A Multicenter, Randomized, Controlled Study To Evaluate The Efficacy and Safety of Short-Term Plasma Exchange Followed by Long-Term Plasmapheresis With Infusion of Human Albumin Combined With Intravenous Immunoglobulin In Patients With Mild-Moderate Alzheimer's Disease
Phase: PHASE2
Conditions: Alzheimer's Disease
Sponsor: Instituto Grifols, S.A.

Confidential 
 
 
 
 
 
A MULTICENTER, RANDOMIZED, CONTROLLED STUDY 
TO EVALUATE THE EFFICACY AND SAFETY OF SHORT-
TERM PLASMA EXCHANGE FOLLOWED BY LONG-TERM  
PLASMAPHERESIS WITH INFUSION OF HUMAN ALBUMIN 
COMBINED WITH INTRAVENOUS IMMUNOGLOBULIN IN 
PATIENTS WITH MILD-MODERATE ALZHEIMER’S 
DISEASE 
 
Sponsor for the Clinical Trial: 
Instituto Grifols, S.A. 
Polígono Levante, C/ Can Guasc 2 
08150 - Parets del Vallès 
Barcelona  
Spain 
 
Contract Resource Organization: 
 
 
 
Product: 
Albutein
Flebogamma® DIF 
Type of study: 
Multicenter, randomized, controlled, parallel-
group. 
 
Protocol Number: 
IG1002 
 
Study Phase 
2b/3 
EudraCT Number 
2011-1598-25 
Version Number: 
5.0  (IND version) 
 
Date: 
February 2018 
 
 
Confidentiality Statement: 
The information contained in this protocol is provided to you in confidence, for review by 
you, your staff and an applicable regulatory authority or institutional review 
committee/research ethics board.  It is understood that this information may not be 
disclosed to any other party, in any form, without prior authorization from Sponsor, 
except to the extent necessary to obtain informed consent from the persons to whom the 
drug may be administered. 
 
 
Protocol IG1002 
Page 1 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
A MULTICENTER, RANDOMIZED, CONTROLLED STUDY TO EVALUATE THE 
EFFICACY AND SAFETY OF SHORT-TERM PLASMA EXCHANGE FOLLOWED 
BY LONG-TERM PLASMAPHERESIS WITH INFUSION OF HUMAN ALBUMIN 
COMBINED WITH INTRAVENOUS IMMUNOGLOBULIN IN PATIENTS WITH 
MILD-MODERATE ALZHEIMER’S DISEASE 
 
Protocol Number: IG1002 
Version Number: Version 5.0 (IND version) 
Version Date: February 2018 
 
 
AUTHORIZED SIGNATURE PAGE 
 
 
I have read this protocol and agree to conduct this trial in accordance with Good Clinical 
Practice (GCP), all stipulations of the protocol, the Declaration of Helsinki and applicable 
regulatory requirements. 
 
I will provide copies of the protocol and all pertinent information to all individuals 
responsible to me who assist in the conduct of this study. I will discuss this material with 
them to ensure that they are fully informed regarding the conduct of the study. 
 
 
 
 
Investigator: 
____________________________________________________________ 
 
 
(Print Name) 
 
 
 
 
____________________________________________________________ 
 
(Signature) 
(Date) 
 
 
Protocol IG1002 
Page 3 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
PRIMARY CONTACT INFORMATION
For the Sponsor 
 
Clinical Project Manager 
Instituto Grifols, S.A. 
Can Guasc, 2 
Parets del Vallès 
08150 Barcelona. SPAIN 
 
 
 
For the Sponsor 
 
Clinical Research Associate 
Instituto Grifols, S.A. 
Can Guasc, 2 
Parets del Vallès 
08150 Barcelona. SPAIN Phone: 
 
 
 
Protocol IG1002 
Page 4 of 68 
Version 5.0 (IND version) / February 2018 

Confidential 
 
 
TABLE OF CONTENTS 
 
SIGNATURE/APPROVAL PAGE ....................................................................................... 2 
AUTHORIZED SIGNATURE PAGE .................................................................................. 3 
PRIMARY CONTACT INFORMATION ........................................................................... 4 
TABLE OF CONTENTS ....................................................................................................... 5 
LIST OF ABBREVIATIONS ................................................................................................ 8 
PROTOCOL SYNOPSIS (ALBUMIN GRIFOLS + FLEBOGAMMADIF) ................. 11 
1.1 Rationale ................................................................................................................ 18 
1.1.1 
Characteristics of Alzheimer’s disease and Its Relation to β-Amyloid Peptide .................... 18 
1.1.2 
Existence of a Dynamic Equilibrium between Brain and Plasma Aβ ................................... 19 
1.1.3 
The Role of Plasma exchange with Albutein® 5% in Alzheimer’s disease ............................ 20 
1.1.4 
Previous Clinical Studies of Plasma exchange with Albutein® 5% in Alzheimer’s disease .. 21 
1.1.5 
The role of intravenous immunoglobulin in Alzheimer’s disease ......................................... 22 
1.1.6 
Potential role of a combination of plasma exchange with Albutein® with Flebogamma®DIF
 
