Clinical trial NCT01645306
Conditions: Carotid Stenosis Atherosclerosis Stroke Transient-ischaemic Attack TIA Amaurosis Fugax
Sponsor: AdvanceCor GmbH
Start date: 2013-03-08; Completion date: 2019-09-23
Enrollment: 158 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

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.

Arms: arm 1: Placebo control with PBS, 1% sucrose and 4% mannitol arm 2: low dose Revacept 40mg in PBS, 1% sucrose, 4% mannitol arm 3: high dose revacept 120mg in PBS, 1% sucrose, 4% mannitol
Interventions: intervention 1: Revacept intervention 2: Placebo
Intervention descriptions: intervention 1: single intravenous injection intervention 2: single intravenous injection

Protocol documents:
Prot_000.pdf: 
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Sponsor:  
advanceCOR GmbH  
 
Fraunhoferstraße 17 
 
D(82152 Martinsried 
 
GERMANY 
Emergency contacts: 
Prof. Dr. med. G. Münch 
 
+49(0)160 / 213 05 92 

 
Coordinating Investigator:  
PD Dr. med. Holger Poppert 
 
Department of Neurology 
 
TU Munich 
 
Klinikum rechts der Isar TU München 
 
Ismaninger Str. 22 
 
D(81675 München 
 
GERMANY 

 
The confidential information in this document is provided to you as an Investigator, a 
potential Investigator or consultant, for review by you, your staff and applicable review 
committee(s). It is understood that the information will not be disclosed to any third 
party without written authorisation from the Sponsor, except to the extent necessary to 
obtain informed consent from those persons to whom the investigational product may be 
administered, or their legally acceptable representative(s). 
 




 
 
 
 


 





 


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By my srgnature b€low, I hereby attest that I have read, discussed and
concemlng the anvesngational product. t have read and discuss€d thls Pr
set out theretn. I agree that the trial shall be cärried out according to ICH I
änd all applicable requlatory reOuirements l accept my obliqations 'elat'nq
rn the ftclaratlon of Helsinki and specifrcally to Independent Ethics Conr
also my obLgätions to advancecoR. or contracted repres€ntatives, as far äs
allowrng monrtoring, auditing, inspection bY domestic and for€ign Regulatory Au
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Revacept in carotid stenosrs
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SIGNATURES
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Protocol Revacept/CS/02 
Revacept in Carotid Stenosis 
Page 3 of 52
Version 8 (22.06.2015)
 
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AMENDMENT HISTORY ................................................................................................................................................................................. 4 
SYNOPSIS .......................................................................................................................................................................................................... 5 
LIST OF ABBREVIATIONS ............................................................................................................................................................................ 9 
1. 
STUDY ADMINISTRATIVE STRUCTURE ................................................................................................................................... 10 
1.1. 
Sponsor Details ............................................................................................................................................................... 10 
1.2. 
Coordinating Investigator ........................................................................................................................................... 10 
1.3. 
Data Safety Monitoring Board ................................................................................................................................... 10 
2. 
INTRODUCTION AND STUDY RATIONALE .............................................................................................................................. 12 
3. 
STUDY ENDPOINTS ........................................................................................................................................................................ 15 
4. 
ETHICAL CONSIDERATIONS ....................................................................................................................................................... 15 
4.1. 
Good Clinical Practice ................................................................................................................................................... 15 
4.2. 
Independent Ethics Committee (IEC) ..................................................................................................................... 16 
4.3. 
Patient information and consent ............................................................................................................................... 16 
5. 
INVESTIGATIONAL PLAN .............................................................................................................................................................. 18 
5.1. 
Study Design and Duration ........................................................................................................................................ 18 
5.2. 
Study Population ............................................................................................................................................................ 19 
6. 
TREATMENT ...................................................................................................................................................................................... 21 
6.1. 
Study Treatment ............................................................................................................................................................ 21 
6.2. 
Blinding/Unblinding ....................................................................................................................................................... 23 
6.3. 
Supportive Care .............................................................................................................................................................. 23 
6.4. 
Treatment Compliance ................................................................................................................................................. 24 
7. 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................................................................... 24 
7.1. 
Procedures by visit ........................................................................................................................................................ 24 
7.2. 
Details of Study Procedures ....................................................................................................................................... 28 
7.3. 
Safety Assessments ...................................................................................................................................................... 32 
8. 
ADVERSE EVENTS........................................................................................................................................................................... 33 
8.1. 
Definitions ......................................................................................................................................................................... 33 
8.2. 
Assignment of Adverse Event Intensity and Relationship to Investigational Product ........................... 35 
8.3. 
Collection and Reporting ............................................................................................................................................. 37 
8.4. 
Laboratory Test Abnormalities .................................................................................................................................. 39 
8.5. 
Overdose ........................................................................................................................................................................... 39 
8.6. 
Pregnancy ......................................................................................................................................................................... 39 
8.7. 
Other Safety Considerations ...................................................................................................................................... 40 
9. 
STATISTICAL CONSIDERATIONS .............................................................................................................................................. 41 
9.2. 
Data Management.......................................................................................................................................................... 41 
9.3. 
Statistical Procedures ................................................................................................................................................... 42 
9.4. 
Final Statistical Analysis Plan ..................................................................................................................................... 43 
9.5. 
Quality Control ................................................................................................................................................................ 43 
10. 
ADMINISTRATIVE SECTION ........................................................................................................................................................ 44 
10.1. 
Investigational Site Training ...................................................................................................................................... 44 
10.2. 
Allocation of Responsibilities ...................................................................................................................................... 44 
10.3. 
Curriculum Vitae (CV) .................................................................................................................................................. 44 
10.4. 
Subject Insurance .......................................................................................................................................................... 44 
10.5. 
Study Participation Card an GP Information Letter ........................................................................................... 44 
10.6. 
Data management and analysis ............................................................................................................................... 44 
10.7. 
Compliance ....................................................................................................................................................................... 45 
10.8. 
Direct Access to Source Data/Documents ............................................................................................................ 46 
10.9. 
Audit and Inspection ..................................................................................................................................................... 46 
10.10. Termination of the Trial ............................................................................................................................................... 47 
10.11. Archiving and Data Retention .................................................................................................................................... 47 
10.12. Publications ...................................................................................................................................................................... 48 
10.13. Investigator Site File ..................................................................................................................................................... 49 
10.14. Data Handling and Record Keeping ......................................................................................................................... 49 
APPENDIX A: SCALES FOR NEUROLOGICAL STATUS ...................................................................................................................... 50 
APPENDIX B: DEFINITIONS OF CLINICAL EVENTS .......................................................................................................................... 51 
References....................................................................................................................................................................................................... 52 

 
 
 
 
 


Protocol Revacept/CS/02 
Revacept in Carotid Stenosis 
Page 4 of 52
Version 8 (22.06.2015)
 
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(03.11.2011) 
• 
Document created
	./-+
(24.11.2011) 
• 
Section 5.2.2: 
o 
Effective birth control is no longer mandatory for sexually active fertile men who 
are partners of women of childbearing potential 
• 
Section 6.1.3: 
o 
Deletion of IMP labelling example 
• 
Section 7.1 & 7.1.4: 
o 
Time frame of visit 4 changed from “treatment + 3 days ((48 hrs /+5 days)” to 
“treatment + 3 days ((69 hrs /+5 days)” 
	./-
(09.01.2012) 
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• 
Section 1.3 & 5.1: 
o 
The data safety monitoring board will monitor patient safety more thoroughly 
o 
The first 10 patients will complete the in(patient phase sequentially at a single 
study centre 
• 
Section 10.12.2: Corimmun abstains from holding overall right to veto publications and 
presentations.  
	./-1
(22.02.2012) 
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• 
Section synopsis and 5.2.2: 
o 
Stricter eligibility criterion for enrolment of hypertensive patients implemented and 
statement on management of hypertension added 
o
Stricter eligibility criterion for ECG abnormalities implemented 
	./-2
(16.05.2012)
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• 
Section 6.1.6: An in(line filter must be inserted in the syringe pump infusion line during 
treatment administration. 
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• 
Section 6.1.7 and 6.2: Emergency unblinding will be performed using the web(based online 
randomisation tool. 
• 
Section 7.2.12: ADP and TRAP concentrations no longer specified due to use of different 
instruments at individual study sites
	./-3
(26.06.2012)
• 
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(28.09.2012)
• 
Section Synopsis, 	4	5	6	/.7'		8--	-/40	9'-(	-6	(	-:, 7.1, 7.2.12: 
PFA100 and/or platelet aggregation will be performed at all sites capable of performing the 
said analysis. 
• 
Section 5.1: Sequential treatment of the first 10 patients is not restricted to a single study 
site. 
• 
Section 5.2.2: Patients who have received tirofiban/Aggrastat are eligible for study 
participation 8 hours after receiving the said anti(platelet agent
	./-;:+
(15.04.2013) 
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• 
Section synopsis, 	4	5	6	/.7'		8--	-/40	9'-(	-6	(	-:, 7.2.6 and 
Appendix A: Amaurosis fugax assessed as secondary endpoint 
• 
Section synopsis, 5.2.1 and 6.1.7:  
o 
European Carotid Surgery Trial (ECST) criteria used for grading of carotid stenosis 
(instead of North American Symptomatic Carotid Endarterectomy Trial criteria) 
o 
Patients with Amaurosis fugax (subgroup of TIA) included in study population 
o 
Flow velocity not assessed as inclusion criterion  
• 
Section 7.2.10: Troponin may be determined instead of CK 

!"	
• 
Section 1.3: Change of address of DSMB member 
• 
Section synopsis and 5.1: Wording ‘carotid endarterectomy’ changed to more general 
definition of intervention 
• 
Section synopsis, 5.2.1 and 6.1.7: 
o 
Wording of exclusion criterion haemorrhagic transformation corrected 
• 
Section synopsis, 7.1 and 7.2.5: Wound healing complications included in general 
assessment of adverse events 
• 
Section 7.2.7: Change of address of TCD core lab 
• 
Several locations throughout document:  
o
thrombocyte function may be analysed by PFA(100 or newer PFA(200 device 
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(08.08.2013)
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•
Section 8.3.1: Update of SAE fax number 
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(12.09.2013)
• 
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(22.07.2014)
• 
		5.2.2: Modification of eligibility criteria$
•
Section 1.3: Change of DSMB meeting interval 
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(22.06.2015)
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Protocol Revacept/CS/02 
Revacept in Carotid Stenosis 
Page 5 of 52
Version 8 (22.06.2015)
 
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)	9-.!
 
advanceCOR GmbH 
Fraunhoferstraße 17  
D(82152 Martinsried 
Germany 
(/-/-0-
	./0!
PD Dr. med. Holger Poppert 
Department of Neurology 
TU München 
Ismaninger Str. 22 
D(81675 München 
Germany 
/	9.'(=!
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. 

/(	-/9//->(	-')*	?!
Revacept/CS/02 
 
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99/=*A	/
	.are: 
• 
Assessment of incidence of microembolic signals (MES) by transcranial Doppler 
(TCD) examination  (before and after treatment) 
• 
Rate of MES per hour (before and after treatment) 
• 
Cerebral lesion analysis by DWI(NMR  
• 
Assessment of neurological status (NIH Stroke Scale) 
• 
Clinical endpoints will be summarised cumulatively i.e. before treatment, after 
treatment, at 3 months and at 12 months. The following endpoints will be 
recorded: 
o 
Rate of all cause death 
o 
Rate of stroke(related death 
o 
Any TIA, amaurosis fugax or stroke including haemorrhagic stroke 
• 
Assessment of cardiovascular outcome including myocardial infarction and re(
intervention up to 3 and 12 months 



Protocol Revacept/CS/02 
Revacept in Carotid Stenosis 
Page 6 of 52
Version 8 (22.06.2015)
 
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9	= *A	/
	. are to investigate whether Revacept compared to placebo induces 
adverse and serious adverse events.  
Haemostasis will be closely monitored by assessing: 
• 
laboratory parameters indicating thrombocytopenia and bleeding according to the 
RE(LY study group criteria  
• 
where feasible: in vitro platelet function with collagen, TRAP and ADP(mediated 
platelet aggregation and in vitro bleeding time by PFA(100 / PFA(200 
4)8/-	/. of Revacept with respect to drug interaction with other antiplatelet 
drugs will also be assessed by determining plasma concentrations at various time points 
after administration of study medication for approximately 20 % of patients. 
 
 	4(0=!
Multicentre, randomised 2:1, double(blind, placebo controlled, parallel groups, analysis. 
Blinded evaluation of efficacy and safety endpoints. 
 
	)	-	0/)	!
Patients suffering from symptomatic carotid artery stenosis, transient ischemic attacks 
(TIAs), amaurosis fugax or stroke receive either Revacept (single dose) plus antiplatelet 
monotherapy (Aspirin or Clopidogrel) 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. 

	)	-%'.!
150 patients currently receiving standard therapy (aspirin p.o. or  Clopidogrel) plus one 
intravenous injection of: 
• 
Placebo (50 patients) 
• 
40 mg Revacept (50 patients) 
• 
120 mg Revacept (50 patients)  


Protocol Revacept/CS/02 
Revacept in Carotid Stenosis 
Page 7 of 52
Version 8 (22.06.2015)
 
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 /-/-'./-/	/
• 
Male and female patients aged >18 years 
/0-./.
• 
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 
 
 /-	B'./-/	/!
0	(/.	.		B	/-
• 
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) 
 	(/4/.=-(-'	-(/.	.	
• 
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/µl), bleeding diathesis or 
coagulopathy (pathological international normalised ratio (INR) or activated partial 
thrompoplastin 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 µmol/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)



Protocol Revacept/CS/02 
Revacept in Carotid Stenosis 
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Trial duration per subject will be approximately 6 days. Both treatment and control groups 
are invited for a 3 months follow up visit and a 12 months follow up telephone interview. 
 
'/-9.'(=! The study was initiated in August 2012. The proposed study end is 
2017.  
/./)	4(.!
 
Since this is an exploratory study, no formal statistical hypothesis testing will be 
conducted. Descriptive summary of efficacy and safety data will be provided and the data 
from this study may be combined and analysed with data from future studies. 
 
 


Protocol Revacept/CS/02 
Revacept in Carotid Stenosis 
Page 9 of 52
Version 8 (22.06.2015)
 
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
 
ADP 
Adenosine Diphosphate 
AE 
Adverse event 
ANCOVA 
Analysis of Covariance 
ANOVA 
Analysis of Variance 
ASA 
Acetyl(Salicylic Acid 
aPTT 
Activated partial 
thromboplastin time  
BfArM 
Bundesministerium für 
Arzneimittel und 
Medizinprodukte 
BMBF 
Bundesministerium für 
Bildung und Forschung 
BP 
Blood pressure 
bpm 
beats per minute 
 
CRF 
Case Report Form 
CRP 
C(reactive protein 
CT scan 
Computerised Tomography 
scan 
CV 
Curriculum Vitae 
D or d 
Day 
DAT 
Digital Audio Tape 
DLR 
Deutsches Zentrum für 
Luft( und Raumfahrt 
DQF 
Data Query Form 
DSMB 
Data Safety Monitoring 
Board 
DWI 
Diffusion(Weighted 
Imaging 
ECST 
European Carotid Surgery 
Trial 
ECG 
Electrocardiogram 
EDTA 
Ethylene diamine tetra(
acetate 
ESR 
Expedited Safety Report 
EU 
European Union 
FSH 
Follicle Stimulating 
Hormone 
FWER 
Family(wise Error Rate 
GCP 
Good Clinical Practice  
GI 
Gastro(Intestinal 
GP 
General Practitioner 
Hr or hrs 
hour or hours 
ICA 
Internal Carotid Artery 
ICH 
International Conference of 
Harmonisation 
IEC 
Independent Ethics 
Committee 
IMP 
Investigational Medicinal 
Product 
INR 
International normalisation 
ratio 
ITT 
intention(to(treat 
LMWH 
Low Molecular Weight 
Heparin 
MACE 
Major Adverse Cardiac 
Event 
MCA 
Middle Cerebral Artery 
MES 
MicroEmbolic Signals 
MI 
Myocardial Infarction 
MRI 
Magnetic Resonance 
Imaging 
MRT 
Mean residence time  
MTD 
maximum tolerated dose 
NA 
Not applicable 
NAV 
Not available 
ND 
Not done 
NIHSS 
National Institute of Health 
Stroke Scale 
OAC 
Oral Anti(Coagulant 
PP 
Per Protocol 
PPP 
Platelet Poor Plasma 
PRP 
Platelet Rich Plasma 
PT 
Prothrombin time 
RBC 
Red Blood Cell 
RRR 
Relative Risk Reduction 
SAE 
Serious adverse event 
SOC 
System Organ Class 
SUSAR 
Suspected Unexpected 
Serious Adverse Event 
TAT 
Thrombin(Antithrombin III 
TCD 
TransCranial Doppler 
TIA 
Transient Ischaemic Attack 
tmax 
Time to Cmax 
UFH 
UnFractionated Heparin 
WBC 
White Blood Cell 
WOCBP 
Women of Childbearing  
 
Potential
 


Protocol Revacept/CS/02 
Revacept in Carotid Stenosis 
Page 10 of 52
Version 8 (22.06.2015)
 
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	
	
 
The sponsor of the investigation is: 
advanceCOR GmbH 
Fraunhoferstraße 17  
D(82152 Martinsried 
GERMANY 
 
 
		
 
The Coordinating Investigator for the investigation is: 
PD Dr. med. Holger Poppert 
Department of Neurology 
TU München 
Ismaninger Str. 22 
D(81675 München 
Germany 
 
Vascular surgery advisor: 
 
Prof. Dr. Hans(Henning Eckstein 
 
Klinik und Poliklinik für Gefäßchirurgie 
Ismaningerstr. 22 
81675 München 
 
Germany 
 
 

				
 
The Data Safety Monitoring Board (DSMB) will consist of a statistician together with two  
independent neurologists who are scientifically well qualified, and who have personal 
experience of large multicentre studies and data monitoring activities.  
 
Chairman:  
 
 
Prof. Dr. med. H. C. Diener 
 
Hufelandstr. 55 
D(45147 Essen 
Tel.: +49(0) 201 723(2460  
Fax: +49(0) 201 723(5901 
 
Members:  
 
 
Prof. Dr. Steffen Massberg  
 
 
Marchioninistraße 15 
 
 
81377 München 
Tel.: +49(0) 89 7095(2371  
Fax: +49(0) 89 7095(8870 
 
Prof. Dr. rer. nat. Ulrich Mansmann 
 
Marchioninistr. 15 
 
D(81377 München 
Tel.: +49(0) 89 7095(4490  
Fax: +49(0) 89 7095(7491 
 
The DSMB will hold regular meetings to review data concerning safety, efficacy and study 
performance. Unblinded data describing clinical endpoints, adverse events and laboratory 
values are to be compiled for these meetings by d.s.h. statistical services. The DSMB will 


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inform and advise the sponsor of all findings with regard to safety, efficacy and study 
performance. Review of data can lead the DSMB to a recommendation to the sponsor to 
stop the study. Minutes of Committee meetings will be recorded and filed. A special 
charter for the DSMB evaluation will be available. In accordance to GCP(V §13, SUSARS 
will be reported to the ethics committee, regulatory authority and the DSMB. If serious 
adverse events are more common in the experimental arm compared to the control arm 
the risk/benefit consideration will be reassessed. The Committee will inform the sponsor in 
writing if the frequency of serious adverse events including deaths exceeds 8 percent in 
one of the groups, and will advise concerning appropriate actions.  
 
