)
Urinary tract infection	3/51 (5.9%)		1/54 (1.9%)		2/53 (3.8%)
Injury, poisoning and procedural complications
Fall	3/51 (5.9%)		0/54 (0%)		1/53 (1.9%)
Procedural pain	3/51 (5.9%)		1/54 (1.9%)		2/53 (3.8%)
Investigations
Cardiac murmur	3/51 (5.9%)		1/54 (1.9%)		1/53 (1.9%)
Haemoglobin decreased	1/51 (2%)		3/54 (5.6%)		0/53 (0%)
Musculoskeletal and connective tissue disorders
Pain in extremity	2/51 (3.9%)		3/54 (5.6%)		2/53 (3.8%)
Nervous system disorders
Paraesthesia	0/51 (0%)		1/54 (1.9%)		3/53 (5.7%)
Transient ischaemic attack	2/51 (3.9%)		1/54 (1.9%)		4/53 (7.5%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	3/51 (5.9%)		1/54 (1.9%)		0/53 (0%)
Vascular disorders
Hypertension	4/51 (7.8%)		2/54 (3.7%)		2/53 (3.8%)

Limitations/Caveats

The study was originally planned as primary endpoint study for the evaluation of reduction of micro-embolic signals (MES) by transcranial Doppler (TCD). Therefore MES incidence was a key inclusion criteria at screening. Due to low incidence of MES in this patient population with high screening failure rate the mandatory presence of MES was abandoned during the course of the study. Consecutively the study was changed to an explorative study of the same protocol specified endpoints.

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.