22 
2. 
STUDY PURPOSE AND OBJECTIVES ................................................ 22 
3. 
INVESTIGATIONAL PLAN ................................................................... 23 
3.1 Global Study Design/Developmental Phase ........................................................ 23 
3.2 Randomization and Treatment Assignment ....................................................... 23 
3.3 Type of Control ...................................................................................................... 24 
3.4 Blinding Techniques .............................................................................................. 24 
3.5 Screening Period (Pre-Randomization or Pharmacological Washout) ............ 24 
4. 
SELECTION OF STUDY POPULATION ............................................. 24 
4.1 Inclusion and Exclusion Criteria ......................................................................... 24 
4.1.1 
Inclusion Criteria .................................................................................................................. 24 
4.1.2 
Exclusion Criteria ................................................................................................................. 25 
4.2 Disease Diagnostic Criteria .................................................................................. 25 
4.3 Planned Number of Subjects ................................................................................ 26 
4.4 Withdrawal Criteria and Planned Analyses of Withdrawals and Dropouts ... 26 
4.5 Treatment of Pre-Randomization Losses, Entry Reclassification .................... 26 
4.6 Estimated Duration of the Recruitment Period ................................................. 26 
5. 
TREATMENT OF SUBJECTS ............................................................... 26 
5.1 Treatment Regimen ............................................................................................... 26 
5.1.1 
Study Treatment Procedure .................................................................................................. 26 
5.1.2 
Dosage and Treatment Regimen ........................................................................................... 27 
5.1.3 
Method of Application........................................................................................................... 27 
5.2 Criteria for Treatment Modification or Interruption ....................................... 29 
5.2.1 
Criteria for Modifying Regimens .......................................................................................... 29 
5.2.2 
Special Warnings and Precautions for Use .......................................................................... 30 
5.3 Concomitant Treatment ....................................................................................... 36 
5.4 Special Guidelines for Study Drug Handling ..................................................... 36 
5.4.1 
Storage of Albutein® and Flebogamma® DIF ....................................................................... 36 
5.5 Measures to Assess Compliance ........................................................................... 37 
 
Protocol IG1002 
Page 5 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
5.6 Rescue Medication ................................................................................................. 37 
6. 
TRIAL CONDUCT AND RESPONSE ASSESSMENT ........................ 37 
6.1 Study Variables ..................................................................................................... 37 
6.1.1 
Primary Efficacy Variable .................................................................................................... 37 
6.1.2 
Secondary Efficacy Variables ............................................................................................... 37 
6.1.3 
Safety Variables .................................................................................................................... 38 
6.2 Conduction of the Trial. Study Procedures. ....................................................... 38 
6.2.1 
Screening Visits (Weeks -3, -2 and -1) .................................................................................. 38 
6.2.2 
Weeks 1 to 6 - Intensive plasma exchange period ................................................................. 39 
6.2.3 
Weeks 7 to 8 – Intermediate visit (Window range +/- 2 days) .............................................. 40 
6.2.4 
Months 3 to 14 - Maintenance Period .................................................................................. 41 
6.2.5 
Final Visit (Month 14) .......................................................................................................... 42 
6.2.6 
Description of the Response Evaluation Methods................................................................. 43 
7. 
SPECIFIC METHODOLOGY ................................................................ 44 
7.1 Behavioral and cognitive impairment scales and tests ...................................... 44 
7.1.1 
Gold standards for the study of dementia ............................................................................. 44 
7.1.2 
Specific neuropsychological battery (NPS battery) .............................................................. 44 
7.2 Method of Behavioral and Cognitive Testing ..................................................... 46 
7.3 Method of Biochemical Marker Testing ............................................................. 48 
7.4 Method of Neuroimaging Studies ........................................................................ 49 
8. 
ASSESSMENT OF EFFICACY .............................................................. 51 
8.1 Efficacy variables .................................................................................................. 51 
8.2 Secondary efficacy variables ................................................................................ 51 
8.3 Safety variables ...................................................................................................... 51 
9. 
ASSESSMENT OF SAFETY ................................................................... 52 
9.1 Adverse Events ...................................................................................................... 52 
9.1.1 
Information to specify ........................................................................................................... 52 
9.1.2 
Imputability criteria .............................................................................................................. 53 
9.1.3 
Expected adverse events ....................................................................................................... 54 
9.2 Procedures for the immediate notification of serious adverse events .............. 55 
10. 
STATISTICAL METHODS..................................................................... 55 
10.1.1 
Analytical Populations .......................................................................................................... 55 
10.1.2 
Missing Data ......................................................................................................................... 55 
10.1.3 
Demographic and Baseline Characteristics ......................................................................... 56 
10.2 Assessment of Efficacy .......................................................................................... 56 
10.2.1 
General ................................................................................................................................. 56 
10.2.2 
Primary Endpoint ................................................................................................................. 56 
10.2.3 
Secondary Endpoints ............................................................................................................ 57 
10.3 Evaluation of Tolerability ..................................................................................... 57 
10.4 Intermediate Analysis and Stopping Rules ......................................................... 57 
10.5 Conduction of the Statistical Analysis ................................................................. 58 
11. 
CHANGES TO THE PROTOCOL ......................................................... 58 
12. 
ETHICS ...................................................................................................... 58 
12.1 General Considerations ........................................................................................ 58 
12.2 Written Informed Consent and Information ...................................................... 59 
12.3 Confidentiality of Subject Records ...................................................................... 59 
 