 
The first safety analysis will be performed by the DSMB once 10 patients have completed 
visit 5. The first 10 patients will be treated sequentially, e.g. only one patient is 
randomised at a time. The next patient will be randomised only once the first patient has 
completed visit 5 and no suspected unexpected serious adverse event has occurred (see 
also section 5.1). In addition, patient randomisation will be stopped by advanceCOR each 
time a serious adverse event occurs which is unexpected and possibly related to the study 
medication (SUSAR, see also section 8.3.2). Patient randomization will be resumed only if 
recommended by the DSMB. Thereafter, the DSMB will perform safety analysis at least 
annually.  
 
 


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: ""
 
Evidence supporting the idea that microemboli accompany transient ischaemic attacks 
(TIAs), amaurosis fugax and stroke is rapidly accumulating and it is now generally 
accepted that such microemboli originate at the site of vascular stenosis (Sitzer et al., 
1995, Siebler et al., 1992). These microemboli are made up of platelet aggregates that 
form by two major mechanisms. Firstly, when atherosclerotic plaques ulcerate and 
rupture, subendothelial tissues expose factors of high platelet(activating potential. 
Secondly, platelet adhesion and activation at the site of stenosis is greatly facilitated by 
increased shear stress resulting from blood flow turbulences in atherosclerotic vasculature 
(Lassila et al., 1990).  
 
In patients with symptomatic stenoses of the internal carotid artery (ICA), a large number 
of microemboli enter the cerebral circulation, thereby potentially producing a symptomatic 
clinical event. They can be detected by Transcranial Doppler (TCD) in the form of 
characteristic microembolic signals (MES) (Ringelstein et al. 1998). Several studies have 
demonstrated that the incidence of MES is a potent prognostic factor for prediction of 
future strokes and TIAs in patients with systematic stenosis, i.e. the risk being 8 to 31 fold 
higher for MES positive patients than for MES negative patients (Valton et al., 1998, 
Molloy et al. 1999, Siebler et al., 1995). 
 
Patients suffering a TIA or stroke are at 30(35 % risk of suffering recurrent stroke within 
the next 5 years and are advised to undergo vascular surgery in order to reduce the risk 
of future brain infarction (NASCET Collaborators 1991). In addition to surgical carotid 
endarterectomy (CEA), administration of antiplatelet agents also favours event free 
survival and reduces MES frequency in patients undergoing carotid endarterectomy (CEA) 
(Molloy et al., 1998) and in patients with symptomatic carotid stenosis (Goertler et al., 
1999).  
 
Although current antiplatelet agents do reduce the risks for recurrent stroke during and 
after CEA, their use is associated with potentially life(threatening bleeding complications. 
It is therefore highly desirable to develop novel therapeutic strategies that selectively 
inhibit thromboembolisation at the site of vascular stenosis whilst not compromising 
systemic haemostasis.  
 
Such selectivity can be achieved by targeting structures that differ between healthy and 
atherosclerotic vasculature. Collagen is an important component of the extracellular 
matrix of arterial walls and thus shielded from the blood stream by the vascular 
endothelium 
under 
normal 
conditions. 
Upon 
vascular 
injury 
or 
atherosclerotic 
transformation, however, collagen becomes increasingly exposed to the arterial lumen 
where it triggers platelet aggregation by activating the GPVI receptor on thrombocytes 
(Nieswandt et al., 2003). By masking collagen exposure to the blood stream at the site of 
atherosclerotic plaques rather than directly inhibiting thrombocytes, one could prevent 
local thrombosis without jeopardising systemic platelet functions and coagulation, which is 
the strategy investigated in this clinical trial. Revacept is a protein that is made up of an 
Fc (fragment crystallisable) fragment fused to the GPVI receptor (an endogenous platelet 
collagen 
receptor). 
Consequently, 
Revacept 
binds 
to 
its 
ligand 
(collagen) 
on 
atherosclerotic plaques preventing circulating thrombocytes from binding to collagen 
exposed by the injured plaque, most importantly not impairing general thrombocyte 
activity in animal models (Massberg et al., 2004). 
 
The mode of action of Revacept was studied in animal models in great detail (Massberg et 
al., 2004, Schönberger et al., 2008, Bültmann et al., 2010). When arterial lesions were 
induced in mice models of atherosclerosis, Revacept was effective at preventing platelet 
adhesion and thrombus formation at these sites without affecting bleeding time. 
Furthermore, bleeding times were not increased when Revacept was combined with 


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conventional antiplatelet agents such as ASA, clopidogrel and heparin. Furthermore, 
Revacept is characterised by a promising pharmacovigilance profile with no toxicities or 
signs of aberrant immune activation detected in preclinical animal studies even after 
repeated dosing (see Investigator Brochure for more detailed information).  
 
Following these encouraging preclinical studies, safety and tolerability of Revacept was 
investigated in a first(in(man study (Ungerer et al., 2011). In a phase I clinical trial, 30 
male human volunteers received a single intravenous dose of Revacept ranging between 
10(160 mg. All investigated doses were well tolerated and no drug(related side effects 
occurred. Moreover, no anti(Revacept antibodies were produced and favourable 
pharmacokinetic and pharmacodynamic profiles were observed. In summary, results from 
both preclinical studies and the phase I clinical trial constitute a solid basis for proceeding 
to a clinical trial in the target patient population. The study presented here aims to 
demonstrate both safety and evidence of efficacy of Revacept treatment in patients 
suffering from symptomatic carotid stenosis.  
 
.	.		/-/-	
Detailed 
background 
information 
on 
preclinical 
pharmacology, 
pharmacokinetics, 
toxicology and on the phase I clinical study of Revacept is provided in the Investigator 
Brochure. When 10 – 160 mg Revacept were administered during a phase I clinical trial, 
maximal pharmacodynamic effects were measured ex vivo, starting at 40 mg, and no 
drug(related adverse events occurred. Pharmacokinetic studies demonstrated that the 
area under the curve and maximum concentration proportionally increased with higher 
dose levels. Because no maximum tolerated dose (MTD) was defined for the adult 
population and with data generated during preclinical and phase I studies we propose that 
maximal therapeutic effect is achieved with low to medium doses of Revacept (40 mg and 
120 mg).  
 

	/.8*	-	9/..	..)	-
 
Revacept is a novel therapeutic agent that potently inhibits platelet aggregation at the site 
of atherosclerotic plaques without compromising systemic coagulation in animal models 
and healthy volunteers. No toxicities were observed during preclinical studies and no 
adverse reactions were observed when Revacept was administered to healthy human 
volunteers. Consequently, safety concerns are limited to adverse reactions specific to the 
target patient population and rare side effects.  
 
As for all antiplatelet drugs, it cannot be entirely excluded at this stage of development 
that Revacept could potentially increase bleeding propensity. Especially the likelihood of 
bleeding problems might occur in combination with multiple anti(thrombotic or antiplatelet 
drugs. In order to keep this risk low, concomitant oral anticoagulation and antiplatelet 
drugs other than anti(thrombotic monotherapy with Aspirin or Clopidogrel are prohibited 
in this study. 
 
The immunogenicity of Revacept is judged to be considerably low, as its components are 
naturally occurring in the human body and should hence be recognised as ‘self’. As for all 
therapeutic proteins, there is residual risk for Revacept triggering an aberrant immune 
reaction.  Potential allergic responses may produce mild symptoms such as skin rashes 
and flue(like symptoms but also severe and potentially life(threatening reactions such as 
anaphylactic shocks. In order to minimise the risk of acute allergic reactions, patients with 
a history of allergic responses to intravenously administered drugs will be excluded from 
study participation. Furthermore, all patients will remain under medical supervision for 24 
hours after receiving study medication. 
 
Although the risk for production of anti(drug antibodies is low for single dose application, 
anti(Revacept autoantibodies could potentially cross(react with circulating platelets. For 
minimisation of this risk, patients with a known history of thrombocytopenia will not be 


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allowed to participate in this study. Furthermore, platelet counts and bleeding time will be 
closely monitored throughout the trial and  blood samples for determination of anti(drug 
antibodies will be collected before and 3 months after exposure to study treatment.  


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1: "
 
The 	99/=	-(/-.are: 
• to evaluate whether the incidence of preoperative microembolic signals (MES) is 
reduced in patients with symptomatic carotid artery stenosis who have been 
treated with Revacept plus antiplatelet monotherapy (aspirin or clopidogrel) 
versus antiplatelet monotherapy alone (placebo). MES will be assessed by 
transcranial Doppler (TCD) examination.(before and after treatment) 
• 
Rate of MES per hour (before and after treatment) 
• 
Assessment of neurological status (NIH Stroke Scale) 
• 
Cerebral lesion analysis by DWI(NMR and correlation to neurological status (before 
and after treatment) 
• 
Clinical endpoints will be summarised cumulatively i.e. before treatment, one and 
three days after treatment, at 3 months and at 12 months. The following endpoints 
will be recorded: 
o 
Rate of all cause death 
o 
Rate of stroke(related death 
o 
Any TIA, amaurosis fugax or stroke including haemorrhagic stroke 
• 
Assessment of cardiovascular outcome including myocardial infarction and re(
intervention up to 3 and 12 months 
 
Safety objectives 
To assess safety, adverse events will be continuously recorded and be overseen by an 
independent Data Safety Monitoring Board (see section 1.3).  
 
Safety will be summarised by treatment group and include the following: 
• 
Vital signs 
• 
ECG parameters 
• 
Anti(drug antibody titres  
• 
Reporting AEs including wound healing complications, laboratory abnormalities and 
use of concomitant medication 
• 
Haemostasis will be closely monitored by assessing: 
o 
laboratory parameters indicating thrombocytopenia and bleeding according 
to the RE(LY study group criteria  
o 
where feasible: in vitro platelet function with collagen, TRAP and ADP(
mediated platelet aggregation and in vitro bleeding time by PFA(100 / PFA(
200 
 
 
2: 
 
			
 
 
The investigation will be performed in accordance with the Declaration of Helsinki (1996), 
Good Clinical Practice (GCP), as defined by the International Conference on Harmonisation 
(ICH), in accordance with the ethical principles underlying European Directive 2001/20/EC 
and applicable local laws and regulations, in particular, the German GCP(Verordnung and 
Arzneimittelgesetz. 
 
The study will be conducted in compliance with the protocol. The protocol and any 


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amendments and the subject informed consent will receive approval/favourable opinion of 
the German Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM) (corresponding 
regulatory authority) and Independent Ethics Committee (IEC) prior to initiation of the 
study.  
 
All potential serious breaches must be reported to advanceCOR GmbH immediately. A 
serious breach is a breach of the conditions and principles of GCP in connection with the 
study or the protocol, which is likely to affect, to a significant degree, the safety, physical 
or mental integrity of the subjects of the study or the scientific value of the study. 
 
Study personnel involved in conducting this clinical trial will be qualified by education, 
training, and experience to perform their respective task(s). Systems with procedures that 
assure the quality of every aspect of the study will be implemented. 
 
This study will not use services of study personnel where sanctions have been invoked or 
where there has been scientific misconduct or fraud (e.g. loss of medical licensure, 
debarment). 
 
 
 
	 	!!	"#	
 
It is the responsibility of the Principal Investigator to obtain approval of the investigation 
plan/ amendments from the IEC and Regulatory Authorities according to local regulatory 
requirements. The Principal Investigator should file all correspondence with the IEC.  
The Principal Investigator is responsible for keeping the IEC informed of the progress of 
the investigation and of any subsequent modifications to the protocol as deemed 
appropriate. This should be performed at least once annually. The Principal Investigator 
must also keep the IEC informed of any serious adverse reactions according to local 
regulatory requirements. In addition, the patient informed consent (or other appropriate 
document) should allow for release of the patient records for investigation documentation 
purposes.  
 
 
	!			
  
It is the responsibility of the Investigator to give each patient (or the patient’s legally 
responsiblerepresentative), prior to inclusion in the investigation, full and adequate verbal 
and written information regarding the objective and procedures of the study and the 
possible risks involved. Written informed consent must be obtained at screening in 
accordance with good clinical practice and local legislation prior to enrolment and 
randomisation. 
 
After the written informed consent form and any other written information has been read 
and explained to the patient, the patient will sign and personally date the informed 
consent form. By signing the consent form, the patient attests that the information in the 
consent form and any other written information was accurately explained and apparently 
understood, and that the patient freely gave the informed consent. In addition, the 
Investigator who obtains the consent must signand date the consent form. 
 
The patients must be informed of their right to withdraw from the investigation at any 
time. Signed consent forms must remain in the Investigator Site File and must be 
available for verification by study monitors or local authorities at any time. 
 
The informed consent and any other information provided to subjects, or, in those 
situations where consent cannot be given by subjects, the subject's legally acceptable 
representative, should be revised whenever important new information becomes available 


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that is relevant to the subject's consent, and should receive IEC approval/favourable 
opinion prior to use. The Investigator, or a person designated by the Investigator should 
fully inform the subject or the subject's legally acceptable representative of all pertinent 
aspects of the study and of any new information relevant to the subject's willingness to 
continue participation in the study. This communication should be documented. During a 
subject's participation in the study, any updates to the consent form and any updates to 
the written information will be provided to the subject. 


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3: %
 
$ 
%	
		
%	
 
This is a double(blind, placebo(controlled, randomised phase II study. Eligible subjects will 
be randomised to one of three treatment groups, receive study treatment and undergo 
endpoint evaluations. Follow ups are scheduled one and three days after treatment, 3 and 
12 months. 
 
The first 10 patients will be treated sequentially, e.g. only one patient is randomised at a 
time. The next patient will be randomised only once the first patient has completed visit 5 
and no suspected unexpected serious adverse event has occurred. Prior to randomisation 
of a new subject, the Investigators must ensure that the patient randomised previously 
has completed visit 5 and not suffered a suspected unexpected serious adverse event. 
Once the first 10 patients have completed the sequential phase and the DSMB has 
recommended continuing the trial, parallel recruitment may start (see also section 1.3).   
 
The study is conducted at a minimum of three study centres which will screen and recruit 
150 eligible patients. During the recruitment period, each study centre is expected to 
provide the capacity and willingness to recruit at least 20 patients. There will be a 
competitive recruitment of patients, which means that some hospitals will enrol more than 
20 patients and some less. 
 
However, if a study centre randomises less than 3 patients in 9 months, further 
recruitment of patients may be stopped because the quality of a study is dependent on 
the number of patients per centre. Very few patients in a centre might be related to a 
higher rate of missing data or patient visits and a higher withdrawal rate. 
 
The centres should have solid experience in clinical research and profound knowledge of 
GCP. Moreover, participating Investigators should have special interest in studying 
patients with carotid stenosis. 
 
 
 
 
 
 
 
 
 
 
Placebo
40 mg Revacept
120 mg Revacept
R
follow up
endpoint 
 
150 patients 


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$ 
%	%	
 
It is imperative that subjects fully meet all eligibility criteria.  
 
$ %		
For entry into the study, the following criteria MUST be met: 
+?/0-	(6/	-/-9)	(-.	-
?0	'/-
 
?/0-./.!
• 
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 

*?0	-(.	B! 	--(6)	-0	(C+<=	.
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. 
 
WOCBP include any female who has experienced menarche and who has not undergone 
successful surgical sterilisation (hysterectomy, bilateral tubal ligation, or bilateral 
oophorectomy) or is not postmenopausal. Post menopause is defined as: 
• 
Amenorrhea ≥ 12 consecutive months without another cause or 
• 
For women with irregular menstrual periods and on hormone replacement therapy 
(HRT), a documented serum follicle stimulating hormone (FSH) level > 35 mIU/mL 
 
Women who are using oral contraceptives, other hormonal contraceptives (vaginal 
products, skin patches, or implanted or injectable products), or mechanical products such 
as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to 
prevent pregnancy, or are practicing abstinence or where their partner is sterile (e.g. 
vasectomy) should be considered to be of childbearing potential. WOCBP must have a 
negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units 
of HCG) within 72 hours prior to the start of study intervention. 
 
 
$ &%		
Subjects must not be included for any of the following reasons: 
 
+?	B-(	('/
	'.!
• 
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 enrolment or prior to investigational 
product administration. 
 
?0	(/.	.		B	/-.
• 
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 


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heart valves) 
 
1? 	(/4/.=-(-'	-(/.	.	
• 
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/µl), bleeding diathesis or 
coagulopathy (pathological international normalised ratio (INR) or activated partial 
thrompoplastin 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), 
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 µmol/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)
 
 
2?4	B'./-/	/
• 
Inability to provide informed consent (except for patient’s legally responsible
representative) 
• 
Acoustic window that does not allow for TCD recording 
• 
Participation in any other interventional study within less than 30 days prior to 
screening  
• 
Suspected poor capability to follow instructions and cooperate 
• 
Prisoners or subjects who are involuntarily incarcerated 
• 
Subjects who are compulsorily detained for treatment of either a psychiatric or 
physical illness (e.g. infectious disease)  
• 
Ongoing drug or alcohol abuse 
 
$ 
%	 	 %'(	 !	 )!	 	 %	
	
 
If a subject was withdrawn before completing the study, then the reason for withdrawal 
must be entered on the appropriate case report form (CRF) page. 
 
Subjects will be withdrawn from the study for the following reasons: 
 
• 
withdrawal of consent by the subject for any reason at any time 
• 
if continued study participation is not in the best interest of the subject, as judged by 
the Investigator (e.g. due to clinical adverse event (AE), laboratory abnormality or 
intercurrent illness) 


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• 
Termination of the study by advanceCOR GmbH, regulatory authorities or ethics 
committee 
• 
Subjects, who become prisoners, involuntarily incarcerated or compulsorily detained 
for treatment of either a psychiatric of physical (e.g. Infectious disease) illness 
 
Patients who discontinue study participation prior to visit 6 for any reason will be invited 
to skip to follow up visit 6.  
$ *+,%		
%	%'(	
 
If the reason for withdrawal is a serious Adverse Event (SAE), the Investigator will follow 
the case up to resolution and provide advanceCOR with a final report of this SAE or justify 
why no final report will be provided.  
 
 
,:  
 
- 
%	)!	
 
In this protocol, the investigational products are Revacept and placebo (phosphate 
buffered saline, 1% sucrose, 4% mannitol). 
 
- .	%	
Other medications used in the study as support or escape medication for preventative, 
diagnostic, or therapeutic reasons, as components of the standard of care for a given 
diagnosis, are considered non(investigational products. 
 
- %		%	!	
Manufacturing of drug substance and filling of IMP vials is subcontracted to Glycotope 
Biotechnology GmbH, Heidelberg, Germany. Labelling and release of drug product is 
conducted at advanceCOR GmbH, Martinsried, Germany. Investigational product will be 
sent to individual study sites after site initiation.  
 
Additional IMP supplies will be sent to individual study sites upon request. Please ensure 
to contact the Monitor or Sponsor of the trial as soon as less than 10 doses of IMP remain, 
or earlier in case of high recruitment rates.  
 
- /	0		'		%	!	
IMP will be supplied to each study centre in kit boxes. Each kit box contains three IMP 
vials that make up one dose of trial medication for one patient. Each of the three vials 
contains 16.7 ml of clear solution of either: 
• 
Placebo (phosphate buffered saline (PBS), 1% sucrose, 4% mannitol) or  
• 
40 mg Revacept (2.4 mg/ml in PBS 4% mannitol, 1% sucrose)  
 
- 1				%	!	
advanceCOR will send the investigational medicinal product to individual study sites. The 
Investigator or member of his team if this task is delegated will sign the Drug Receipt 
Form confirming receipt of clinical supplies for the study and provide assurance that the 
investigational product will be handled and stored properly. It is the responsibility of the 
Principal Investigator to ensure that investigational product is only distributed to trial 
participants. The investigational product must be dispensed by authorised personnel only. 
The Principal Investigator will ensure that the investigational product is stored in 
accordance with the environmental conditions (temperature, light, and humidity) as 
determined by advanceCOR. The investigational product shall be stored in a temperature(
controlled freezer at (20 to (90°C in a secured area according to local regulations. If 


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concerns regarding the quality or appearance of the investigational product arise, do not 
dispense the investigational product and contact advanceCOR immediately. 
 
-$ 
%	
2%'	
	
3%	
	

%	
	
	%	
 
advanceCOR GmbH will supply a Drug Accountability Form, to be kept up(to(date by the 
Investigator.  
 
At the Study Centre 
5	
	6
Disposal at site according to local policy. 
 
15
-	
Return to advanceCOR GmbH, preferably in the original 
package, a Drug Return Record Form must be completed. 
 
*Used/partially used vials are accounted for in the Drug Accountability Form and therefore do not 
need their disposal accounted for separately (nor certificates of disposal) as it is inherent in the ‘use’ 
of the vials. 
 
 
-- )!	2!	
Revacept/placebo will be administered once per patient by intravenous injection as 
described in the handling instructions of the study medication. One patient dose is 
prepared by combining 3 IMP vials of a single kit box. Please equilibrate all vials of a kit 
box to room temperature before combining them in a 50 ml syringe pump. An in(line filter 
rated for syringe pump use must be inserted in the syringe pump infusion line. Infusion of 
IMP should be for 20 minutes. 
 
-4 3!	
Patients will be assigned to a treatment group by web(based online randomisation. Each 
patient will be allocated to one of the three treatment arms using a minimised 
randomisation method in order to balance potential prognostic factors between individual 
treatment arms. The following stratification factors will impact on treatment allocation: 
 
(1) 
Patient has received anti(platelet therapy with aspirin or clopidogrel prior to 
screening 
o 
No 
o 
Yes 
 
(2) 
Patient has received statin therapy prior to screening 
o 
No 
o 
Yes 
 
(3) 
Degree of carotid stenosis (ECST criteria) 
o 
50(70% 
o 
> 70% 
 
Once a patient is found to fulfil all eligibility criteria of the study the patient’s identification 
number and details on concomitant medication are submitted to a web(based online 
randomisation program accessible at: 
 
 
https://www.randomizer.at/random/web/login.php  
 
All trial staff involved in patient randomisation will receive their log in data for the 
program after a short introduction to the system. In order to randomise a new patient, 
select “
	” in the control panel on the left, enter the patient number (numeric 
format, including centre specific prefix, e.g. 01(005), select the applicable stratification 


Protocol Revacept/CS/02 
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Page 23 of 52
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factors and click “
	”. 
 
In case a reduced set of medication kit boxes is available at the study centre (e.g. due to 
damage or expiry of trial medication), you may tick option “
”, 
select “-”, highlight all '-
/*	 kit box numbers and then click on “
	”. 
 
After successful randomisation of a patient, the web(based online system will send a 
confirmation email to the person who randomised the patient which contains the patient(
specific random kit box number. This confirmation is to be printed, dated, signed and filed 
in the Investigator Site file.  
 
Please check the number of remaining IMP kit boxes after each patient enrolment and 
make sure to request additional supplies as soon as less than 10 kit boxes remain, or 
earlier, in case of high recruitment rates. 
 
-5 3		!	
Randomisations may be revised if incorrect data have been entered into the web(based 
randomisation system, if the random kit box number allocated is not available for any 
reason or if a patient discontinued study participation prior to completion visit 5. In order 
to revise or reject a patient’s randomisation, the following procedure shall be followed: 
 			

If a wrong patient number was entered into the web(based randomisation system, the 
entry may be corrected by logging onto the system, choosing “revise randomisation” in 
the control panel on the left, entering the randomisation number and corrected patient 
number in the corresponding fields, selecting “change patient(ID” from the drop down 
menu and providing a reason for the change. 
 
A randomisation must be rejected (and repeated if applicable) for any of the following 
reasons: 
• 
The medication kit box of the allocated random number is not available for any 
reason (was damaged, already used etc.) 
• 
A wrong selection was made when entering the patient’s stratification factors 
(degree of stenosis and/or previous Aspirin therapy) 
• 
A patient may be replaced for example because he/she did not complete visit 5 
 
Rejection of randomisation can only be performed by the Sponsor. Please contact the 
Monitor or the advanceCOR Clinical Development Department as soon as possible. 
 
- 
67'	
 
Emergency unblinding is performed using the web(based online randomisation tool. The 
Investigator should ensure that the code is broken only in accordance with the protocol. 
For unblinding, the Investigator should note the date, time and reason for unblinding in 
the patient notes and promptly inform the Monitor or Sponsor and the Coordinating 
Investigator of any premature unblinding (e.g. accidental unblinding, unblinding due to a 
serious adverse event) of the investigational product(s).  
 
- 
%		
The accompanying medication will encompass the entire spectrum medication for 
treatment of carotid stenosis, TIA, amaurosis fugax and stroke in accordance with the 
corresponding guidelines. The investigation plan will in no way present restrictions in this 
sense, see section 5.2.2 for prohibited treatments. Most importantly, this clinical trial will 
not delay or hinder carotid artery desobliteration. Any required change of concomitant 
medication in accordance with clinical needs will be documented. 
 


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Page 24 of 52
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- 
)!	!	
 
The study site must keep a record of all study medication dispensed or disposed off 
throughout the study no matter whether on purpose or accidentally. Subjects who are 
noncompliant to receiving study medication will be discontinued from study treatment and 
are offered a follow(up visit including all assessments scheduled for visit 3 and 5.  
 
 
;: " "
 
4 
%	'		
Informed consent must be obtained prior to any study procedure that would not have 
been performed as part of normal subject care. Additional follow(up visit(s) will be 
required every 4 weeks until all study related toxicities resolve to baseline, stabilise or are 
deemed irreversible, whichever is longer. Any additional medical testing and procedures, 
whether more frequent or in addition to those described, should be performed as 
medically indicated. 


Protocol Revacept/CS/02 
Revacept in Carotid Stenosis 
Page 25 of 52
Version 8 (22.06.2015)
 
 
 
 
 
 
r	
5
	
6.	
			
.		
7	*)
			(7$3&7
	/±3
	0*)		(
88/±%0*)		
.		
+,/±,0*)		
.		
&/±,#0*)		
.		
&
/±%
0*)		
.	








	
 
		

/0
9+,
/±++0
9&/"84
5930
'9+,
/±+,0
:.

)
	
9&

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0
9%+

/±%
0
	('	 
/./ 
+
$

1
2
3
,
; 
Informed consent 
x 
 
 
 
 
 
 
4.3
Randomisation 
 
x 
 
 
 
 
 
6.1.7
Study medication  
(Revacept or placebo) 
 
 
x 
 
 
 
 
6
CEA or other intervention 
 
 
 
 
xf 
 
 
7.2.3
CEA / intervention outcome 
 
 
 
 
 
xf 
 
Anamnesis 
x 
 
 
 
 
 
 
7.2.1
Concomitant medication 
x 
 
x 
x 
x 
x 
x 
Physical examination 
xr 
 
x 
x 
xr 
xr 
x 
7.2.2
Adverse events 
 
 
x 
x 
x 
x 
x 
7.2.5 and 8
MRS, Barthel Index 
 
 
xr 
 
 
 
x 
7.2.4
NIH Stroke Scale 
 
 
xr 
 
 
xr 
x 
Clinical outcome 
 
 
 
 
 
 
x 
x 
7.2.6 
TCD  
x
 
 
x 
 
 
 
7.2.7
Electrocardiogram 
xr 
 
 
x 
 
xr 
x 
7.2.8
DWI(NMR 
xa,r
 
 
 
 
x 
 
7.2.9
*=	..
Biochemistry  
xr 
 
 
xr 
 
xr 
x 
7.2.10
Haematology / Bleeding 
xr 
 
 
xr 
 
xr 
x 
7.2.11
Coagulation 
xr 
 
 
xr 
 
xr 
x 
7.2.10
Urinalysis 
xr 
 
 
xr 
 
xr 
x 
7.2.13
In vitro bleeding time 
(PFA100 / PFA200) and 
aggregation* 
 
 
x* 
x* 
x* 
 
x*
7.2.12
Pregnancy test 
x 
 
 
 
 
 
 
7.2.14
Pharmacokinetics  
(selected patients) 
 
 
xb 
xc 
xd 
 
xe 
7.2.15
Anti(drug antibodies  
 
 
x 
 
 
 
x 
 


Protocol Revacept/CS/02 
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Page 26 of 52
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
4 8	9			
Successfully screened subjects may be re(screened if necessary. Visit 1 procedures shall 
be performed within 24 hours; the order of these procedures shall be as follows: 
 
1) Informed consent must be obtained prior to conducting any procedure that would 
not have been performed as part of normal subject care  
2) date of birth, gender, race, general medical and surgical history (including pre(/ 
concomitant medication for the last 3 months) will be recorded.  
3) physical examination including measurement of body weight, pulse rate and blood 
pressure and assessment of heart, lung and abdomen will be performed. 
4) ECG examination 
5) Baseline TCD examination (acoustic window required for eligibility!)  
6) clinical biochemistry, clinical haematology (incl. assessment of bleeding according 
to RE(LY study group criteria), coagulation and urinalysis  
7) Urine pregnancy tests are to be performed for all eligible women of childbearing 
potential (WOCBP).  
8) Assessment of eligibility criteria 
9) Eligible patients only: Cerebral DWI(NMR (may be performed any time prior to 
treatment) 
 
-()/./-!
Once all screening examination results are available and indicate that the patient is 
eligible for the study, patients are allocated to a treatment arm by ./9/	(
-()/./-. Stratification factors are listed in section 6.1.7 p.22. 
 
4 8	9	)!		
• 
Physical examination/ vital signs 
• 
Review of concomitant medication 
• 
The trial participant will be given the opportunity to report adverse events (AE) 
spontaneously, a general prompt will also be given, all adverse events will be followed 
up until resolution or stabilisation  
• 
Assessment of neurological status (MRS, Barthel Index, NIH Stroke Scale) 
• 
Before administration of study medication, in vitro bleeding time PFA100 / PFA200 and 
platelet aggregation assay (response to collagen, ADP and TRAP)  
• 
Before administration of study medication, a blood sample for detection of anti(
Revacept antibodies will be collected (negative control)  
• 
Pharmacokinetic blood sampling (for approximately 20 % of patients) 
o 
:				         prior to IMP administration,  
o 
	:$       30 mins (± 5 mins) after start of IMP infusion 
o 
	-           6 h (± 1 hr) after start of IMP infusion 
• 
()/-/./-9.'(=)	(//- will be performed by intravenous infusion for 
20 minutes; the time of administration must be recorded.  
 
 
4 8	 9	 	  	 	 !	 "'+	 	  	 	 -	  	
	!#		
• 
Physical examination/ vital signs 
• 
Review of concomitant medication 


Protocol Revacept/CS/02 
Revacept in Carotid Stenosis 
Page 27 of 52
Version 8 (22.06.2015)
 
 
 
• 
Assessment of AEs  
• 
TCD RECORDING  
• 
ECG examination 
• 
clinical biochemistry, clinical haematology (incl. assessment of bleeding according to 
RE(LY study group criteria), coagulation and urinalysis  
• 
in vitro bleeding time PFA100 PFA200 and platelet aggregation assay (response to 
collagen, ADP and TRAP)  
• 
Pharmacokinetic blood sampling (for approximately 20 % of patients) 
o 
 		       24 hours (± 4 hrs) after start of IMP infusion 
 
4 8	9	2	6		"			!/	,-;	 	
6	<	$	#	
• 
Physical examination/ vital signs 
• 
Review of concomitant medication 
• 
Assessment of AEs  
• 
in vitro bleeding time PFA100 /PFA200 and platelet aggregation assay (response to 
collagen, ADP and TRAP)  
"%
 &" 
• 
Pharmacokinetic blood sampling (for approximately 20 % of patients) 
o 
)		       3 days (± 48 hrs) after start of IMP infusion 
 
4$ 8	$9		 		2		 		"±		 #	
• 
Physical examination/ vital signs 
• 
Review of concomitant medication 
• 
Assessment of AEs including wound healing complications 
• 
Assessment of clinical outcome 
• 
ECG examination 
• 
Assessment of interventional outcome and NIHSS 
• 
Cerebral DWI(NMR post intervention (12(72 hrs after intervention) 
• 
clinical biochemistry, clinical haematology (incl. assessment of bleeding according to 
RE(LY study group criteria), coagulation and urinalysis  
 
4- 8	-9	+	%		! 		!	"±		! #	
• 
Physical examination/ vital signs 
• 
Review of concomitant medication 
• 
Assessment of AEs including wound healing complications 
• 
Assessment of neurological status (MRS, Barthel Index, NIH Stroke Scale) 
• 
Assessment of clinical outcome 
• 
ECG examination 
• 
clinical biochemistry, clinical haematology (incl. assessment of bleeding according to 
RE(LY study group criteria), coagulation and urinalysis  
• 
in vitro bleeding time PFA100 /PFA200 and platelet aggregation assay (response to 
collagen, ADP and TRAP)  
• 
Pharmacokinetic blood sampling (for approximately 20 % of patients) 
o 
)!		       3 months (± 1 month) after IMP infusion 
• 
detection of anti(Revacept antibodies 
 
44 8	49		! 	 	+	%	"±		! #	
• 
Assessment of clinical outcome 
 


Protocol Revacept/CS/02 
Revacept in Carotid Stenosis 
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Version 8 (22.06.2015)
 
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4 

		%	%	
4 3+		!	
General medical and surgical history (including pre(/ concomitant medication for the last 3 
months) will be recorded at screening. 

%	-	/.89.>(	(9)$?!
1) Blood pressure both arms, if difference > 20/10 mm Hg: angiologic assessment 
performed (n/y) 
    Heart rate 
2) Height, weight, BMI 
3) Physical exercises > 30 min / week (none, 1(2x, ≥ 3x, not known) 
4) Lab values glucose (fasting), HbA1c, Cholesterine, HDL, LDL, Triglyceride 
5) Smoking habits 
 
Non(smoker 
 
Ex(smoker / smoker 
 
 
From (year) to (year) 
 
 
No. cigarettes per day 
6) Alcohol consumption (y/n), if yes ml/day consumed beer, wine, spirits 
 
4  	&!	
Body height will be measured at visit 1. Body weight, heart rate, blood pressure will be 
recorded at each study visit. The heart rate will taken by feeling the pulse, unless an 
electrocardiogram is scheduled for the corresponding visit. Blood pressure will be 
measured once on both arms auscultatorily while the subject is seated, first after 5 
minutes of physical and emotional rest. Furthermore, physical examination of heart, lung 
and abdomen will be performed and any signs of peripheral oedema or ascites will be 
assessed.  
 
4 	!	

'/;		,0
Detailed CEA specifications will be recorded according to the SPACE(2 study: 
• 
Site of intervention (left/right) 
• 
Anaesthesia (general / local) 
• 
Technique used  
• 
Duration of surgery (minutes) 
• 
Duration of clamping (minutes) 
• 
Degree of residual stenosis 
• 
leakiness at the end of surgery (y/n) 
 
Immediate outcome of CEA will be recorded by assessing: 
• 
Completion of vascularisation procedure 
• 
Discontinuation of vascularisation procedure 
o 
Prior to carotis opening 
o 
after probe clamping 
 

'		
/;		30
Adapted from SPACE(2 
Complications 
• 
no 
• 
yes 
o 
Haematoma 
o 
Other, specify 
Further details are given in the CRF formats. 
 


Protocol Revacept/CS/02 
Revacept in Carotid Stenosis 
Page 29 of 52
Version 8 (22.06.2015)
 
 
 
4 .%	!	
See Appendix A for neurological assessment scores. NIH score should be assessed by a 
certified physician. 
 
4$ 2!				
Adverse events will be closely monitored including any unexpected effects on cerebral or 
myocardial ischemia and bleeding events. Wound healing complications will be 
documented as part of general adverse event reporting (see also section 8). 
 
4- 	=%!	
Clinical outcome will be summarised cumulatively i.e. before treatment, one and three 
days after treatment at 3 months and at 12 months. See Appendix B for definitions of 
clinical events. The following endpoints will be recorded: 
 
• 
Rate of all cause death 
• 
Rate of stroke(related death 
• 
Any TIA, amaurosis fugax or stroke including haemorrhagic stroke,  
• 
Assessment of cardiovascular outcome including myocardial infarction and re(
intervention up to 3 and 12 months 
 
44 )	
	
	< 
Each study centre shall send a test dataset to the central core laboratory prior to starting 
patient recruitment. The core lab will notify the study centre and sponsor of successful 
completion of a test run. TCD recordings are to be sent to the following core lab for central 
analysis: 
 
PD Dr. med. M. Ritter 
Facharzt für Neurologie 
Prinzipalmarkt 11
48143 Münster 
Tel.: +49(0) 251 512 55 
Fax: +49(0) 251 899 28 61
 
Central analysis will be performed for both TCD datasets recorded for each patient 
enrolled (i.e. visit 1 and 3).  
 
There is no need for local analysis of TCD recordings. Both TCD recordings are analysed 
centrally only.    
 
'	1
TCD recordings will be made from the middle cerebral artery (MCA), via the trans(
temporal route. Each TCD assessment is recorded for one hour as specified below. 
All TCD recordings must be performed under similar conditions, i.e.: 
• 
Same apparatus 
• 
Same position of patient 
• 
System settings 
 
All recordings shall be performed with a DWL TCD machine with single(depth 2(MHz 
transducers. Standard settings should be used. Machine settings shall be adapted to 
harmonised consensus guidelines (Ringelstein et al., 1998) and agreed upon by all study 
centers. For TCD recording, patients are to be placed in a sitting or supine position. The 
MCS will be identified via transtemporal window and a transducer will be attached using a 


Protocol Revacept/CS/02 
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Version 8 (22.06.2015)
 
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standard headset. TCD signals are recorded for one hour. The total number of MES per 
hour will be analysed. 
 