Protocol IG1002 
Page 6 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
12.4 Institutional Review Board and Data Monitoring Committee (DMC) ............ 60 
12.5 Responsibilities of the Participants in the Clinical Trial, and Applicable 
Regulations ............................................................................................................. 60 
13. 
QUALITY CONTROL AND QUALITY ASSURANCE ...................... 61 
13.1 Audits and Inspections by the Health Authorities ............................................. 61 
14. 
DATA HANDLING AND RECORD KEEPING ................................... 61 
14.1 Handling of the Principal Study File ................................................................... 61 
14.1.1 
Documents Required Before the Start of the Study ............................................................... 61 
14.1.2 
Study File .............................................................................................................................. 61 
14.1.3 
Data Handling, Processing and Correction ......................................................................... 62 
14.1.4 
Identification of the Clinical Research Samples and Persons Responsible for Their Supply 
and Storage. Labeling of Samples ............................................................................................................... 62 
15. 
PUBLICATION POLICY ........................................................................ 62 
16. 
LIABILITIES AND INSURANCE .......................................................... 62 
16.1 Trial Budget Contents ........................................................................................... 62 
16.2 Insurance / Compensation .................................................................................... 63 
LITERATURE REFERENCES.......................................................................................... 64 
 
 
APPENDIX 1  
FULL PRESCRIBING INFORMATION (Albutein®) 
APPENDIX 2  
FULL PRESCRIBING INFORMATION (Flebogamma® DIF) 
APPENDIX 3a  
AUTO-C CLINICAL PROTOCOL 
APPENDIX 3b  
AURORA CLINICAL PROTOCOL 
APPENDIX 4  
REPORTING OF SERIOUS ADVERSE EVENTS 
APPENDIX 5  
DECLARATION OF HELSINKI 
APPENDIX 6  
E6 GCP GUIDELINES 
APPENDIX 7  
BEHAVIORAL AND COGNITIVE IMPAIRMENT SCALES 
AND TESTS 
APPENDIX 8  
STUDY SUMMARY TABLE AND STUDY FLOW CHART 
APPENDIX 9  
SHAM MANUAL GUIDELINE 
APPENDIX 10 
HYPOVOLEMIA GUIDELINE 
APPENDIX 11 
FEVER MANAGEMENT GUIDELINE  
APPENDIX 12  
TROMBOEMBOLIC EVENTS GUIDELINE 
 
 
Protocol IG1002 
Page 7 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
LIST OF ABBREVIATIONS 
ABS 
Agitated Behavior Scale 
ACD-A 
Acid Citrate-Dextrose A 
ACEI 
Angiotensin-Converting Enzyme Inhibitor 
AChEI 
Acetylcholine Esterase Inhibitor 
AD 
Alzheimer’s Disease 
ADAS-Cog 
Alzheimer’s Disease Assessment Scale-Cognitive 
ADCS-ADL 
Alzheimer’s Disease Cooperative Study-Activities of Daily Living 
ADCS-CGIC 
Alzheimer’s Disease Cooperative Study-Clinical Global Impression 
of Change 
ADL 
Activities of Daily Living 
AE 
Adverse Event 
ANCOVA 
Analysis of covariance 
APP 
Amyloid Precursor Protein 
Apo E 
Apoenzyme E 
Apo J 
Apoenzyme J 
aPPT 
activated Partial Thromboplastine Time 
AR 
Adverse Reaction 
Aβ 
Beta-amyloid 
Aβ1−40 
Beta-amyloid 40 peptide 
Aβ1−42 
Beta-amyloid 42 peptide 
BBB 
Blood brain barrier 
BNT 
Boston Naming Test 
BST 
Banc de Sang i Teixits 
CAT 
Computed Axial Tomography 
CDR-sb 
Clinical Dementia Rating-Sum of boxes 
CI 
Confidence Interval 
CK 
Creatine Kinase 
cm 
Centimeter 
CNS 
Central Nervous System 
CHMP 
Committee for Human Medicinal Products 
CRF 
Case Report Form 
CSDD 
Cornell Scale for Depression in Dementia 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CSF 
Cerebral Spinal Fluid 
3D-SPGR 
Three-Dimensional SPoiled Gradient-Recalled  
DICOM 
Digital Imaging and Communications in Medicine 
dL 
Deciliter 
EC 
European Commission 
ECG 
Electrocardiogram 
EMEA 
European Medicines Agency 
FDA 
Food and Drug Administration 
FFP 
Fresh Frozen Plasma 
 
Protocol IG1002 
Page 8 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
GCP 
Good Clinical Practice 
GOT 
Aspartate aminotransferase (Glutamate Oxaloacetate Transaminase) 
GPT 
Alanine aminotransferase (Glutamic Pyruvic Transaminase) 
HBsAg 
Hepatitis B surface Antigen 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus 
HDL 
High Density Lipoprotein 
ICH 
The International Conference on Harmonisation (of Technical 
Requirements for Registration of Pharmaceuticals for Human Use)  
IEC 
Independent Ethics Committee 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
IL-1 
Interleukin-1 
IL-6 
Interleukin-6 
IP 
Investigational Product 
IRB 
Institutional Review Board 
i.v. 
Intravenous 
IVIG 
Intravenous Immunoglobulin 
kg 
Kilogram 
L 
Liter 
LDH 
Lactate Dehydrogenase 
LDL 
Low Density Lipoprotein 
MBq  
Megabecquerel 
MEDRA 
Medical Dictionary for Regulatory Activities 
µg 
Microgram 
mg 
Milligram 
min. 
Minute 
µL 
Microliter 
mL 
Milliliter 
mm 
Millimeter 
MMSE 
Mini-Mental Status Examination 
MRI 
Magnetic Resonance Imaging 
mT/m 
Millitesla per meter 
NGF 
Nerve Growth Factor 
NINCDS-ADRDA 
National Institute of Neurological and Communication Disorders 
and Stroke and the Alzheimer's Disease and Related Disorders 
Association 
NPI 
Neuropyschiatric Inventory 
NPS Battery 
Neuropyschiatric Battery 
OAS 
Overt Aggression Scale 
OSEM 
Object Search Engine Mapping 
pg 
Picogram 
p.o. 
By mouth (Latin “per os”) 
PP 
Per protocol 
 
Protocol IG1002 
Page 9 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
p-Tau 
Phosphorylated Tau protein 
QoL-AD 
Quality of Life Alzheimer Disease 
RUD-Lite® 
Resource Utilization in Dementia 
s.c. 
Subcutaneous 
SDMT 
Symbol Digit Modalities Test 
SPECT 
Single Photon Emission Computed Tomography 
SPM  
Statistical Parametric Mapping 
99mTc-ECD 
Technetium-99m Ethyl Cysteinate Dimer 
TGF 
Transforming growth factor 
T/m/s 
Tesla per meter per second 
T-Tau 
Total Tau protein 
UBC 
United Biosource Corporation 
ULN 
Upper Limit of Normal 
VLDL 
Very Low Density Lipoprotein 
WHO 
World Health Organization 
 
Protocol IG1002 
Page 10 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
PROTOCOL SYNOPSIS (ALBUMIN GRIFOLS + FLEBOGAMMADIF)  
 
STUDY TITLE 
A multicenter, randomized, controlled study to evaluate the 
efficacy and safety of short-term plasma exchange followed 
by long-term plasmapheresis with infusion of human 
albumin combined with intravenous immunoglobulin in 
patients with mild-moderate Alzheimer’s disease. 
SPONSOR 
Instituto Grifols, S.A. 
INVESTIGATIONAL 
PRODUCT AND 
FORMULATION 
Treatment Group: Albutein® 
                              Flebogamma® DIF 
Albutein® and Flebogamma® DIF are approved in USA. 
Control group: Sham procedure. 
INDICATIONS 
Probable mild to moderate Alzheimer’s disease 
OBJECTIVES 
Primary objective 
To evaluate the changes in the cognitive, functional, 
behavioral and global domains based on the different 
applicable psychometric batteries and scales. 
Secondary objectives 
• 
To determine the changes in the concentration of beta-
amyloid peptide in plasma and cerebrospinal fluid (CSF) 
in the treatment group of patients with Alzheimer’s 
disease (AD).  
• 
To evaluate the structural changes in volume of the 
hippocampus, posterior cingulate area, and other 
associated areas based on neuroimaging studies with 
Magnetic Resonance Imaging (MRI) (variations versus 
baseline).  
• 
To determine functional brain functional changes 
through FDG-PET (fluordeoxyglucose-PET). 
• 
To determine whether plasma exchange with human 
albumin combined with intravenous immunoglobulin 
(IVIG) is safe, taking into account the following factors:  
- 
Type, severity and frequency of adverse reactions 
during and after the procedure and infusions. 
- 
Changes in vital signs and clinically relevant 
changes, according to the laboratory test findings. 
- 
Control of episodes of cerebrovascular accidents 
with MRI. 
METHODOLOGY 
A clinical trial comprised of 364 subjects with probable mild 
to moderate AD will be conducted primarily to determine 
whether short-term followed by long-term, low-volume 
plasma exchange with human albumin combined with IVIG 
is able to modify patient’s cognitive, functional, behavioral 
 