Spectral display and audio signals will be monitored acoustically and visually online by an 
experienced observer during all recordings. Audio and visual signals will be recorded onto 
suitable storage media for central analysis. 
 
MES will be identified visually as predominantly unidirectional short(duration intensity 
increase accompanied by characteristic acoustic clicking, chirping or moaning sounds. A 
previously agreed threshold will be set at all participating study centres following 
validation by analysis of standard reference tapes. MES intensity will be measured in dB 
and be calculated as the ratio of peak intensity of MES divided by the intensity of the 
background signal. The same algorithm will be used throughout the study. Central offline 
analysis of all recordings will be performed using the same machine and same algorithm.  
 
45 !	"#	
A 12(lead ECG will be recorded at rest in supine position: unipolar precordial leads V1(V6 
(according to Wilson), bipolar limb leads I, II, III (according to Einthoven), and unipolar 
limb leads aVR, aVL, aVF (according to Goldberger). The following parameters will be 
collected:  
• 
Type of rhythm 
• 
PQ interval  
• 
QRS complex  
• 
QT interval 
• 
Assessment of ST(segment deviation  
 
4; 
>,.3		
 
The following parameters will be recorded: 
• 
Occurrence of new cerebral lesions from baseline (visit 1) to visit 5 
• 
If possible, number of new cerebral lesions developed between baseline (visit 1) 
and visit 5 
 
 
 
4: 
	
 !9	
 !/	
1!/	
%	", %#	
2	
	
• 
ALAT/SGPT, albumin, alkaline phosphatase, ASAT/SGOT, blood urea nitrogen, calcium, 
chloride, creatine phosphokinase / CK(MB or cardiac troponin (selection not to be 
changes for an individual patient), γ(GT, creatinine, lactate dehydrogenase, glucose, 
sodium, potassium, total bilirubin, total protein, total cholesterol, triglycerides, uric 
acid and C(reactive protein (CRP) will be determined. 
 


• 
Haemoglobin, platelet count, haematocrit (where feasible), white blood cell count 
(WBC) and red blood cell count (RBC), detailed differential hemogram. In case WBC is 
< 3.500/µl or > 11.000/µl a differential blood count has to be performed i. e., 
neutrophils, lymphocytes, eosinophils, basophils and monocytes. 

	
• 
Activated partial thromboplastin time (aPTT), prothrombin time (PT), International 
normalisation ratio (INR)  
 


Protocol Revacept/CS/02 
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Version 8 (22.06.2015)
 
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4 
	
Assessment of bleeding will be performed at all visits for which Haematology laboratory 
parameters are scheduled, in addition to adverse event documentation.  

 A*		(/-0 is defined as a reduction in haemoglobin level of at least 20 g per litre, 
transfusion of at least 2 units of blood, or symptomatic bleeding in a critical area or organ. 
/9	$4		-/-0 *		(/-0 is a subcategory of major bleeding that consisted of fatal 
bleeding, symptomatic intracranial bleeding, bleeding with a decrease in haemoglobin 
level of at least 50 g per litre, or bleeding requiring transfusion of at least 4 units of blood 
or inotropic agents or necessary surgery.  All other bleeding is considered )/- 
(Connolly et al., 2009). 
 
4 
> 	 '9	 *2	 ::	 6	 *2	 ::	 	 	
	
 
PFA100 / PFA200 and/or platelet aggregation will be performed at all sites capable of 
performing the said analyses, or within close enough proximity to the advanceCOR 
laboratory. 

)	
In vitro platelet aggregation will be performed after stimulation with collagen, ADP and 
thrombin receptor activated peptide (TRAP). Details on sample processing, test 
performance and shipping requirements or logistics will be provided to the individual 
centres prior to trial initiation.  
 
4 
7	", %#	
10 ml urine are to be collected. The following parameters are to be analysed: 
Total protein, glucose, blood and pH. In case of any abnormality urinary sediment (where 
feasible) is also to be determined. 
 
 
4 
		", %#	
For women of child(bearing potential (WOCBP) a urine pregnancy test (minimum 
sensitivity 25 IU/L) will be performed at screening (visit 1). Urine pregnancy tests will be 
supplied by advanceCOR to the study site. 
 
4$ 
 !0	!				,%	
'	"	=3	!'1#	
)
=		
	
For pharmacokinetic assessment, several 2 ml serum blood samples will be collected as 
specified in section 7. 
 
Blood collection at visit 2 must be performed on the opposite arm of administration of 
study medication. The time points correspond to the time from starting (not finishing) 
administration of study medication. Times of administration of study medication and blood 
sampling must be noted both in the patient’s notes and case report form.  
 
Pharmacokinetic measurements are required for approximately 10 patients per treatment 
group, based on the results obtained in the preceding phase I study. advanceCOR will 
notify study sites as soon as no further pharmacokinetic samples are required.  
 


Protocol Revacept/CS/02 
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Page 32 of 52
Version 8 (22.06.2015)
 
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
			"		
For measurement of anti drug antibodies, 2 ml of serum blood will be collected at visit 1 
and visit 6. 
 
)		


 
Details on sample processing and shipping requirements and logistics will be provided to 
the individual centres prior to trial initiation.  
 
			 
=		

Analyses of anti drug antibodies and Revacept pharmacokinetics will be conducted at the 
advanceCOR GmbH according to validated protocols and SOPs effective at that moment in 
time. 
 
4 
	2!	
 
The safety variables are AE, SAE, data from physical examination, routine laboratory 
results, ECG, blood pressure, antibody production and heart rate. Signs and symptoms 
present within 2 weeks of starting therapy (regardless of relationship to current disease) 
will be obtained at baseline. Study drug toxicities will be assessed continuously. Adverse 
events will be classified as outlined in section 8 below. 


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<: 
5 

	
 
An (
	.	
	->? is defined as any new untoward medical occurrence or worsening 
of a pre(existing medical condition in a patient or clinical investigation subject that does 
not necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding, for 
example), symptom, or disease temporally associated with the participation in the clinical 
trial, whether or not considered related to the investigational product. 
 
	$	B/./-0 -(//-., i.e. a disorder present before participation in the clinical trial 
should not be reported as an adverse event unless the condition worsens or episodes 
increase in frequency during administration of study medication. 
 
Classifications of Adverse Events and documentation and reporting requirements are 
visualised in the following scheme alongside the responsibilities of the Sponsor 
(advanceCOR) and Investigators (see also section 8.3 p. 37). 
  
 


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5 %	2		
.	/'.>? is any untoward medical occurrence that at any dose: 
 
• 
results in death 
• 
is life(threatening (defined as an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have 
caused death if it were more severe) 
• 
requires inpatient hospitalisation or causes prolongation of existing hospitalisation (see 
note below for exceptions) 
• 
results in persistent or significant disability/incapacity 
• 
is a congenital anomaly/birth defect 
• 
is an important medical event (defined as a medical event(s) that may not be 
immediately life(threatening or result in death or hospitalisation but, based upon 
appropriate medical and scientific judgment, may jeopardise the subject or may 
require intervention [eg, medical, surgical] to prevent one of the other serious 
outcomes listed in the definition above.) Examples of such events include, but are not 
limited to, intensive treatment in an emergency room or at home for allergic 
(
	.	 
	-
not serious 
(
	.	

	-
(
	.	
	/-
../*	,  
**	 or 
4/04=**	 
relationship to IMP 
- or 
'-/8	= 
relationship 
to IMP 
serious
../*	,  **	 or 
4/04=**	 
relationship to IMP 
- or 
'-/8	= 
relationship  
to IMP 
	/'.
(
	.	

	-
	/'.
(
	.	
	/-
expected 
not expected 
'.		(
"-	B		(
	/'.
(
	.	
	/-
	
	
'-
Reporting (PI):
: 
 
Records in notes & CRF 
 
Submit list to sponsor when requested 
/  / ": 
Records in notes & CRF 
 
Fax SAE report form to sponsor  
 
Reporting (Sponsor): 
//:  
Submit to DSMB regularly 
: Submit to DSMB regularly 
 
Include in annual safety report 
": 
 
Notify CI and DSMB as soon as possible 
 
Notify EC and RA within 15 days 
 
(7 days if fatal or life threatening) 
 
Include in annual safety report


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bronchospasm; blood dyscrasias or convulsions that do not result in hospitalisation.) 
 
All pregnancies, regardless of outcome, must be reported to the sponsor on a Pregnancy 
Report Form, not an SAE form.  
 
The following hospitalisations are not considered SAEs in advanceCOR GmbH clinical 
studies: 
 
• 
a visit to the emergency room or other hospital department < 24 hours, that does not 
result in admission (unless considered “important medical event” or event life 
threatening) 
• 
elective surgery, planned prior to signing consent 
• 
admissions as per protocol for a planned medical/surgical procedure 
• 
routine health assessment requiring admission for baseline/trending of health status 
(e.g. routine colonoscopy) 
• 
medical/surgical admission for purpose other than remedying ill health state and was 
planned prior to entry into the study. Appropriate documentation is required in these 
cases 
• 
admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (e.g. lack of housing, economic 
inadequacy, care(giver respite, family circumstances, administrative) 
 
5 .,%	2		
All AEs that are not classified as serious. 
 
5 
2!		2				3 		
	%	
 
The following guidelines and definitions should be used by the Investigator for the 
description of an AE when reporting information: 
 
Nature of the AE : 
Preferably an overall diagnosis or syndrome, rather 
than individual symptoms or signs. The Investigator 
must report adverse events using standard medical 
terminology.  
Any discrepancies between the subject’s own words on 
his/her own records (e.g. diary card) and the 
corresponding medical terminology should be clarified 
in the source documentation. 
Date of onset: 
 
Date the AE started. 
Intensity: 
 
Mild  
The subject is aware of the sign or symptom 
/
0, but it does not interfere with his/her usual 
activities and/or it is of no clinical consequence. 
 
Moderate 
The AE interferes with the usual activities of the subject 
or it is of some clinical consequence. 
 
Severe  
 
The subject is unable to work normally or to carry out 
his/her usual activities, or the AE is of definite clinical 
consequence. 
Actions taken : 
All actions taken are to be noted 
 
None  
No other action was taken for this AE 


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Concomitant 
medication  
Drug treatment: the subject took a concomitant 
medication (either prescription or non(prescription) 
specifically for this AE 
 
existing concomitant medication dosage was modified 
as a result of this AE. 
 
Hospitalisation or 
prolongation of 
hospitalisation 
The subject was hospitalised for this AE or subject’s 
stay in hospital was prolonged because of this AE. 
 
Therapeutic or 
diagnostic 
procedure  
Subject used other therapeutic measures (e.g. ice, 
heating pad, brace, cast, etc.) or subject underwent a 
diagnostic procedure (e.g., additional lab test, x(ray, 
etc.) for this AE. 
Date of outcome: 
 
Date the AE abated. If the AE consists of several signs 
and symptoms (syndrome), the sign or symptom with 
the longest duration determines the duration of the AE. 
If the AE is marked "ongoing", the outcome date should 
be blank. 
Outcome: 
 
 
Resolved 
The AE is no longer present at any intensity ( 
completely abated. 
 
Resolved 
with sequelae 
The AE is resolved but residual effects are still present. 
 
Worsened 
The AE is still present but at a heightened intensity. 
The rule of repetition of AE reporting should be applied. 
 
Fatal  
This AE caused or directly contributed to subject’s 
death. 
 
Ongoing  
The AE is still present at the last contact with the 
subject. 
Relationship to investigational product: 
 
None 
only applicable when no investigational product was 
taken or when the subject is taking single(blind 
placebo, or when the AE can be ascribed with 
reasonable certainty to another cause. 
 
Unlikely 
there are good reasons to think that there is no 
relationship, e.g. the AE is a known adverse drug 
reaction of a concomitant medication, or the same AE 
does not reappear after re(administration of the 
investigational product. 
 
Possible 
equally valid arguments can be considered for or 
against an implication of the investigational product, 
e.g. the AE : 
• 
follows a reasonable temporal sequence from the 
administration of the investigational product; 
• 
follows a known or expected response pattern to 
the investigational product; 
• 
but could readily have been produced by a 
number of other factors. 


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Probable 
the relationship is likely, e.g. the AE : 
• 
follows a reasonable temporal sequence from 
administration of the investigational product; 
• 
follows a known or expected response pattern to 
the investigational product; 
• 
is confirmed by improvement on stopping or 
reducing 
the 
dosage 
of 
the 
investigational 
product; 
• 
could not be reasonably explained by the known 
characteristics of the subject’s clinical state. 
 
Highly probable 
there is a strong relationship, e.g. the AE : 
• 
follows a reasonable temporal sequence from 
administration of the investigational product or in 
which the investigational product level has been 
established in body fluids or tissues; 
• 
follows a known or expected response pattern to 
the investigational product; 
• 
is confirmed by improvement on stopping or 
reducing 
the 
dosage 
of 
the 
investigational 
product, and reappearance of the AE on repeated 
exposure (rechallenge). 
 
5 
		3	
 
The trial participant will be given the opportunity to report AEs spontaneously. A general 
prompt will also be given to detect AEs at each study visit after treatment has been 
administered, e.g., “Did you notice anything unusual about your health (since your last 
visit)?” (In order to prevent reporting bias, subjects should not be questioned regarding 
the specific occurrence of one or more AEs.) 
 
If known, the diagnosis of the underlying illness or disorder should be recorded, rather 
than its individual symptoms. The following information should be captured for all AEs: 
onset, duration, intensity, seriousness, relationship to investigational product, action 
taken, and treatment required. If treatment for the AE was administered, it should be 
recorded on the appropriate CRF page. The Principal Investigator shall supply the sponsor 
and Ethics Committee with any additional requested information, notably for reported 
deaths of subjects. 
 
Completion of supplemental CRFs may be requested for AEs and/or laboratory 
abnormalities that are reported/identified during the course of the study. 
 
5 %	2			
 
Following the subject’s written consent to participate in the study, all SAEs must be 
collected, including those thought to be associated with protocol(specified procedures. All 
SAEs must be collected that occur within 30 days of discontinuation of dosing of the 
investigational product. If applicable, SAEs must be collected that relate to any later 
protocol(specified procedure. The Investigator should notify advanceCOR of any SAE 
occurring after this time period that is believed to be related to the investigational product 
or protocol(specified procedure. 
 
Serious adverse events, whether related or unrelated to investigational product, must be 
recorded on the SAE page of the CRF and reported expeditiously to advanceCOR to comply 


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with regulatory requirements. An SAE report should be completed for any event where 
doubt exists regarding its status of seriousness. 
 
All SAEs must be reported to advanceCOR within 24 hours after becoming aware of the 
event by confirmed facsimile transmission (fax) and mailing of the completed SAE page. 
In some instances where a facsimile machine is not available, overnight express mail may 
be used. If only limited information is initially available, follow(up reports are required. 
(Note: Follow(up SAE reports should include the same Investigator term(s) initially 
reported.)  
 
If the Investigator believes that an SAE is not related to the investigational product, but is 
potentially related to the conditions of the study (such as withdrawal of previous therapy, 
or a complication of a study procedure), the relationship should be specified in the 
narrative section of the SAE page of the CRF. 
 
If an ongoing SAE changes in its intensity or relationship to the investigational product, a 
follow(up SAE report should be sent immediately to the sponsor. As follow(up information 
becomes available it should be sent immediately using the same procedure used for 
transmitting the initial SAE report. All SAEs should be followed to resolution or 
stabilisation. 
 
./)/	-.)/../-!
0049((0)89(2000 204(20 
Local contact: Prof. Dr. med. Götz Münch or Prof. Dr. med. Martin Ungerer (Clinical 
Research Physicians) 
 
 //-0((	..!
advanceCOR GmbH 
Clinical Development Department 
Fraunhoferstr. 17 
D(82152 Martinsried  
Germany 
5 1		&		3	
 
advanceCOR will notify Principal Investigators of all SAEs that are suspected (related to 
the investigational product) and unexpected (i.e. not previously described in the 
Investigator Brochure). In the European Union (EU), an event meeting these criteria is 
termed a Suspected, Unexpected Serious Adverse Reaction (SUSAR). Investigator 
notification of these events will be in the form of an expedited safety report (ESR). 
 
Other important findings which may be reported by the sponsor as an ESR include: 
increased frequency of a clinically significant expected SAE, an SAE considered associated 
with study procedures that could modify the conduct of the study, lack of efficacy that 
poses significant hazard to study subjects, clinically significant safety finding from a 
nonclinical (e.g. animal) study, important safety recommendations from a study data 
safety monitoring board, or sponsor decision to end or temporarily halt a clinical study for 
safety reasons. 
 
Upon receiving an ESR from advanceCOR, the Principal Investigator must review and 
retain the ESR with the Investigator Brochure. Where required by local regulations or 
when there is a central IEC for the study, the sponsor will submit the ESR to the 
appropriate IEC. The Principal Investigator and IEC will determine if the informed consent 
requires revision. The Investigator should also comply with the IEC procedures for 
reporting any other safety information.  
 
 


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5 .,%	2		
The collection of nonserious AE information should begin at initiation of study 
participation, i.e. from the timepoint of obtaining informed consent. Nonserious AE 
information should also be collected from the start of a placebo lead(in period or other 
observational period intended to establish a baseline status for the subjects.  
 
If an ongoing nonserious AE worsens in its intensity or its relationship to the 
investigational product changes, a new nonserious AE entry for the event should be 
completed. Nonserious AEs should be followed to resolution or stabilisation, or reported as 
SAEs if they become serious (see Section 8.3.1). Follow(up is also required for nonserious 
AEs that cause interruption or discontinuation of investigational product, or those that are 
present at the end of study participation. Subjects with nonserious AEs at study 
completion should receive post(treatment follow(up as appropriate. If no follow(up report 
is being provided, the Investigator must provide a justification. 
 
All identified nonserious AEs must be recorded and described on the appropriate 
nonserious AE page of the CRF. 
 
5 
?'	)	2'!	
 
All laboratory test abnormalities captured as part of the study should be recorded on the 
appropriate pages of the CRF, or be submitted electronically from a central laboratory. In 
addition, the following laboratory abnormalities should also be captured on the nonserious 
AE CRF page or SAE paper CRF page as appropriate: 
 
• 
Any laboratory test result that is clinically significant or meets the definition of an SAE 
• 
Any laboratory abnormality that required the subject to have the investigational 
product discontinued or interrupted 
• 
Any laboratory abnormality that required the subject to receive specific corrective 
therapy 
 
It is expected that wherever possible, the clinical, rather than the laboratory term would 
be used by the reporting Investigator (e.g. anaemia versus low haemoglobin value). 
 
5$ 
=	
An overdose is defined as the accidental or intentional ingestion or infusion of any dose of 
a product that is considered both excessive and medically important. All occurrences of 
overdose must be reported as an SAE. 
 
5- 
	
Sexually active WOCBP must use an effective method of birth control during the course of 
the study, in a manner such that risk of failure is minimised. 
 
5- 3@%!			)	
All WOCBP MUST have a negative pregnancy test within 72 hours prior to receiving the 
investigational product. The minimum sensitivity of the pregnancy test must be 25 IU/L or 
equivalent units of HCG. If the pregnancy test is positive, the subject must not receive the 
investigational product and must not continue in the study. 
 
Pregnancy testing must also be performed throughout the study as specified the flow 
chart/time and events schedule (page 24) and the results of all pregnancy tests (positive 
or negative) recorded on the CRF or transferred electronically. 
 
In addition, all WOCBP should be instructed to contact the Investigator immediately if they 
suspect they might be pregnant (e.g., missed or late menstrual period) at any time during 
study participation. 


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5- 3			
If, following initiation of the investigational product, it is subsequently discovered that a 
study subject is pregnant or may have been pregnant at the time of investigational 
product exposure, the Investigator must immediately notify advanceCOR of this event and 
record the pregnancy on the Pregnancy Report Form (not an SAE form). Initial information 
on a pregnancy must be reported immediately to advanceCOR and the outcome 
information provided once the outcome is known. Completed Pregnancy Report Forms 
must be forwarded to advanceCOR according to SAE reporting procedures described in 
Section 8.3.1. 
 
Protocol(required procedures for study discontinuation and follow(up must be performed 
on the subject unless contraindicated by pregnancy (e.g. x(ray studies). Other appropriate 
pregnancy follow(up procedures should be considered if indicated. Follow(up information 
regarding the course of the pregnancy, including perinatal and neonatal outcome must be 
reported. 
 
Any pregnancy that occurs in a female partner of a male study participant should be also 
reported to advanceCOR.  
 
 
54 
= 			
Any significant worsening noted during interim or final physical examinations and any 
other potential safety assessments, whether or not these procedures are required by the 
protocol, should also be recorded on the appropriate nonserious AE page of the CRF or 
SAE paper CRF page. 
 
Classification of cause specific mortality will be performed according to the guidelines 
listed in Appendix B. 
 
In addition to the regular SAE reporting requirements described in section 8.3.1, any 
death of any patient randomised into the study must be reported by the Principal 
Investigator to the Regulatory authority, leading ethics committee as well as the local 
ethics committee of the study site at which the patient was enrolled as soon as possible. 


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D: 
; 	2	
Endpoint analysis will be performed when 150 patients have completed visit 5 or when 
advised by the DSMB, whichever occurs earlier. Endpoint analysis includes all data 
generated from visits 1 to 3.  
 
; 2	2	
Additional analysis will be performed after the trial has been completed i.e. when the last 
patient has completed visit 5 or when advised by the DSMB. Additional analyses include all 
data generated from visit 1(7.  
 
; 

	!	
 
; 
	1		A%		
Data management and data quality assurance will be performed in compliance with 
international guidelines (GCP, ICH) and SOPs and working instructions of d.s.h. statistical 
services effective at that moment in time. 
 
d.s.h. statistical services will document receipt of completed CRFs and perform a general 
check for legibility, completeness of pages, mandatory values, dates and signatures of 
Investigators. Subsequently, independent personnel will enter trial data into a validated 
database system (double data entry) during which incorrect data types and values out of 
defined ranges will be detected. Changes made in valid data or system operations will be 
documented by audit trail. Following double data entry, first and second entries will be 
reconciled using the SAS Compare procedure (data verification). 
 
Data will be checked for plausibility and consistency. Automatic and manual checks 
required to identify discrepancies will be described in a Data Cleaning Plan. All identified 
discrepancies are reviewed by data management personnel. Discrepancies can be resolved 
internally by inspection of the CRF and related data (e.g. if caused by data entry) or by 
producing Data Query Forms (DQFs) to be sent to the Investigator’s site(s) for resolution. 
Once these queries are resolved and corrections have been implemented in the database, 
verification and validation procedures will be repeated until no further queries remain. 
Subsequently, a 10% quality control audit is performed. For this purpose, a computer 
program randomly selects 10% of the patients from the database for complete data 
comparison with the original CRFs. 
 
Furthermore, 100 % of all patients’ key data (i .e. adverse events) will be checked and 
formal quality control will be performed according to d.s.h. statistical services’ SOP DM09. 
Once all Data Quality Control steps are completed and written authorisation of the project 
leader, data manager and statistician is obtained, the database is locked and records are 
released for reporting and statistical evaluation  
 
; 
		
AE coding and coding of concomitant diseases will be performed according to MedDRA 
Version 13.0 or higher. Concomitant medication will be coded using the ATC code. 
 
; 
'	?0	
The database will be only locked after the following requirements are fulfilled: 
• 
All data have been entered in the database 
• 
Decisions on how individual protocol violations are to be dealt with have been 
agreed upon  
• 
Written authorisation from the project leader of trial at advanceCOR GmbH has 


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been granted 
 
; 
	%	

The number and proportion of patients experiencing each type of event will be 
summarised per treatment group. Only treatment(emergent events will be included in the 
analysis (i.e. those that began or worsened after screening (visit 1)). 
 
The incidence and event (or event grouping) will be summarised and compared between 
treatment groups using Pearson’s chi(squared tests. 
 
2	 	.5:				)
A blinded review of the data shall be performed within the framework of the requirements 
of the ICH Guideline E9. The Blind Review Report will include the final statistical analysis 
plan (updated statistical analysis plan) and the final definition of data sets. If the blind 
review suggests changes to the principal features stated in the protocol, these should be 
documented in a protocol amendment. 
 
The Blind Review Report will be finalised before the blind will be broken. Formal records 
shall be kept of when the statistical analysis plan was finalised as well as when the blind 
was subsequently broken. 
 
 
; 
		%	
Before study unblinding or data review, possible protocol violations will be classified as 
“major”, “minor“, or “none”. Subjects will be allocated to the individual data sets with 
regard to the classification of possible protocol violations. The final data sets shall be 
described in detail in the Blind Review Report. 
 
)	
All Subjects who have received study medication and have had one contact with the 
Investigator afterwards are analysed for safety.  
 
*)	/:	0
For efficacy, all subjects who have had at least one dose of medication will be included in 
the ITT analysis. The ITT analysis is defined as the first line efficacy analysis.  
 
)")/))0)	
The PP population includes all subjects who are eligible for ITT evaluation and who, in 
addition, do not show major protocol deviations.  
 
 
; %	2	
The analysis of combined centers is the primary analysis of efficacy endpoints. Individual 
center results will be presented in a graphical overview with effect sizes and confidence 
intervals for efficacy data. 
 
; 	8%	
Rules on how missing values of efficacy variables will be replaced are to be described in 
the Statistical Analysis Plan. 
 
; +	
Data analysis will be performed in a validated working environment in compliance with the 


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requirements of the ICH(Guidelines E9 [1998]. The software to be used for data 
evaluation will be described in the statistical analysis plan. 
 
;$ 	2	
 
)	-
				
Findings of physical examinations and changes in vital signs (blood pressure and heart 
rate) and body weight from baseline will be presented with descriptive statistics. 
 

Adverse events (AEs) will be categorised by primary system organ class (SOC) and 
MedDRA preferred term as coded using the MedDRA dictionary. The number, intensity, 
relation to study medication and action taken will be described by frequency tables. 
Serious adverse events will be discussed separately. 
 
>	
Laboratory variables will be presented as: 
• 
Tables with raw values (“data as available“) and descriptive statistics with 
markings of values outside reference range and  
• 
Tables with changes from baseline and with descriptive statistics. 
 
; 
*		2		
The statistical analysis plan will be included in the Blind Review Report and finalised by the 
statistician before the blind will be broken and decoding takes place. 
 
;$ 
A%		
Statistical analysis will be performed according to the statisticians SOPs (d.s.h. Statistical 
Services), the statistical analysis plan, the clinical study protocol and all its amendments. 
All evaluation steps will be completely documented and the software to be used is 
validated. In(process controls will be performed and documented. 


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+: 
 
 
: 
		)	
advanceCOR will provide investigational staff training prior to study initiation. Training 
topics will include but are not limited to: GCP, AE reporting, study details and procedure, 
study documentation, informed consent and enrolment of WOCBP. 
 
: 
2		3'	
 
The Principal Investigator of a particular study centre is responsible for the 
implementation of the protocol but can delegate tasks to the research team. He/she 
remains responsible for coordinating and informing his/her staff about the protocol and 
the possible changes made to it. 
 
The Principal Investigator should maintain a list of appropriately qualified persons to 
whom he/she has delegated significant trial(related duties ("Medical Staff List" document 
with name, function, signature, initials, dates of participation in the trial conduct and type 
of delegated tasks). 
 
This list should be kept up to date. 
 
: 
%%%!	8	"8#	
The Investigator should supply his/her updated CV, dated and signed, together with a list 
of his/her collaborators responsible for the practical conduct of the trial. These 
collaborators should also provide a recent version of their CVs, dated and signed. 
 
: 
%'(	%	
advanceCOR declares that it has subscribed insurance, for the total duration of the trial, 
covering the subjects, in respect of the risks involved in this trial carried out according to 
this protocol. In case of injury or disability deriving from participation in the study, the 
subject is requested to inform without delay the insurance company and the treating 
physician responsible for the trial. 
 
:$ 
%					!	?	
Subjects will be given a study participation card containing emergency contact details of 
their corresponding study site and advanceCOR GmbH and will be asked to keep this with 
them at all times until the last visit of the study. Patients will be offered written 
notification of their GP. 
 
:- 

	!!			
d.s.h. statistical services GmbH will be responsible for database management during the 
progress of the study, and for file data analysis. Data will be collected from each 
participating centre on CRFs supplied by advanceCOR. The CRFs will be monitored and 
collected by the study monitor and the data entered into the database at d.s.h. statistical 
services GmbH.   
 
Data management based on GCP refers to the activities defined to achieve safe routines to 
enter Subject information into a database, efficiently and avoiding errors. The data 
management routines include procedures for handling of CRFs, database set(up and 
management, data entry and verification, data validation of database and documentation 
of the performed activities including information of discrepancies in the process. 
 
The database, the data entry screens and program will be designed in accordance with the 
study protocol and the CRF. Data recorded in the CRFs and electronically saved data sent 
from the central laboratories will be entered/ transmitted into the database at d.s.h. 


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statistical services GmbH and computerised logical checks will be used to ensure the 
quality of the data (e.g. double data entry). Errors found in the data will be issued on Data 
Query Forms (DQFs) by d.s.h. statistical services GmbH and the DQFs or queries will then 
be returned to the study site for resolution. The database will be updated according to the 
query resolutions and the DQFs will then be archived with the corresponding CRF. 
 
The database will be locked when clean file has been declared. Any changes to the 
database after that time can only be made by joint written agreement between the 
Sponsor, the Study Statistician, the Study Data Manager. The breaking of the code will 
take place after clean file. 
The computerised data processing will be the responsibility of d.s.h. statistical services 
GmbH. Data will be processed in agreement with local legislations. 
	
:4 
!	
:4 
!	+ 	 				3	
 
The Investigator should conduct the trial in compliance with the protocol agreed to by 
advanceCOR GmbH, the Drug regulatory authority(ies) and for which an approval by the 
IEC was given. The investigator and advanceCOR should sign the protocol to confirm 
agreement.  
 
A protocol deviation should only occur in an emergency that requires such a procedure, for 
example an Adverse Event. The Investigator must contact the monitor or Sponsor by 
telephone as soon as possible. An explanatory note in the CRF will describe the deviation 
from the protocol and state the reason for it. 
 
Normally, all other deviations should be discussed in advance through the trial monitor 
and agreed with advanceCOR GmbH. Every deviation must be documented in the CRF. 
Any significant protocol deviation will be documented and explained by the Investigator or 
the person designated by the Investigator and will be included in the clinical trial report. 
 
The study shall be conducted as described in this approved protocol. All revisions to the 
protocol must be discussed with, and be prepared by, advanceCOR. The Investigator 
should not implement any deviation or change to the protocol without prior review and 
documented approval/favourable opinion from the IEC of an amendment, except where 
necessary to eliminate an immediate hazard(s) to study subjects. Any significant deviation 
must be documented in the CRF. 
 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) 
prior to obtaining IEC approval/favourable opinion, as soon as possible the deviation or 
change will be submitted to: 
 
• 
advanceCOR GmbH 
• 
IEC for review and approval/favourable opinion 
 
Documentation of approval signed by the chairperson or designee of the IEC(s) must be 
sent to advanceCOR. If an amendment substantially alters the study design or increases 
the potential risk to the subject:  
(1) the consent form must be revised and submitted to the IEC(s) for review and 
approval/favourable opinion;  
(2) the revised form must be used to obtain consent from subjects currently enrolled in 
the study if they are affected by the amendment; and  
(3) the new form must be used to obtain consent from new subjects prior to enrolment. 
 
If the revision is an administrative letter, Principal Investigators must inform their IEC(s). 
 


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:4 
	
The arrangement for proper monitoring of the trial is the responsibility of the sponsor 
advanceCOR GmbH. The monitor (the individual responsible for monitoring) will advise the 
Investigator regarding the practical conduct of the trial and assist him/her in working 
according to the protocol, ICH/GCP, and the regulatory requirements. 
 
The Principal Investigator will allow the monitor to periodically monitor at mutually 
convenient times during and after the trial has been completed, all CRFs and the 
corresponding source documents. Therefore, the monitor will have direct access to these 
records. The extent and frequency of monitoring and percentage of source data 
verification performed will be defined in the Monitoring Plan. Depending on recruitment 
rate and data quality of individual study sites, the extent of monitoring will be increased or 
adapted as required.  The monitoring visits provide the monitor with the opportunity to 
evaluate the progress of the trial, to verify the accuracy and completeness of CRFs, to 
ensure that all protocol requirements, applicable local authority regulations and 
Investigator's obligations are being fulfilled, and to resolve any inconsistencies in the trial 
records. 
 
The Principal Investigator will also allow advanceCOR or its representatives to periodically 
co(monitor at mutually convenient times during and after the trial, all CRFs and the 
corresponding source documents. Therefore, advanceCOR or its representatives will have 
direct access to these records. 
 
:5 

	2		%	
6
%!	
The Principal Investigator(s)/institution(s) will permit trial(related monitoring, audits by or 
on behalf of advanceCOR, IEC review, and regulatory inspection(s), providing direct 
access to source data/documents. advanceCOR may also perform for(cause monitorings 
/audits and/or inspections in case of emergencies upon short notice. 
 
Source documents are original records in which raw data are first recorded. These may 
be: hospital/clinic/General Practitioner (GP) records, charts, diaries, x(rays, laboratory 
results, ECG, and other printouts, pharmacy records, care records, completed 
psychometric scales, daily record cards, quality of life questionnaires, etc. 
 
All source documents must be accurate, clear, unambiguous, permanent and capable of 
being audited. They should be made using a permanent form of recording (ink, typing, 
printing, optical disc). 
 
Hospital/clinic/medical files that are computer generated and stored on magnetic support 
media must be printed. The Investigator will sign and date the print(out. The Investigator 
will authorise the monitor to compare the content of the print(out and the data stored in 
the computer to ensure all data are consistent. 
 
:; 
2%			
The Principal Investigator will permit trial(related audits by auditors mandated by 
advanceCOR and inspections by domestic or foreign regulatory authorities, after 
reasonable notice. The main purposes of an audit or inspection are to confirm that the 
rights and well(being of the subjects enrolled have been protected, and that all data 
relevant for the evaluation of the investigational product have been processed and 
reported in compliance with the planned arrangements, ICH/GCP, and applicable 
regulatory requirements. The Investigator will provide direct access to all trial documents, 
source records, and source data. If a regulatory inspection is announced, the Principal 
Investigator will immediately inform advanceCOR. 
 
Representatives of advanceCOR must be allowed to visit all study site locations 
periodically to assess the data quality and study integrity. On site they will review study 


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records and directly compare them with source documents, discuss the conduct of the 
study with the Investigator, and verify that the facilities remain acceptable. 
 
advanceCOR GmbH will ensure that appropriate training relevant to the study is given to 
the medical, nursing, and other staff involved in each centre. 
 
In addition, the study may be evaluated by auditors and government inspectors who must 
be allowed access to CRFs, source documents, other study files, and study facilities.  
 
The Principal Investigator must notify advanceCOR promptly of any inspections scheduled 
by regulatory authorities and promptly forward copies of inspection reports to 
advanceCOR. 
 
:: )!		 	)	
Upon completion of the trial, the monitor will conduct the following activities in 
conjunction with the investigator, as appropriate: 
 
• 
return of all trial data to advanceCOR or its representative, 
• 
data clarification and/or resolution, 
• 
accountability, reconciliation, and arrangements for used and unused trial drugs, 
• 
review of site trial records for completeness, 
• 
discussion/ reminder on archiving responsibilities. 
 
In addition, advanceCOR reserves the right to temporarily suspend or prematurely 
discontinue this trial either at a single site or at all sites at any time for reasons including 
safety 
or 
ethical 
issues, 
severe 
non(compliance, 
recurrent 
non(compliance, 
or 
unsatisfactory enrolment with respect to quality or quantity. 
 
If the study is prematurely terminated or suspended, advanceCOR will promptly inform 
the Principal Investigators and the regulatory authority(ies) of the termination or 
suspension and the reason(s) for the termination or suspension. The IEC should also be 
informed promptly and provided with the reason(s) for the termination or suspension by 
advanceCOR or by the Principal Investigator, as specified by the applicable regulatory 
requirement(s).  
 
 
: 2 		
	3	
The Principal Investigator will maintain adequate records for the trial including CRFs, 
medical records, laboratory reports, informed consent documents, drug disposition 
records, safety reports, information regarding participants who discontinued, and other 
pertinent data. 
 
All records are to be retained by the Principal Investigator for a maximum of 15 years. 
Any further storage has to be agreed separately between the sponsor and the Principal 
Investigator. He/she will contact advanceCOR for authorisation prior to the destruction of 
any trial records or in the event of accidental loss or destruction of any trial records.  
The Principal Investigator must retain investigational product disposition records, copies of 
CRFs, and source documents for the maximum period required by applicable regulations 
and guidelines, or institution procedures, or for the period specified by the sponsor, 
whichever is longer. The Principal Investigator must contact advanceCOR prior to 
destroying any records associated with the study. 
 
advanceCOR will notify the Principal Investigator when the study records are no longer 
needed. If the Principal Investigator withdraws from the study (e.g. relocation, 
retirement), the records shall be transferred to a mutually agreed upon designee (e.g. 
another Investigator). Notice of such transfer will be given in writing to advanceCOR. 


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: 	3	*!	
advanceCOR will prepare case report forms to record all observations and other data 
pertinent on each individual treated or entered as a control in the investigation. Data 
reported in the CRF, that are derived from source documents, should be consistent with 
the source documents or the discrepancies should be explained in these source 
documents. 
 