Protocol IG1002 
Page 11 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
and global domains. There will be 3 treatment groups and 
one control group. The subjects will be randomized in a 
1:1:1:1 proportion.   
After screening and randomization,  treatment groups will 
proceed as follows:  
• 
One month and a half (6 weeks) of intensive treatment 
with one plasma exchange per week. All 3 treatment 
groups are the same during the intensive treatment phase. 
• 
Two of the three groups will follow 12 months of 
maintenance treatment with one low-volume plasma 
exchange every month combined with IVIG every 4 
months administered at the end of the corresponding 
plasmapheresis 
instead 
of 
albumin 
(that 
is, 
9 
plasmaphereses with Albumin replacement and 3 
plasmaphereses with IVIG replacement). During this 
year patients will follow one of the two different pre-
allocated treatment arms: 1) with the doses of albumin 
and IVIG needed to replace those removed during the 
plasmapheresis, 2) with half of the doses of albumin and 
IVIG, (see Investigational Product Dosage below for 
specific dosage and schedule). 
• 
One of the three groups will follow the same schedule as 
the above two groups but with half of the doses of 
albumin alone (without IVIG), that is, 12 plasmaphereses 
with half-dose albumin alone.  
Patients in the control group will undergo sham procedures 
mimicking plasmaphereses but with neither fluid exchange 
nor albumin or IVIG administrations. 
CLINICAL STUDY 
DESIGN AND 
DESCRIPTION  
A multicenter, randomized, controlled, parallel-group study 
POPULATION SIZE 
AND GROUPS 
364 subjects with probable mild to moderate AD (NINCDS-
ADRDA criterion; McKhann, et al. 1984.) and Mini-mental 
Status Examination (MMSE) score between ≥18 and ≤26.  
There will be sites in Spain and USA. 
The site of the Coordinating Investigator (Fundació 
ACE/Hospital Vall d’Hebron, Barcelona, SPAIN) will be the 
first site to be included. The rest of the sites will be 
incorporated progressively after the first site. Several months 
can elapse between the inclusion of the Spanish sites and the 
rest of sites. 
CLINICAL STUDY 
DURATION 
Enrollment period: 
Aproximately 12 months 
Subject participation (since 
enrollment): 
Up to 14 months 
MAIN SUBJECT 
INCLUSION CRITERIA 
In order to be eligible for participation in the trial, the 
patients must meet the following requirements: 
 
Protocol IG1002 
Page 12 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
1. Males or females between 55-85 years of age at the time 
of signing of the informed consent document. 
2. A diagnosis of AD (NINCDS-ADRDA criterion), and 
Mini-mental Status Examination (MMSE) score between 
≥18 and ≤26. 
3. Current stable treatment with acetylcholine esterase 
inhibitors (AChEIs) and/or memantine for the previous 
three months. 
4. The patient and a close relative or legal representative 
must read the patient information sheet, agree to 
participation in the trial, and then sign the informed 
consent document (the patient personally and the close 
relative/legal representative). 
5. The patient must be able to follow the study protocol, 
receive the treatment in the established time period, and 
continue during the follow-up interval.  
6. A brain Computed Axial Tomography (CAT) or 
Magnetic Resonance Imaging (MRI) study, obtained in 
the 12 months prior to recruitment, showing the absence 
of 
cerebrovascular 
disease, 
should 
be 
available. 
Nevertheless, it is mandatory to use the MRI obtained 
during 
the 
screening 
period 
to 
rule 
out 
any 
cerebrovascular disease such as microhemorrages, 
infarction, hematoma, stroke, meningioma or other 
finding that could affect patient safety.  
7.  A stable care taker must be available, and must attend 
the patient study visits. 
 
Patients meeting any of the following criteria will not be able 
to participate in the trial:  
1. Any contraindication for plasma exchange due to 
behavioral disorders or abnormal coagulation parameters, 
such as for example: 
• Hypocalcemia (Ca++ < 8.7 mg/dL). 
• Thrombocytopenia (<100,000/µL). 
• Fibrinogen <1.5 g/L. 
• Prothrombin time (Quick) p<60% versus control 
(INR>1.5). 
• Beta-blocker treatment and bradycardia <55/min. 
• Treatment 
with 
angiotensin-converting 
enzyme 
inhibitors (ACEIs) (increased risk of allergic 
reactions). 
2. Hemoglobin < 10 g/dL 
3. Difficult venous access precluding plasma exchange. 
4. A history of frequent adverse reactions (serious or 
 
Protocol IG1002 
Page 13 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
otherwise) to blood products. 
5. Hypersensitivity to albumin or allergies to any of the 
components of Albutein®. 
6. History of immunoglobulin A (IgA) deficiency. 
7. Known allergies to Flebogamma® DIF components such 
as sorbitol. 
8. History of thromboembolic complications of intravenous 
immunoglobulins. 
9. Plasma creatinine > 2 mg/dL.  
10. Uncontrolled high blood pressure (systolic blood 
pressure of 160 mmHg or higher and/or diastolic blood 
pressure of 100 mmHg or higher despite regular 
treatment during the last 3 months). 
11. Liver cirrhosis or any liver problem with alanine 
aminotransferase (GPT) > 2.5 x upper limit of normal 
(ULN), or bilirubin > 2 mg/dL. 
12. Heart diseases as evidenced by myocardial infarction, 
severe or unstable angina, or heart failure (New York 
Heart Association Class II, III or IV) in the past 12 
months. 
13. Participation in other clinical trials, or the reception of 
any other investigational drug in the three months prior 
to the start of the study. 
14. Any condition complicating adherence to the study 
protocol (illness with less than one year of expected 
survival, known drug or alcohol abuse, etc.). 
15. Pregnant or nursing women or women not using effective 
contraceptive methods for at least one month after 
plasma exchange. 
16. Fewer than six years of education (exclusion criteria 
under medical criterion). 
17. Less than three months with stable treatment for 
behavioral disorders insomnia. 
18. Patients being treated with anticoagulants or antiplatelet 
therapy (antiaggregants) should not be recruited in the 
study. 
INVESTIGATIONAL 
PRODUCT DOSAGE 
During the treatment phase, and after the screening visits, the 
subject will undergo the following plasma exchanges:  
• 
a maximum of six full replacements with albumin 5% 
(Albutein®, an approved medicinal product) within six 
weeks during the intensive treatment period (all groups) 
• 
a maximum of 9 plasmaphereses with albumin 20% 
(Albutein®, an approved medicinal product) replacement 
plus 3 plasmaphereses with IVIG replacement during the 
maintenance period (two groups). 
• 
one group will undergo 12 plasmaphereses with albumin 
 
Protocol IG1002 
Page 14 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
20%, without IVIG 
The six full replacement sessions of the intensive treatment 
period will be completed in six weeks (one session per 
week). Conventional plasma-exchange devices will be used 
in this intensive period. 
The 12 low-volume replacement sessions (plasmapheresis + 
albumin or IVIG replacement) of the maintenance period 
will be completed in 12 months (one session per month). A 
prototype based on the Auto-CTM device (Fenwal Inc, Lake 
Zurich, IL, USA. FDA PMA approval # BP850001) or the 
AuroraTM device (Fenwal Inc, Lake Zurich, IL, USA. FDA 
510(k) clearance # BK110072) will be used in all sites where 
the low-volume replacement sessions will be performed. 
The volume of plasma taken on each full plasma exchange 
during the intensive period will be approximately that of the 
plasma volume of the subject as calculated from body 
weight, height and hematocrit (approximately 35-45 mL/kg, 
corresponding 
to 
a 
volume 
of 
2500-3000 
mL). 
Approximately the same volume will be replaced with 
albumin 5%. 
 
During the maintenance period the volume of plasma taken 
on each low-volume replacement will be that of a regular 
plasmapheresis (maximun of 880 mL, depending on the 
patient weight) which will be replaced with albumin 20% or 
IVIG, according to the treatment arm, as follows:  
- 1st arm: a maximum of 200 mL of albumin 20% since this 
volume of albumin 20% contains approximately the same 
amount of albumin as that of 880 mL of plasma. When IVIG 
is used, 20 g of IVIG will be administered after 
plasmapheresis for the same reason as above.  
- 2nd arm: a maximum of 100 mL of albumin 20% and 10 g 
of IVIG. 
- 3rd arm: a maximum of 100 mL of albumin 20% alone, 
without IVIG. 
Albumin doses will be adjusted according to the actual 
volume of plasma removed (depending on the patient 
weight). IVIG doses will be fixed for each group. 
COMPARATOR 
PRODUCTS 
N/A 
MODALITIES OF 
TREATMENT 
ADMINISTRATION 
Albutein® administered intravenously. 
Flebogamma® DIF administered intravenously. 
MAIN STUDY 
PARAMETERS 
Efficacy variables:  
• 
Change from baseline in the cognitive scores as 
measured by ADAS-Cog (6 measurements: weeks -3, -2 
 
Protocol IG1002 
Page 15 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
or -1, and 7-8, months 6, 9, 12 and 14) within the 3 
treatment arms. 
• 
Change from baseline in ADCS-ADL inventory (6 
measurements: weeks -3, -2 or -1 and 7-8; months 6, 9, 
12 and 14) within the 3 treatment arms. 
Secondary variables: 
• 
Change from baseline in the cognitive, functional and 
neuropsychiatric scores and overall development as 
measured by MMSE, NPS battery, NPI, CDR-Sb, 
ADCS-CGIC, CSDD, C-SSRS. (6 measurements: weeks 
-3, -2 or -1 and 7-8; months 6, 9, 12 and 14) and QoL-
AD, RUD-Lite® (5 measurements: weeks -3, -2 or -1; 
months 6, 9, 12 and 14). Moreover the optional 
questionnaires like OAS and ABS could be used at any 
visit in case any sign of aggression or restlessness. 
• 
Variation in levels of Aβ1−40 and Aβ1-42 in CSF in the 
period between baseline lumbar puncture (before the start 
of the Intensive treatment period) and lumbar puncture 
immediately after the end of the last low-volume 
plasmapheresis (whenever this may be) 
• 
Variation in the levels of Aβ1−40 and Aβ1−42  in CSF 
between the finalization and beginning of each of the two 
treatment periods. 
• 
Levels of β1−40 , Aβ1−42,  T-tau and P-tau in CSF 
throughout the study. 
• 
Plasma levels of Aβ1−40 and Aβ1−42 before and after 
each plasma exchange for both treatment periods. 
• 
Structural changes in volume of the hippocampus, 
posterior cingulate area, and other associated areas by 
MRI. Five measurements will be made (weeks -3, -2 or -
1 and 7-8; months 6, 9 and 14). 
• 
Variation in FDG-PET patterns (4 measurements: weeks 
-3, -2 or -1 and 7-8; months 9 and 14). 
 