CRFs supplied by advanceCOR contain all data collection fields except for fields specific to 
SAEs and pregnancy, which will be reported on separate SAE and Pregnancy 
Report/Follow(Up Forms. The Principal Investigator will maintain a signature sheet to 
document signatures and initials of all persons authorised to make entries and/or 
corrections on CRFs. 
 
The Investigator will keep a subject screening log to document identification of subjects 
who entered pre(trial screening. The Investigator must submit to advanceCOR or its 
representatives a completed CRF for each participant. 
 
CRFs will be filled in using a ballpoint pen, and must be legible. Subjects are to be 
identified by birth date (month and year) and subject number, if applicable. All requested 
information must be entered on the CRF in the spaces provided. advanceCOR cannot 
interpret a blank answer. Therefore, all fields must be completed. If the data are not 
available, the Investigator should write "NA" for not applicable, "NK" for not known, and 
"ND" for not done in all applicable fields. CRFs will be signed and dated by the Investigator 
as indicated. The Investigator’s signature on the CRF attests to its accuracy and 
completeness.  
 
Corrections must be made by striking through the incorrect entry with a single line and 
entering the correct information adjacent to the incorrect entry. The correction must be 
dated, initialed and explained (if necessary) by the person making the correction and must 
not obscure the original entry. 
 
The completed CRF, including any paper SAE/pregnancy CRFs, must be promptly 
reviewed, signed, and dated by a qualified physician who is a Principal Investigator or 
Investigator. The Investigator must retain a copy of the CRFs including records of the 
changes and corrections. 
 
All supportive documentation submitted to advanceCOR in addition to the CRF, such as 
laboratory results or hospitalisation records, must be clearly identified with the trial or 
protocol number, and trial participant number; any personal information, including the 
trial participant's name, must be removed or rendered illegible to preserve individual 
confidentiality. 
 
: %'	
 
: 	)	3	
d.s.h. Statistical Services GmbH will prepare a statistical trial report according to the 
relevant ICH guidelines, on the basis of which advanceCOR will issue a final clinical trial 
report. The report will include a thorough description of the clinical and laboratory 
methods, a discussion of the results and a list of all measurements.  
This report may be included in submissions to government drug regulatory authorities 
world(wide, or used for whatever reason considered appropriate by advanceCOR. No use 
should be made of the report before approval by advanceCOR. 
 
The Coordinating Investigator will sign the report for approval. 
 


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: %'				
The information generated by this trial is the property of advanceCOR GmbH. It is agreed 
that the results of the trial will not be submitted for presentation, abstract, poster 
exhibition or publication by the Principal Investigator until advanceCOR GmbH has 
reviewed and commented on such a presentation or publication manuscript. The Principal 
Investigator agrees that all reasonable comments made by advanceCOR in relation to a 
proposed publication by the Principal Investigator will be incorporated by the Investigator 
into the publication. advanceCOR does not hold overall right to veto publications and 
presentations. 
 
: 		*	
The content of the investigator file is structured in a manner that aids in the filing, 
retrieval, and/or auditing of study(related documents. All documents will be filed 
according to standard file categories that identify specific aspects of the trial. 
 
The contents and format of the Investigator Site File must conform to Annex 8 of the ICH(
GCP guideline. 
 
The investigator files will be prepared by and provided to the study sites by advanceCOR 
GmbH.  
 
: 
	1		3	B	
d.s.h. statistical services GmbH will be responsible for data processing under the 
supervision of advanceCOR. 
 
CRF data will be entered in an electronic database using a clinical data management 
system. Computerised data cleaning checks will be used in addition tomanual review to 
check for discrepancies and to ensure consistency of the data. An electronic audit trail 
system will be used to track all data changes in the database. The SAS system will be 
used for the statistical analysis of the data. Regular back(ups of the electronic data will be 
carried out. 
 
For subjects who signed an informed consent and underwent study specific procedure(s) 
before entering the treatment phase of the trial, the data collected during the screening 
period will be entered in the CRF. In case of screening failure, only data on demography, 
adverse events, and reason for screening failure (i. e. randomisation/treatment allocation 
status) will be entered into the clinical database and should therefore be monitored and 
retrieved from the site. 
 
For subjects who signed an informed consent but terminate study participation prior to the 
performance of any study procedures, the only data that will be monitored, retrieved, and 
databased will be data on demography and randomisation/treatment allocation status. 
 


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incontinent 
occasional accident (1 
per week) 
continent 
( 
((	
incontinent or 
catheterised & 
unable to 
manage 
occasional accident (max 
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( 
%)/-0
needs help 
independent, face, hair, 
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( 
( 
/	'.	
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needs some help but can 
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( 
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needs help cutting, 
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-.9	
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needs help  
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wheelchair independent 
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Slight disability; unable to carry out all previous activities, but able to look after own affairs 
without assistance 
1
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2
Moderately severe disability; unable to walk without assistance and unable to attend to own 
bodily needs without assistance 
3
Severe disability; bedridden, incontinent and requiring constant nursing care and attention 
,
Dead 


Protocol Revacept/CS/02 
Revacept in Carotid Stenosis 
Page 51 of 52
Version 8 (22.06.2015)
 
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
 
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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 
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Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, 
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with atrial fibrillation. N Engl J Med. 2009 Sep 17;361(12):1139(51. 
Goertler M, Baeumer M, Kross R, Blaser T, Lutze G, Jost S, Wallesch CW. Rapid decline of cerebral 
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Lassila R, Badimon JJ, Vallabhajosula S, Badimon L. Dynamic monitoring of platelet deposition on 
severely damaged vessel wall in flowing blood. Effects of different stenoses on thrombus growth. 
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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 
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. 
Molloy J, Markus HS. Asymptomatic embolization predicts stroke and TIA risk in patients with carotid 
artery stenosis. Stroke. 1999 Jul;30(7):1440(3. 
Molloy J, Martin JF, Baskerville PA, Fraser SC, Markus HS. S(nitrosoglutathione reduces the rate of 
embolization in humans. Circulation. 1998 Oct 6;98(14):1372(5. 
Nieswandt B, Watson SP. Platelet(collagen interaction: is GPVI the central receptor? Blood. 2003 Jul 
15;102(2):449(61. 
North American Symptomatic Carotid Endarterectomy Trial Collaborators. Beneficial effect of carotid 
endarterectomy in symptomatic patients with high(grade carotid stenosis. N Engl J Med. 1991 
Aug 15;325(7):445(53. 
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. 
Siebler M, Nachtmann A, Sitzer M, Rose G, Kleinschmidt A, Rademacher J, Steinmetz H. Cerebral 
microembolism and the risk of ischemia in asymptomatic high(grade internal carotid artery 
stenosis. Stroke. 1995 Nov;26(11):2184(6. 
Siebler M, Sitzer M, Steinmetz H. Detection of intracranial emboli in patients with symptomatic 
extracranial carotid artery disease. Stroke. 1992 Nov;23(11):1652(4. 
Sitzer M, Müller W, Siebler M, Hort W, Kniemeyer HW, Jäncke L, Steinmetz H. Plaque ulceration and 
lumen thrombus are the main sources of cerebral microemboli in high(grade internal carotid 
artery stenosis. Stroke. 1995 Jul;26(7):1231(3. 
Ungerer M, Rosport K, Bültmann A, Piechatzek R, Uhland K, Schlieper P, Gawaz M, Münch G. The novel 
anti(platelet drug Revacept (dimeric GPVI(Fc) specifically and efficiently inhibited collagen(
induces platelet aggregation without affecting general haemostasis in humans. Circulation, 2011; 
123: 1891(9. 
Valton L, Larrue V, le Traon AP, Massabuau P, Géraud G. Microembolic signals and risk of early 
recurrence in patients with stroke or transient ischemic attack. Stroke. 1998 Oct;29(10):2125(8. 
 

SAP_001.pdf: 
Statistical Analysis Plan 
Test product: Revacept    
EudraCT number: 2011-001006-10 
Date 10.06.2019 
1 (30) 
 
 
Statistical Analysis Plan 
 
Test Product 
Revacept 
 
EudraCT number 2011-001006-10 
 
 
Protocol 
Revacept/CS/02 
22.06.2015 (Version 8) 
 
 
 
 
 
 
 
 
 
 
 
 
 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
 
 
Sponsor:
AdvanceCor GmbH 
Fraunhoferstrasse 9A 
D-82152 Martinsried 
GERMANY 
 
Coordinating Investigator:
PD Dr. med. Holger Poppert 
Department of Neurology 
TU Munich 
Klinikum rechts der Isar TU Munchen 
Ismaninger Str. 22 
D-81675 Munchen 
GERMANY 
 
Responsible Statistician: 
Peter Klein, Dipl.-Math. 
d.s.h. statistical services GmbH 
Turmbergweg 5 
D - 85296 Rohrbach 
 
 
 
Study period: 
Early 2012 – End of 2019 


Statistical Analysis Plan 
Test product: Revacept    
EudraCT number: 2011-001006-10 
Date 10.06.2019 
2 (30) 
 
TABLE OF CONTENTS 
TITLE PAGE ......................................................................................................................... 1 
1. 
OVERVIEW ......................................................................................................... 5 
2. 
STUDY OBJECTIVES ........................................................................................ 5 
3. 
STUDY DESIGN ................................................................................................. 6 
3.1 
Assigning Subjects to Treatment Groups / Randomisation ........................... 6 
3.2 
Blinding ............................................................................................................. 7 
3.3 
Sample size ....................................................................................................... 7 
4. 
STUDY VARIABLES .......................................................................................... 8 
4.1 
Efficacy endpoints ............................................................................................ 8 
4.2 
Safety endpoints: .............................................................................................. 8 
5. 
STUDY PLAN ..................................................................................................... 9 
6. 
ANALYSIS SETS .............................................................................................. 11 
6.1 
Safety Set......................................................................................................... 11 
6.2 
Full Analysis Set ............................................................................................. 11 
6.3 
Per Protocol Set .............................................................................................. 11 
7. 
STATISTICAL CONSIDERATIONS AND DEFINITIONS .................................. 12 
7.1 
Statistical Software ......................................................................................... 12 
7.2 
Protocol Deviations and Violations/Data Review .......................................... 12 
7.3 
Handling of Drop-outs or Missing Values ..................................................... 13 
7.4 
Multicentre Analysis ....................................................................................... 13 
7.5 
Multiple Comparison ....................................................................................... 13 
7.6 
General Calculation Rules .............................................................................. 13 
8. 
STATISTICAL ANALYSIS ................................................................................ 14 
8.1 
Disposition of Subjects and Withdrawals ..................................................... 14 
8.2 
Demographics and Baseline Characteristics ................................................ 15 
8.2.1 
Demographics ................................................................................................... 15 
8.2.2 
Baseline characteristics – Anamnesis ............................................................... 16 
8.2.3 
Baseline characteristics – Physical examinations .............................................. 16 
8.2.4 
Previous and concomitant medication ............................................................... 17 
8.2.5 
Risk factors ....................................................................................................... 17 
8.2.6 
Bleeding ............................................................................................................ 18 
8.2.7 
Electrocardiography .......................................................................................... 19 
8.2.8 
TCD .................................................................................................................. 20 
8.2.9 
DWI-NMR of eligible patients ............................................................................ 20 
8.3 
Duration of infusion ........................................................................................ 20 


Statistical Analysis Plan 
Test product: Revacept    
EudraCT number: 2011-001006-10 
Date 10.06.2019 
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8.4 
Efficacy analysis ............................................................................................. 21 
8.4.1 
Reduction of incidence of preoperative microembolic signals ............................ 21 
8.4.2 
Rate of MES per hour (before and after treatment, before CEA) ....................... 23 
8.4.3 
Assessment of neurological status (NIH Stroke Scale) ...................................... 23 
8.4.4 
Cerebral lesion analysis by DWI-NMR 1 day after CEA and correlation 
to neurological status ........................................................................................ 24 
8.4.5 
Clinical endpoints summarised cumulatively i.e. before treatment, 
before CEA, 1 day after CEA, at 3 months and at 12 months. ........................... 25 
8.4.6 
Ischemic events and rate of rescue medication during the study ....................... 25 
8.5 
Assessment of safety ..................................................................................... 25 
8.5.1 
Vital signs ......................................................................................................... 25 
8.5.2 
Physical examination ........................................................................................ 26 
8.5.3 
ECG parameters ............................................................................................... 26 
8.5.4 
Adverse events ................................................................................................. 27 
8.5.5 
Laboratory results ............................................................................................. 27 
8.5.6 
Pharmacokinetics .............................................................................................. 28 
8.6 
Change in concomitant medication ............................................................... 28 
8.7 
Individual patient listing ................................................................................. 29 
9. 
LITERATURE ................................................................................................... 30 
 
List of Abbreviations 
 
AE  
 
Adverse event 
ANCOVA  
Analysis of Covariance 
BP  
 
Blood pressure 
CEA 
 
Carotid endarterectomy 
CI 
 
Confidence Interval 
DSMB  
Data Safety Monitoring Board 
ECG   
Electrocardiogram 
ICA 
 
Internal carotid artery 
ICH 
 
International Conference of Harmonisation 
ITT  
 
Intention-To-Treat 
MES  
MicroEmbolic Signals 
MTD  
Maximum tolerated dose 
PP  
 
Per Protocol 
PT 
 
Preferred Term 
SAE   
Serious adverse event 
SAP 
 
Statistical Analysis Plan 
SOC   
System Organ Class 
TCD   
TransCranial Doppler 
TIA 
 
Transient Ischaemic Attack 
WOCBP  
Women of childbearing potential 
 


Statistical Analysis Plan 
Test product: Revacept    
EudraCT number: 2011-001006-10 
Date 10.06.2019 
4 (30) 
 
  
 
Statistical Analysis Plan  
Approval Form 
 
 
The Statistical Analysis Plan has been reviewed and approved by the following signatories: 
 
 
 
Biostatistician (d.s.h.) 
Signature:   ______________________________ 
Date: _____________________ 
 
Name printed: ___________________________________________________________ 
 
 
 
 
Sponsor: 
Signature: 
______________________________ Date: _____________________ 
 
Name printed: ___________________________________________________________ 
 
 


Statistical Analysis Plan 
Test product: Revacept    
EudraCT number: 2011-001006-10 
Date 10.06.2019 
5 (30) 
 
1. 
OVERVIEW 
This statistical analysis plan (SAP) provides a comprehensive and detailed description of the 
strategy, rationale, and statistical techniques to be used for in the assessment of the efficacy 
and safety of Revacept in subjects with extracranial carotid artery stenosis and  thrombotic 
secondary complications such as microembolic signals (MES) and microinfarctions in the brain 
(DWI-NMR). This SAP provides additional details concerning the statistical analyses outlined in 
the protocol Revacept/CS/02 (22.06.2015). 
 
A blind review of the data shall be performed before the final analysis within the framework 
of the requirements of the ICH Guideline E9. The Blind Review Report will include the final 
statistical analysis plan (updated statistical analysis plan) and the final definition of data 
sets. If the blind review suggests changes to the principal features stated in the protocol, 
either a formal protocol amendment (in case of a major change, e.g. change in the defini-
tion of a primary endpoint) will be issued or it will be documented in the SAP and the Clini-
cal Study Report.  
The Blind Review Report will be finalized before the blind is broken at the stage of the 
interim and/or final analysis. Formal records shall be kept of when the statistical analysis 
plan was finalized as well as when the blind was subsequently broken. 
2. 
STUDY OBJECTIVES 
 
The efficacy endpoints are: 
 
• 
to evaluate whether the incidence of preoperative microembolic signals (MES) is re-
duced in patients with symptomatic carotid artery stenosis who have been treated with 
Revacept plus antiplatelet therapy (aspirin or clopidogrel) versus antiplatelet therapy-
therapy alone (placebo) prior to carotid endarterectomy (CEA) or carotid artery stenting. 
MES will be assessed by transcranial Doppler (TCD) examination (before and after 
treatment). 
• 
Rate of MES per hour (before and after treatment) 
• 
Assessment of neurological status (NIH Stroke Scale) 
• 
Cerebral lesion analysis by DWI-NMR and correlation to neurological status (before and 
after treatment and CEA or stenting) 
• 
Clinical endpoints will be summarised cumulatively i.e. before treatment, one and three 
days after treatment, at 3 months and at 12 months. The following endpoints will be re-
corded: 
o Rate of all cause death 
o Rate of stroke-related death 
o Any TIA or stroke including haemorrhagic stroke 
• 
Assessment of cardiovascular outcome including myocardial infarction and re-
intervention up to 3 and 12 months 
• 
Combined clinical endpoints for ischemic events (myocardial infarction and ischemic 
stroke/TIA) and rate of rescue medication (additional anti-platelet co-medication) during 
the study 
 


Statistical Analysis Plan 
Test product: Revacept    
EudraCT number: 2011-001006-10 
Date 10.06.2019 
6 (30) 
 
 
Safety will be summarised by treatment group and include the following: 
 
• 
Vital signs 
• 
ECG parameters 
• 
Anti-drug antibody titres 
• 
Reporting AEs including wound healing complications, laboratory abnormalities and use 
of concomitant medication 
• 
Haemostasis will be closely monitored by assessing: 
o laboratory parameters indicating thrombocytopenia and bleeding according to the 
RELY study group criteria 
o where feasible: in vitro platelet function with collagen, TRAP and ADP-mediated 
platelet aggregation and in vitro bleeding time by PFA-100 / PFA-200 
 
3. 
STUDY DESIGN 
 
Number of centers:  
16 active centers (planned ≥3 centers) 
Randomized:  
Yes  
Blinded:  
double-blinded  
Design:  
Phase II study 
Dosing:  
Dose-finding - 2 doses 
Placebo controlled:  
Yes  
Strata:  
Yes 
 
 - anti-platelet therapy prior to screening 
 
 - statin therapy prior to screening  
 
 - degree of carotid stenosis 
Treatments:  
Placebo 
 
40 mg Revacept 
 
120 mg Revacept 
3.1 Assigning Subjects to Treatment Groups / Randomisation 
 
Eligible subjects were randomised to one of three treatment groups. 
 
The first 10 patients were  treated sequentially, e.g. only one patient was randomised at a time. 
The next patient was randomised only once the first patient has completed visit 5 and and not 
suffered a suspected unexpected serious adverse event. Once the first 10 patients have com-
pleted the sequential phase and the DSMB has recommended continuing the trial, parallel re-
cruitment was started (see also section 1.3 of the protocol). 


Statistical Analysis Plan 
Test product: Revacept    
EudraCT number: 2011-001006-10 
Date 10.06.2019 
7 (30) 
 
 
The study was conducted at 16 study centres which were planned to screen and recruit 150 
eligible patients. During the recruitment period, each study centre was expected to provide the 
capacity and willingness to recruit at least 20 patients. There was a competitive recruitment of 
patients, which means that some hospitals were to enrol more than 20 patients and some less. 
However, if a study centre randomised less than 3 patients, further recruitment of patients may 
have been stopped because the quality of a study was dependent on the number of patients 
per centre. Very few patients in a centre might be related to a higher rate of missing data or 
patient visits and a higher withdrawal rate. 
 
Patients were assigned to a treatment group by web-based online randomisation. Each 
patient was allocated to one of the three treatment arms using a minimised 
randomisation method in order to balance potential prognostic factors between individual 
treatment arms. The following stratification factors had impact on treatment allocation: 
 
 
(1)  Patient has received anti-platelet therapy with aspirin or clopidogrel prior to  
 
 
screening (Yes/No) 
  
(2)  Patient has received statin therapy prior to screening (Yes/No) 
 
(3)  Degree of carotid stenosis (50 - 70% / > 70%) 
 
3.2 Blinding 
 
Emergency unblinding is performed using the web-based online randomisation tool. The 
Investigator should ensure that the code is broken only in accordance with the protocol. 
For unblinding, the Investigator should note the date, time and reason for unblinding in 
the patient notes and promptly inform the Monitor or Sponsor and the Coordinating 
Investigator of any premature unblinding (e.g. accidental unblinding, unblinding due to a 
serious adverse event) of the investigational product(s). 
 
3.3  Sample size 
 
Primary sample size estimation was conducted based on the CARESS study results (Markus 
et al., 2005). 50 patients should be allocated to each treatment arm. Due to low incidence 
of MES (high screening failure rates) study design was changed to exploratory study (Ver-
sion 8 of the study protocol). 
 
 


Statistical Analysis Plan 
Test product: Revacept    
EudraCT number: 2011-001006-10 
Date 10.06.2019 
8 (30) 
 
4. 
STUDY VARIABLES 
4.1 Efficacy endpoints 
 
• 
to evaluate whether the incidence of preoperative microembolic signals (MES) is re-
duced in patients with symptomatic carotid artery stenosis who have been treated with 
Revacept plus antiplatelet therapytherapy (aspirin or clopidogrel) versus antiplatelet 
therapytherapy alone (placebo) prior to carotid endarterectomy (CEA) or carotid artery 
stenting.  
MES was assessed by transcranial Doppler (TCD) examination (before and after treat-
ment). 
• 
Rate of MES per hour (before and after treatment) 
• 
Assessment of neurological status (NIH Stroke Scale) 
• 
Cerebral lesion analysis by DWI-NMR and correlation to neurological status (before and 
after treatment and CEA or stenting) 
• 
Clinical endpoints will be summarised cumulatively i.e. before treatment, one and three 
days after treatment, at 3 months and at 12 months. The following endpoints will be re-
corded: 
o Rate of all cause death 
o Rate of stroke-related death 
o Any TIA or stroke including haemorrhagic stroke 
• 
Assessment of cardiovascular outcome including myocardial infarction and re-
intervention up to 3 and 12 months 
• 
Combined clinical endpoints for ischemic events (myocardial infarction and ischemic 
stroke/TIA) and rate of rescue medication (additional anti-platelet co-medication) during 
the study 
 
4.2 Safety endpoints: 
 
• 
Vital signs 
• 
ECG parameters 
• 
Anti-drug antibody titres 
• 
Reporting AEs including wound healing complications, laboratory abnormalities and use 
of concomitant medication 
• 
Haemostasis will be closely monitored by assessing: 
o laboratory parameters indicating thrombocytopenia and bleeding according to the 
RELY study group criteria 
o where feasible: in vitro platelet function with collagen, TRAP and ADP-mediated 
platelet aggregation and in vitro bleeding time by PFA-100 / PFA-200 
 


Statistical Analysis Plan 
Test product: Revacept    
EudraCT number: 2011-001006-10 
Date 10.06.2019 
9 (30) 
 
5. 
STUDY PLAN  
 
The study schedule was as follows: 
 
• 
Visit 1: Screening  
Unsuccessfully screened subjects may have been re-screened if necessary. Visit 1 
procedures should have been performed within 24 hours. 
 
• 
Randomisation  
Once all screening examination results were available and indicated that the patient 
was eligible for the study, patients were allocated to a treatment arm by stratified ran-
domization. 
 
• 
Visit 2: Treatment 
Pharmacokinetic blood sampling (for approximately 20 % of patients) 
− t0  
prior to IMP administration 
− t0.5h  30 mins (± 5 mins) after start of IMP infusion 
− t6h  
6 h (± 1 hr) after start of IMP infusion 
Administration of study medication was performed by intravenous infusion for 20 
minutes. 
 
• 
Visit 3: 24 hrs after treatment (between 2 hrs and 46 hrs after treatment) 
Pharmacokinetic blood sampling (for approximately 20 % of patients) 
− t24h  24 hours (± 4 hrs) after start of IMP infusion 
 
• 
Visit 4: CEA / intervention (3 days after treatment, -69 hrs / + 5 days) 
Pharmacokinetic blood sampling (for approximately 20 % of patients) 
− t3d  
3 days (± 48 hrs) after start of IMP infusion 
 
• 
Visit 5: 24 hrs after CEA or other intervention (± 24 hrs)  
 
• 
Visit 6: follow up 3 months after treatment (± 1 month) 
Pharmacokinetic blood sampling (for approximately 20 % of patients) 
− t3m  
3 months (±1 month) after IMP infusion 
 
• 
Visit 7: 12 months follow up (± 1 month) 
Assessment of clinical outcome 
 
 
 
 
 
 


Statistical Analysis Plan 
Test product: Revacept    
EudraCT number: 2011-001006-10 
Date 10.06.2019 
10 (30) 
 
 
 
Screening 
Randomisation 
Treatment 
(T) 
T +24 hrs 
(±22 hrs) 
CEA T + 3 d 
(-69 hrs/+5d) 
CEA + 24 hrs 
(±12 hrs) 
Follow Up 
 
T+ 3 m 
(±1 m) 
T + 12 m 
(±1 m) 
Procedure        Visit
1 
-
2 
3 
4 
5 
6 
7 
Informed consent 
x 
 
 
 
 
 
 
 
Randomisation 
 
x 
 
 
 
 
 
 
Study medication 
(Revacept or placebo) 
 
 
x 
 
 
 
 
 
CEA or other 
intervention
 
 
 
 
xr 
 
 
 
CEA / intervention 
outcome 
 
 
 
 
 
xr 
 
 
Assessment of wound 
healing 
Complications 
 
 
 
 
 
xr 
x 
 
Anamnesis 
x 
 
 
 
 
 
 
 
Concomitant 
medication 
x 
 
x 
x 
x 
x 
x 
 
Physical examination 
xr 
 
x 
x 
xr 
xr 
x 
 
Adverse events 
 
 
x 
x 
x 
x 
x 
 
MRS, Barthel Index 
 
 
xr 
 
 
 
x 
 
NIH Stroke Scale 
 
 
xr 
 
 
xr 
x 
 
Clinical outcome 
 
 
 
 
 
 
x 
x 
TCD 
x 
 
 
x 
 
 
 
 
Electrocardiogram 
xr 
 
 
x 
 
xr 
x 
 
DWI-NMR 
Xa,r 
 
 
 
 
x 
 
 
Laboratory Tests 
Biochemistry 
xr 
 
 
xr 
 
xr 
x 
 
Haematology / 
Bleeding 
xr 
 
 
xr 
 
xr 
x 
 
Coagulation 
xr 
 
 
xr 
 
xr 
x 
 
Urinalysis 
xr 
 
 
xr 
 
xr 
x 
 
In vitro bleeding 
time (PFA100) and 
aggregation 
 
 
X* 
X* 
X* 
 
X* 
 
Pregnancy test 
x 
 
 
 
 
 
 
 
Pharmacokinetics 
(selected patients) 
 
 
xb 
xc 
xc 
 
xe 
 
Anti-drug antibodies 
 
 
x 
 
 
 
x 
 
rroutine assessment / blood sampling 
*  where feasible 
aeligible patients only 
bdrawing times: t0 prior to IMP administration, t 0.5h 30 mins (±5 mins) after start of IMP infusion, t 6h: 6 
h (±1 hr) after start of IMP infusion 
cdrawing time: t24h (±4 hrs) after start of IMP infusion 
ddrawing time: t3d (±48hrs) after start of IMP infusion 
edrawing time: t3m (±1month) after start of IMP infusion 
  


Statistical Analysis Plan 
Test product: Revacept    
EudraCT number: 2011-001006-10 
Date 10.06.2019 
11 (30) 
 
6. 
ANALYSIS SETS 
6.1 Safety Set  
 
All Subjects who have received study medication and have had one contact with the 
Investigator afterwards will be analysed for safety. 
 
6.2  Full Analysis Set  
 
For efficacy, all subjects who have had at least one dose of medication will be included in 
the ITT analysis. The ITT analysis is defined as the first line efficacy analysis. 
6.3 Per Protocol Set  
 
The PP population includes all subjects who are eligible for ITT evaluation and who, in 
addition, do not show major protocol deviations. 
 
Exclusion criteria for the study are: 
 
 
Extracranial carotid artery stenosis (diagnosed by vascular duplex ultrasound peak flow 
or angiography)  - Lesions with < 50 % stenosis according to European Carotid Surgery 
Trial (ECST) criteria 
 
NIHSS score > 18 
 
Recent intracerebral haemorrhage by X-ray computed tomography (CT) or nuclear 
magneticresonance (NMR) 
 
Cardiac cause of embolisation (atrial fibrillation or other cardiac source e.g. artificial 
heart valves) 
 
History of hypersensitivity, contraindication or serious adverse reaction to inhibitors of 
platelet aggregation, hypersensitivity to related drugs (cross-allergy) or to any of the ex-
cipients in the study drug 
 
History or evidence of thrombocytopenia (<30.000/µl), bleeding diathesis or coagulopa-
thy (pathological international normalised ratio (INR) or activated partial thrompoplastin 
time (aPTT)) 
 
Thrombolysis within the last 48 hours 
 
Relevant haemorrhagic transformation as determined by CT or anamnesis 
 
Oral anticoagulation or dual anti-platelet therapy within aspirin or clopidogrel and other 
P2Y inhibitor at screening (3 days for dipyridamole extended release; 8 hours for 
tirofiban/Aggrastat) 
 
Sustained hypertension (systolic BP >179 mmHg or diastolic BP >109 mmHg), hyper-
tensive patients shall be treated in accordance with current guidelines for the manage-
ment of arterial hypertension 
 
History of severe systemic disease such as terminal carcinoma, renal failure (or current 
creatinine >200 µmol/l), cirrhosis, severe dementia, or psychosis 


Statistical Analysis Plan 
Test product: Revacept    
EudraCT number: 2011-001006-10 
Date 10.06.2019 
12 (30) 
 
 
Current severe liver dysfunction (transaminase level greater than 5-fold over upper 
normal range limit) 
 
Active autoimmune disorder such as systemic lupus erythematosus, rheumatoid arthri-
tis,vasculitis or glomerulonephritis 
 
Known atrial fibrillation or other clinically significant ECG abnormalities (at present) 
 
Acoustic window that does not allow for TCD recording 
 
Subjects who are compulsorily detained for treatment of either a psychiatric or physical 
illness (e.g. infectious disease) 
 
Ongoing drug or alcohol abuse 
 
7. 
STATISTICAL CONSIDERATIONS AND DEFINITIONS 
7.1 Statistical Software  
 
All statistical analyses will be performed using the SAS® system (Version 9.4).  
 
7.2 Protocol Deviations and Violations/Data Review  
 
After all queries issued and answered to the extent possible, all medical codes are approved, 
all SAEs are reconciled, and prior to locking and unblinding the database, a Data Review Meet-
ing will be held. The primary purpose of the meeting will be to resolve outstanding data issues, 
to examine protocol deviations, to define the analysis sets, and to finalize other statistically 
related issues.  
 
At the Blinded Data Review Meeting, possible protocol violations will be classified as “major”, 
“minor“, or “not a protocol violation”. Subjects will be allocated to the individual data sets with 
regard to the classification of possible protocol violations. The final data sets shall be described 
in detail in the Blinded Data Review Report.  
 
Major protocol deviations - leading to exclusion from the PP population - are - but not limited to 
- any of the following conditions:  
 
 
Patient did not receive the study medication as planned  
 
Oral anticoagulation or dual anti-platelet therapy within aspirin or clopidogrel and other 
P2Y inhibitors at screening (3 days for dipyridamole extended release; 8 hours for 
tirofiban/Aggrastat) 
 
Other concomitant medication prohibited according to the exclusion / inclusion criteria 
 
Systolic blood pressure >190 mmHg 
 
Cardiac cause of embolisation (atrial fibrillation or other cardiac cause e.g. artificial 
heart valves)  
 
 
Definitions of protocol deviations checked by program are summarized in the following table. 
This table also includes proposals for classifying protocol deviations as “major”, which are re-
ferred to as protocol violations. These should be seriously considered and discussed during the 


Statistical Analysis Plan 
Test product: Revacept    
EudraCT number: 2011-001006-10 
Date 10.06.2019 
13 (30) 
 
data review meeting with regard to their impact on statistical analysis and the validity of the 
results, and the definition of subject populations. 
 
Table 6-1: Definitions of protocol deviations 
No. 
Criterion 
Major deviation (violation) 
1 
Any of the inclusion criteria answered with 'No' 
Answers will be checked by other sources in 
the CRF - if possible 
Yes or otherwise declared in 
the definitions in blind review 
report 
2 
Any of the exclusion criteria answered with 
'Yes' 
Answers will be checked by other sources in 
the CRF - if possible  
Yes or otherwise declared in 
the definitions in the blind re-
view report 
3 
Patient did not receive the study medication as 
planned  
Yes 
 
 
7.3 Handling of Drop-outs or Missing Values 
 
Missing values for the primary analyses at Visit 3  respectively 5 will be imputed by the last 
observation carried forward approach. This means patients who dropped out before Visit 3 
respectively 5 will be counted as non-responder. 
 
7.4 Multicentre Analysis 
 
The analysis of combined centers is the primary analysis of efficacy endpoints. A meta-
analysis approach will be chosen to pool the center dependent results for statistical analysis 
and to investigate for heterogeneity in the strata (e.g. Whitehead, 2003). 
 
7.5 Multiple Comparison 
 
As this was an exploratory study no confirmatory hypotheses have to be tested 
 
7.6 General Calculation Rules 
 
Binary, categorical and ordinal parameters will be summarised by means of absolute and per-
centage numbers (including ‘missing data’ as valid category at visit 1). Numerical data will be 


Statistical Analysis Plan 
Test product: Revacept    
EudraCT number: 2011-001006-10 
Date 10.06.2019 
14 (30) 
 
summarised by means of standard statistics (i.e. number of available data, mean, standard 
deviation, minimum, median, maximum, lower and upper quartile). Wherever useful, the sum-
mary statistics will be presented by stratification according to centers and/or visit. 
In addition, adequate figures (e.g. bar charts, Box-Whisker-Plots) will be presented to summa-
rise the results for some parameters.  
 
All statistical tests will be performed two-sided and will be interpreted in a descriptive-
exploratory way. Two-sided confidence intervals (CIs) will be displayed for important variables. 
Appropriate methods will be used to derive confidence intervals, depending on data nature and 
distribution. All safety and tolerability data will be presented in a purely descriptive manner as 
outlined below.  
8. 
STATISTICAL ANALYSIS 
8.1 Disposition of Subjects and Withdrawals 
 
Patients without any documented application of any study medication (without any documented 
infusion) will be excluded from all statistical analyses, but will be displayed in all data listings.  
• 
The disposition of patients with regard to 
- 
enrolment of 1st  patient and last follow-up of last patient 
- 
the number of patients enrolled (=subjects who gave informed consent), 
- 
number of study centres 
- 
number of enrolled patients by study centre 
- 
the number and percent of patients who discontinued prematurely within the study 
period, 
- 
the number and percent of patients who completed the study by treatment group 
and study centres. 
will be summarised by means of frequency tables. 
• 
For patients with a premature discontinuation the frequency of reason for discontinua-
tion due to 
− AE 
− SAE 
− Withdrawal of consent 
− Investigator decision 
− Death  
− Termination criterion arose: Specification 
− other 
will be summarised by treatment group and study centres. 
 


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In addition, all treated patients who discontinued prematurely from the study treatment 
and/or the study (according to the corresponding CRFs) will be listed; at least the time-
point of discontinuation and the main reason for discontinuation.  
 
 
• 
Analysis population 
 
Inclusion/Exclusion criteria will be listed in the individual listing of raw data 
 
Adherence to the protocol will be described by  
- 
number and percent of patients with at least one deviation from the protocol 
- 
number and percent of patients with at least one major deviation from protocol 
- 
number and percent of patients with major deviations from protocol by type of pro-
tocol deviation 
- 
number and percent of patients adhering to each analysis population 
using frequency tables 
8.2 Demographics and Baseline Characteristics 
Demographic data and all other important characteristics assessed at the Screening visit (Visit 
1) will be presented for the Safety, Intention-To-Treat and Per-Protocol analysis set. The 
results will be presented in a descriptive way.  
Laboratory assessments at the Screening visit will be evaluated in the Safety analysis section. 
8.2.1 Demographics  
Demographic variables will be evaluated from the Screening assessment (Visit 1). 
• 
Continuous demographic variables (age, height, weight) will be summarized using usual 
descriptive statistics. 
• 
Nominal data (ethnic origin, gender and hormone status) and ordinary data (age 
classes) will be summarized by means of absolute and percent numbers. 
A homogeneity analysis will be performed for the ITT and PP population. 
 


Statistical Analysis Plan 
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8.2.2 Baseline characteristics – Anamnesis 
The following categorical baseline data will be analyzed descriptively by means of absolute and 
percent numbers 
• 
Medical history 
            Pre-existing diseases including surgeries/interventions for the last 3 months will be  
            described presenting 
 
− 
number and percent of patients with previous diseases or surgeries if documented 
− 
frequency distribution of diseases and surgeries as reported by the investigator 
and will be summarized by means of frequency tables. 
A homogeneity analysis will be performed for number of patients with previous diseases or 
surgeries for the ITT and PP population using statistical tests as appropriate. 
8.2.3 Baseline characteristics – Physical examinations 
• 
Results of physical examination, assessment of  
− heart (normal/abnormal) 
− lung (normal/abnormal) 
− abdomen (normal/abnormal) 
− oedema (normal/abnormal) 
will be described presenting number and percent of patients with abnormal findings and 
summarized by means of frequency tables.  
A homogeneity analysis will be performed for physical assessment (using Fisher's exact test) 
for the ITT and PP population. 