Safety variables: 
• 
The primary criterion of safety will be the percentage of 
plasma exchanges associated with at least one adverse 
event that may be related to the study procedure (adverse 
reactions) within 72h after infusion completion (or after 
the infusion stops). In addition, the percentage of plasma 
exchanges involving some adverse event, whether or not 
related to the procedure, will be considered in general. 
• 
Vital signs will be recorded before, during and after each 
plasma exchange session, where required. Various 
laboratory test parameters (blood cell counts, platelet 
count, prothrombin time (Quick), aPTT, fibrinogen, total 
proteins, and calcium) will also be assessed when 
 
Protocol IG1002 
Page 16 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
necessary. 
• 
During the treatment periods (before each plasma 
exchange) and on the days when there is no replacement, 
anxiety and restlessness tests will be made based on the 
Overt Aggression Scale (OAS) and the Agitated 
Behavior Scale (ABS), whenever considered opportune. 
• 
According to the criterion of the investigator, all 
clinically relevant changes in vital function, laboratory 
test parameters and neuroimaging findings will be 
evaluated. 
ANALYTICAL PLAN / 
STATISTICAL METHOD 
All subjects included in the study and subjected to at least 
one plasma exchange session (i.e., randomized and treated) 
during the intensive treatment phase (the six first weeks of 
treatment) will form part of the efficacy population. Control 
group subjects will also be included (without the plasma 
exchange) if they attended at least 1 of the 6 intensive 
treatment phase visits. 
A second efficacy analysis will also be carried out (per 
protocol analysis, PP) with the subjects who complete the 
treatment without major breaches in the study protocol.  
The statistical tests will be performed with a 5% significance 
level and will be two-sided. In addition to the tests, two-
sided 95% confidence intervals (95% CI) will be reported. 
The analysis of tolerability will be based on description of 
the safety variables according to their nature. 
The adverse reactions will be coded according to the adverse 
events classification of the World Health Organization 
(WHO) (MedDRA current version), and will be described by 
a synonym (Lowest Level Term) and the affected organ / 
system, the intensity, causality and seriousness. 
The statistical analysis will be carried out by UBC (United 
Biosource Corporation). 
 
 
Protocol IG1002 
Page 17 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
INTRODUCTION   
1.1 
Rationale 
1.1.1 Characteristics of Alzheimer’s disease and Its Relation to β-Amyloid Peptide 
Dementia, a mental condition that is related to aging, has become a major public health 
problem.  The proportion of elderly people is increasing in the population, and in future the 
number of individuals with dementia inevitably will increase as well.  This in turn will imply 
an increased burden for health care systems.  Over half of all patients with dementia suffer 
Alzheimer’s disease (AD).  At present, the prevalence of AD in Europe is 2% for the 65-69 
years age interval, 4% for the 70-74 years age interval, and 8% in the 75-80 years age group.  
The incidence increases exponentially with advancing age and doubles every five years. 
AD is characterized by progressive memory and cognitive impairment, with an important 
impact upon patient social and occupational activities.  It is currently accepted that there is no 
cure for AD, and its molecular causes have not been fully clarified to date.  It is assumed that 
the clinical phase is preceded by a 15- to 30-year preclinical period.  However, no existing 
AD diagnostic or follow-up methods based on biological markers or tests are able to detect all 
early cases of the disease. Indeed, the detection and analysis of the histopathological changes 
must be based on the brain findings at autopsy, thus, diagnosis can only be confirmed post-
mortem.  Current treatment is not curative but symptomatic, and its objective is to improve 
patient memory and cognitive functions, or at least to stabilize them to ensure maximum 
patient autonomy1.  It is assumed that in the future treatment will not be based on a single 
management modality; rather, simultaneous interventions will focus on several therapeutic 
targets. 
At present it is only possible to evaluate progression of the disease on the basis of the clinical 
data, cognitive function scales and imaging and biochemical marker (i.e., subrogate marker) 
diagnostic tests. 
AD, as a neurodegenerative process, is expressed by cognitive impairment, which manifests 
in the form of memory loss, speech alterations, visual-spatial deficits, impaired recognition 
capacity and attentional loss among the most relevant neuropsychological aspects.  The 
cognitive alterations are correlated to the evolutional stage of AD and the capacity of the 
affected individual to perform activities of daily living (ADL).  Non-cognitive symptoms or 
neuropsychiatric alterations often accompany AD, depression and behavioral disorders being 
the most prevalent manifestations in the early stages of the disease.  The neuropsychological 
defects and the functional capacities and behavioral disorders or mood states are assessed by 
means of neuropsychological batteries and scales (designed ad hoc).  The differences in pre- 
and post-interventional measures are the parameters used to evaluate the efficacy of the 
currently employed pharmacological treatments and the drugs being evaluated by the different 
Medicinal Agencies.  
On the other hand, the diagnostic utility of different neuroimaging techniques is being 
explored. Computed Axial Tomography (CAT) is useful for detecting some causes of 
dementia, though it is unable to precisely distinguish between early AD and normal aging.  In 
a way similar to CAT, Single-Photon Emission Computed Tomography (SPECT) may prove 
useful for establishing a differential diagnosis in dementia.  Lastly, Magnetic Resonance 
Imaging (MRI) offers superior anatomical discrimination, and generates a more precise image 
of the affected brain areas.  Other technologies and other ways of evaluating the images 
obtained are also being investigated. 
 