Statistical Analysis Plan 
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8.2.4 Previous and concomitant medication 
The following classification of medication taken for the last 3 months will be performed: 
 
a) Previous medication - discontinued before start of treatment 
b) Previous medication - continued at start of treatment (infusion) 
 
Previous and concomitant medication will be described presenting  
− number and percent of patients 
−  type of medication (as reported) 
− type of medication (ATC4 level) by indication (Preferred Term) 
and summarized by means of frequency tables.  
A homogeneity analysis will be performed for number of patients with previous and concomi-
tant medication of categories a) and b) using Fisher’s exact test for the ITT and PP population. 
8.2.5 Risk factors 
The following risk factors were assessed at the Screening visit:  
• 
Blood pressure 
will be summarized by means of descriptive statistics. 
• 
Physical exercises >30 min/week 
will be summarized by means of frequency tables 
• 
Laboratory values 
− 
Glucose (fasting) [mg/dL] 
− 
HbA1c [mg/dL] 
− 
Cholesterine [mg/dL] 
− 
HDL [mg/dL] 
− 
LDL [mg/dL] 
− 
Triglyceride [mg/dL] 
will be summarized by means of descriptive statistics 
 
 
 


Statistical Analysis Plan 
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• 
Smoking habits 
− 
Type of smoker (smoker, ex-smoker, non-smoker) 
− 
Smoking period (duration in years) 
− 
Number of cigarettes per day with the classes <5 cigarettes, 5-<10 cigarettes10-<20 
cigarettes, 20-<30 cigarettes, 30-<40 cigarettes, 40-<50 cigarettes, >50 cigarettes, 
other 
will be summarized by means of frequency tables 
• 
Alcohol consumption 
consumption of  
− beer  with the classes (none,<250mL, 250-500mL,500mL-
1000mL,>1000mL,other) 
− wine with the classes (none,<100mL, 100-250mL,>250mL,other) 
− spirits with the classes (none,<10mL,10-20mL,>20mL,other) 
will be summarized by means of frequency tables 
 
A homogeneity analysis will be performed for the risk factor parameters using Fisher’s exact 
test, Wilcoxon test and Mantel-Haenszel test for the ITT and PP population. 
8.2.6 Bleeding 
The following assessments of bleeding will be evaluated exploratory using descriptive methods 
of statistics.  
 
− Reduction in haemoglobin level 
 by at least 20 g/L 
 by at least 50 g/L 
− Requiring transfusion 
 of ≥2 units of blood 
 of ≥4 units of blood  
− Symptomatic bleeding in a critical area of organ  
 Intra-ocular 
 Intra-spinal 
 Intra-musculär 
 Retro-peritoneal 
 Intra-articular 
 Pericardial 


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 Subdural intra-cranial 
 Intra-cerebral 
− Other symptomatic bleeding 
 Gastrointestinal 
 Other organ 
− Involving hypotension 
− Surgery necessary 
− Fatal 
 
A homogeneity analysis of bleeding parameters will be performed using Fisher’s exact test for 
the ITT and PP population. 
 
8.2.7 Electrocardiography 
Parameters examined are heart rate, type of rhythm, clinically significant ST-segment deviation 
and interval times. 
• 
Heart rate [beats/minute] 
will be summarized by means of descriptive statistics. 
• 
Type of rhythm 
− Sinus rhythms 
− Atrial fibrilation 
− Other rhythm 
will be summarized by means of descriptive statistics. 
• 
Clinically significant ST-segment deviation 
will be summarized by means of descriptive statistics. 
• 
Interval times 
− P [ms] 
− PQ interval [ms] 
− QRS complex  [ms] 
− QTc [ms] 
will be summarized by means of descriptive statistics. 
 
A homogeneity analysis will be performed for the parameter heart rate using the Wilcoxon test, 
type of rhythm using the Mantel-Haenszel test and interval times using the Wilcoxon test for 
the ITT and PP population. 
 


Statistical Analysis Plan 
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8.2.8 TCD  
The result of the TCD central assessment (Dr. Ritter, Münster) is a key element for the efficacy 
analysis of the study, see 8.4  
The technical possibility to perform TCD (sufficient bone window) determines whether a patient 
is eligible for the study. 
• 
TCD assessment was successful 
Due to high rate of no microembolic signals we abandoned the criterion that if no microembolic 
signal was detected during the recording period then the patient was rated not eligible during 
the course of the study. In the further course of the study patients were included irrespective 
whether they present with microemboli or not. 
8.2.9 DWI-NMR of eligible patients 
Number of cerebral lesions in perfusion area of carotid artery stenosis is determined by a 
central reading lab (Dr. Hauser, Tübingen). 
• 
back,  front right and front left 
Classes will be built for the number of lesions 
0, 1, 2, 3-5, 6-10, >10 
A homogeneity analysis will be performed for the number of cerebral lesions using the Mantel-
Haenszel chi-square test for the ITT and PP population. 
8.3 Duration of infusion 
 
At Visit 2 study medication was administered by intravenous infusion for 20 minutes. As the 
start and end time of administration is documented the duration of infusion can be calculated. 
• 
Duration (in minutes) of infusion will be summarized using descriptive statistics.  
 
Comparability of groups will be assessed on base of duration of infusion using non-parametric 
Wilcoxon tests.  
 
 


Statistical Analysis Plan 
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8.4 Efficacy analysis 
 
All statistical tests will be performed two-sided and will be interpreted in a descriptive-
exploratory way. Test for numerical data will be performed under normality assumptions using 
ANOVA. In addition normality of distribution will checked based on goodness of fit tests. If 
normality can not be assumed sensitivity analyses will be performed using the Wilcoxon test. 
Two-sided confidence intervals (CIs) will be displayed for important variables. Appropriate 
methods will be used to derive confidence intervals, depending on data nature and distribution.  
 
8.4.1 Reduction of incidence of preoperative microembolic signals 
 
This endpoint is to evaluate whether the rate of patients with incidence of preoperative 
microembolic signals (MES) was reduced (from Visit1 to Visit 3). Compared will be patients 
who have been treated with Revacept plus antiplatelet therapy (aspirin or clopidogrel) versus 
antiplatelet therapy alone (placebo) prior to carotid endarterectomy (CEA). MES data from the 
central reading lab (Dr. Ritter, Münster) are evaluated. 
 
The evaluation will be performed using a two-sided test of superiority. Groups will be compared 
for the combined centers using Fisher’s exact test.  
 
The sequence of a priory defined hypotheses, with π rate of patients with MES V3 < MES V1 
for the specified group, will be:    
 
1) H01: π Revacept 120 mg = π Placebo  vs.   
HA1:  π Revacept 120 mg > π Placebo  
 
2) H02: π Revacept 40 mg = π Placebo  vs.   
HA2:  π Revacept 40 mg > π Placebo 
 
3) H03: π Revacept 120 mg = π Revacept 40 mg   
HA3:  π Revacept 120 mg > π Revacept 40 mg 
 
4) H04: π Revacept 120 mg + 40 mg = π Placebo  vs.   
HA4:  π Revacept 120 mg + 40 mg > π Placebo 
 
Each hypothesis will be tested using Fisher’s exact test. 
 
With the first two and the last of hypotheses the test product for a given dose level ot overall 
will be tested against Placebo. With the third  hypothesis the higher dose level of the test prod-
uct will be compared against the lower dose of the test product.  
 


Statistical Analysis Plan 
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Date 10.06.2019 
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All tests will be interpreted exploratively. 
 
The between group risk difference and its 95% confidence interval (CI) will be estimated for 
each group comparison. 
 
The prime analysis will be based on the ITT population. The PP population will be used for the 
supportive analyses.  
In a subgroup analysis, only patients will be compared who did not receive any change in the 
concomitant medication with anti-platelet activity (=rescue medication) between the initial as-
sessment at V1 and the follow-up investigation at V3 / V5. 
 
Additionally the prevalence / rate of patients with microembolic signals (>0) at Visit 3 will be 
compared in a similar manner as in the hypothesis 1- 4  
Missing values for the primary analyses at Visit 3 will be imputed by the last observation 
carried forward approach. This means patients who dropped out before Visit 3 will be counted 
as non-responder. 
 
An additional analysis of the first endpoint will be performed including the factor center as a 
stratum. Fisher’s exact test will be performed for each stratum and meta-analysis approach will 
be chosen. Centers with less than 3 patients will be combined into a ‘small number of patients’ 
combined stratum. 
 
Individual center results will be presented in a graphical overview with risk differences and their 
confidence intervals. 
 
In case of heterogeneities in the baseline parameters, sensitivity analyses will be per-
formed for the first endpoint using Fisher’s exact test and by including the respective parameter 
as a stratum (binary, ordinal or categorical data). For continuous data these data will be trans-
formed into classes before used as stratum.  
 
A meta-analysis approach will be chosen to pool the stratum dependent results and to investi-
gate for heterogeneity in the strata (e.g. Whitehead, 2003). 
 
The following baseline parameters will be used for the analysis of heterogeneity: 
 
• 
Demographics 
− 
Age 
− 
Height 
− 
Weight 
− 
Ethnic origin 
− 
Gender 
− 
Hormone status 
• 
Anamnesis – Medical history 
− 
Number of patients with previous diseases and surgeries 
 
• 
Vital signs  
− 
systolic and diastolic blood pressure (right and left arm) 
 


Statistical Analysis Plan 
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• 
Physical examination 
− 
Abnormal findings of assessment of heart, lung, abdomen and oedema (Yes/No) 
8.4.2 Rate of MES per hour (before and after treatment, before CEA) 
The rate of MicroEmbolic Signals (MES) as assessed at Visit 1and at Visit 3 will be 
summarized using descriptive statistics.  Data will be analysed from the central 
reading lab. 
 
Groups will be compared for  
• 
difference of MES at Visit 1 versus post treatment at Visit 3 (delta MES) and  
• 
percent change of MES at Visit 3 compared to Visit 1 (delta MES) 
 
 using the ANOVA.  
 
In a subgroup analysis, only patients will be compared who did not receive any change in the 
concomitant medication with anti-platelet activity (=rescue medication) between the initial as-
sessment at V1 and the follow-up investigation at V3 / V5. 
 
In addition normality of distribution will checked based on goodness of fit tests. If normality can 
not be assumed sensitivity analysis will be performed using the Wilcoxon test.  
8.4.3 Assessment of neurological status (NIH Stroke Scale) 
The neurological status was assessed at Visit 2, Visit 5, and Visit 6  by the NIH stroke scale. It 
comprises 15 items.  
1a 
 Level of Conciousness  
 
 
0 
1 
2 
3 
1b 
LOC Questions  
 
 
 
0 
1 
2 
1c 
LOC Commands 
 
 
 
0 
1 
2 
2 
Best Gaze 
 
 
 
 
0 
1 
2 
3 
Visual  
 
 
 
 
0 
1 
2 
3 
4 
Facial Palsy 
 
 
 
 
0 
1 
2 
3 
5a 
Motor Arm 
 
left arm  
 
0 
1 
2 
3 
4 
9 
5b 
 
 
 
right arm 
 
0 
1 
2 
3 
4 
9 
6a 
Motor Leg 
 
left leg  
 
0 
1 
2 
3 
4 
9 
6b 
 
 
 
right arm 
 
0 
1 
2 
3 
4 
9 
7 
Limb Ataxia 
 
 
 
 
0 
1 
2 
 
8 
Sensory 
 
 
 
 
0 
1 
2 
9 
Best Language  
 
 
 
0 
1 
2 
3 
10 
Dysarthria 
 
 
 
 
0 
1 
2 
11 
Extinction and Inattention 
 
 
0 
1 
2 
            Total Score  
 
 
 
 
Maximum = 62 
                                                                                  
with rating options on the scale 0, 1, 2, 3, 4 and 9 depending on the single item.   
Frequencies of scale values will be summarized by visit and by item. Comparison between 
groups will be performed using the Mantel-Haenszel Chi-square test.  


Statistical Analysis Plan 
Test product: Revacept    
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Date 10.06.2019 
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The total score of the NIH Stroke Scale will be compared between groups by visit using 
ANOVA. 
8.4.4 Cerebral lesion analysis by DWI-NMR 1 day after CEA and correlation to 
neurological status 
Cerebral lesions: Number of cerebral lesions in perfusion area of carotid artery stenosis 
assessed at Visit 5 by the central reading lab (Dr. Hauser, Tübingen). 
− back 
− front right  
− front left  
− and total 
 
Groups will be compared for 
• 
change of number of DWI lesions V5 compared to  V1 (delta number of lesions) 
• 
percent change of number of DWI lesions V5 compared to  V1  
using ANOVA. 
 
In addition groups will be compared for 
• 
rate of incidence of patients with DWI lesions after treatment (V5) 
• 
rate of incidence of patients with new DWI lesions after treatment (V5) 
• 
rate of patients with DWI lesions in V5 reduced compared to V1 
using Fisher's exact test. 
 
Neurological status: Modified Rankin Scale (MRS) assessed at Visit 6: 
0 
No symptoms at all 
1 
No significant disability despite symptoms; able to carry out all usual duties and activities 
2 
Slight disability; unable to carry out all previous activities, but able to look after own affairs  
             without assistance 
3 
Moderate disability; requiring some help, but able to walk without assistance 
4 
Moderately severe disability; unable to walk without assistance and unable to attend to own  
             bodily needs without assistance 
5 
Severe disability; bedridden, incontinent and requiring constant nursing care and attention 
6 
Dead 
The following correlations will be performed by treatment group: 
− Cerebral lesions of back area of carotid artery stenosis x MRS 
− Cerebral lesions of front right area of carotid artery stenosis x MRS 


Statistical Analysis Plan 
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− Cerebral lesions of front left area of carotid artery stenosis x MRS 
Correlation analysis will be performed by calculating the Pearson correlation coefficient. 
In a subgroup analysis, only patients will be compared who did not receive any change in the 
concomitant medication with anti-platelet activity (=rescue medication) between the initial as-
sessment at V1 and the follow-up investigation at V3 / V5. 
8.4.5 Clinical endpoints summarised cumulatively i.e. before treatment, before 
CEA, 1 day after CEA, at 3 months and at 12 months.  
 
For the following endpoints 
• 
Rate of all cause death 
• 
Rate of stroke-related death 
• 
Any TIA or stroke including haemorrhagic stroke 
• 
Rate of Myocardial infarctions and coronary re-intervention 
the number of patients will be summarized by means of frequency tables. Groups will be 
compared using Fisher’s exact test. 
8.4.6 
Ischemic events and rate of rescue medication during the study 
Combined clinical endpoints for ischemic events (myocardial infarction and ischemic 
stroke/TIA) and rate of rescue medication (additional anti-platelet co-medication) during the 
study will be analyzed comparing groups for 
• 
incidence of events adjusted for application of rescue medication during the study 
(yes/no)  
using the Cochran-Mantel-Haenszel procedure. 
 
8.5 Assessment of safety 
Safety outcome between groups and between placebo and the combined Revacept groups will 
be compared. 
8.5.1 Vital signs  
Vital signs were assessed at Screening (Visit 1, Baseline) and Visit 2 to Visit 6.  
Results of  


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• 
vital signs  
− Weight 
− Blood pressure systolic and diastolic (right arm / left arm) 
will be summarized by visit by means of descriptive statistics. Change from baseline in weight, 
heart rate, systolic and diastolic blood pressure will be summarized by means of statistics and 
compared between treatment groups using the Wilcoxon test. 
8.5.2 Physical examination 
Physical examination was assessed at Screening (Visit 1, Baseline) and Visit 2 to Visit 6.  
Results of assessment of 
− heart 
− lung 
− abdomen 
− oedema 
will be described presenting number and percent of patients with abnormal findings at post-
baseline visits and with normal values at baseline (Screening, Visit 1) and summarized by 
means of frequency tables.  
 
8.5.3 ECG parameters 
ECG parameters which were assessed at Screening (Visit 1, Baseline), Visit 3, Visit 5 and Visit 
6 are heart rate, type of rhythm, clinically significant ST-segment deviation and interval times. 
Results for 
• 
Heart rate [beats/minute] 
will be summarized by means of descriptive statistics 
• 
Type of rhythm 
− Sinus rhythms 
− Atrial fibrilation 
− Other rhythm 
will be summarized by means of frequency tables 
• 
Clinically significant ST-segment deviation 
will be summarized by means of frequency tables 
• 
Interval times 


Statistical Analysis Plan 
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− P [ms] 
− PQ interval [ms] 
− QRS complex  [ms] 
− QTc [ms] 
will be summarized by means of descriptive statistics 
Change from baseline in heart rate, and interval times will be summarized by means of 
statistics and compared between treatment groups. 
8.5.4 Adverse events 
Adverse events will be categorised by primary system organ class (SOC) and MedDRA pre-
ferred term (PT) as coded using the MedDRA dictionary. 
• 
The inquiries for AEs will be summarised with respect to the type of inquiry 
− 
Patient showed up for follow up visit and AE/SAE was reported during a follow up 
visit 
− 
Patient did not show up for follow-up visit and AE/SAE was reported by telephone or 
in writing with  
 the patient 
 a family member 
 an attending physician 
 another person 
  
• 
An overview table will be presented with the number (and percentage) of patients with 
at least one AE, with at least one SAE, with AEs leading to treatment discontinuation 
and with drug-related AEs.   
• 
The number (%) of patients with at least one AE will be presented in frequency tables 
by adverse events as reported. 
 
8.5.5 Laboratory results 
 
The following endpoints will be evaluated exploratory using descriptive methods of statistics. 
Generated p-values will be interpreted in an explorative way. 
 
• 
Laboratory results 
− Biochemistry 
− Haematology 
− Coagulation 
− Urinanalysis 
 
• 
Bleeding 


Statistical Analysis Plan 
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Date 10.06.2019 
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− Reduction in haemoglobin level 
 by at least 20 g/L 
 by at least 50 g/L 
 of ≥ 2 units of blood 
 of ≥ 4 units of blood 
− Requiring transfusion 
 of ≥2 units of blood 
 of ≥4 units of blood  
− Symptomatic bleeding in a critical area of organ  
 Intra-ocular 
 Intra-spiral 
 Intra-musculär 
 Retro-peritoneal 
 Intra-articular 
 Pericardial 
 Subdural intra-cranial 
 Intra-cerebral 
− Other symptomatic bleeding 
 Gastrointestinal 
 Other organ 
− Involving hypotension 
− Surgery necessary 
− Fatal 
 
8.5.6 Pharmacokinetics 
 
Analyses of anti drug antibodies and Revacept pharmacokinetics will be conducted at the 
AdvanceCor GmbH according to validated protocols and SOPs effective at that moment in 
time. 
 
 
8.6 Change in concomitant medication 
 
• 
Change in concomitant medication will be described presenting  
- number and percent of patients with new concomitant medication - taken first time 
after start of treatment (during the course of the study) 
- number and percent of patients with changes of pre-existing concomitant   
  medication according to  
  - dose increased 
  - dose decreased 
  - discontinued 
- type of medication 


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- type of medication by indication 
and summarized by means of frequency tables.  
• 
Change in concomitant rescue medication with anti-platelet or anti-thrombotic effects. 
 
8.7 Individual patient listing 
Individual patient listings will be produced for all raw data and a selection of the derived data.  
Listings will be ordered by treatment group, and by gender and study centre within treatment 
group. 


Statistical Analysis Plan 
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9. 
LITERATURE 
 
1. Whitehead, Anne (2003) Meta-Analysis of Controlled Clinical Trials. Statistics in Practi-
ce