Protocol IG1002 
Page 18 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
Regarding the biochemical markers, a number of studies suggest that the concentration of β-
amyloid 42 peptide (Aβ1-42) and of tau protein (total, T-tau and phosphorylated, P-tau) in 
cerebrospinal fluid (CSF) may be of diagnostic value. Thus, the CSF concentration of T-tau 
and P-tau is known to be increased in AD patients, while Aβ1-42 is lower than in healthy 
subjects2,3. 
The accumulation of β-amyloid (Aβ) in the extracellular spaces of the brain and in the walls 
of the cerebral blood vessels is one of the most significant characteristics of AD, and 
presently constitutes one of the most important targets for the development of new therapies4.  
Two predominant types of Aβ plaques are found in the brain of AD patients: neuritic plaques 
and diffuse plaques.  Neuritic plaques contain dense bundles of Aβ fibers surrounding the 
dystrophic neurites, astrocytes and microglia.  The diffuse plaques in turn contain non-
structured Aβ and are not surrounded by dystrophic neurites.  It is believed that the neuritic 
plaques may develop from diffuse plaques3.  The number of neuritic plaques has not shown a 
clear correlation to the severity of dementia in AD; a high density of these structures has also 
been found in elderly persons without dementia3. 
A number of researchers believe that some options for treatment may be to prevent the 
accumulation of such deposits, inhibiting binding of the Aβ monomers, favoring their 
clearance or reducing monomer production.  Unfortunately, there are no adequate animal 
models for reproducing the pathology of Alzheimer’s disease5,6.  Nevertheless, treatments are 
still being investigated to reduce the brain deposits of Aβ.  Recently, studies have been made 
involving active and passive immunization in both transgenic mice and in patients - 
reductions in Aβ being achieved in both cases7,8,9,10. 
In humans, approximately 100-150 mL of cerebrospinal fluid (CSF) circulates within the 
brain ventricles and subarachnoid space.  Each day, 400-500 mL of CSF are generated, 
resulting in replacement of the total CSF volume four to five times a day.  As to the 
composition of CSF, 99% is water, and approximately 20% of its protein content is 
synthesized in the brain. From the proteic perspective, CSF may be regarded as a window to 
the brain.  As a result, studies have centered on the changes in its composition.  If a protein 
quantified in CSF is also present in significant amounts in plasma, and the protein is able to 
cross the blood-brain barrier (BBB), then the concentration in CSF may be influenced by 
changes both within the central nervous system (CNS) and in plasma.  The concentration of a 
particular agent in CSF is a net effect of diffusion from blood, synthesis in the brain, 
clearance and degradation of the agent in the extracellular space, and its final dilution in the 
total volume of CSF. 
1.1.2 Existence of a Dynamic Equilibrium between Brain and Plasma Aβ 
Both tau protein and Aβ1-42 peptide are able to cross the BBB.  Aβ is normally detectable in 
plasma, though the levels are 100-fold lower than in CSF, suggesting that Aβ1-42 is 
predominantly produced in the CNS3.  Earlier studies in both animal models and humans have 
detected the presence of a bidirectional flow of Aβ peptide between the CSF compartment and 
plasma11-19, with involvement of the subependymal and choroid plexus capillaries3.  In some 
cases, it has even been shown that the elimination half-life of Aβ between CSF and plasma is 
about 30 minutes11,18.  On the other hand, some researchers have demonstrated that the plasma 
levels of Aβ decrease as the deposits of the latter within the brain increase20,21, while other 
investigators have reported high plasma levels of Aβ both after active immunization with Αβ7 
and after passive immunization with anti-Aβ antibodies8, 22. 
Taken globally, the above data, i.e., bidirectional flow and deliberate imbalance of the flow in 
one or the other direction, supports the existence of a dynamic equilibrium between plasma 
 
Protocol IG1002 
Page 19 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
and brain Aβ.  In this context, Sigurdsson et al.9, among other authors4, have suggested 
intervention upon Aβ pertaining to the plasma compartment, to induce a reduction in the 
peptide and thus alter the aforementioned equilibrium.  Specifically, Sigurdsson et al. 
recommend the adoption of an Aβ peripheral clearance strategy based on the use of IgM type 
antibodies.  This strategy would have the advantage of sequestering peripheral Aβ, with 
preservation of the brain tissue, since IgM is practically undetectable in CSF9.  In this way, 
the above mentioned authors consider that it would be possible to avoid adverse events 
directly produced by interaction of the antibodies with the brain tissue, as in the documented 
cases of encephalitis that recently have made it necessary to prematurely interrupt a phase II 
clinical trial testing active immunization with Aβ1-42.  Although the precise mechanism 
underlying this complication is not known, some investigators have demonstrated the 
existence of brain vascular microhemorrhages after passive immunization in animal 
studies23,24. 
Other investigators have taken a step further.  Likewise based on the dynamic equilibrium 
principle, they have demonstrated that peripheral sequestering of plasma Aβ using substances 
other than antibodies - though with high affinity for the peptide - is able to reduce both Aβ in 
CSF and in the brain tissues.  Specifically, Matsuoka et al.25 demonstrated the above using 
two different substances, gelsolin and GM1 ganglioside.  Neither of these two substances 
appeared to any appreciable degree in CSF, and both produced the desired imbalance in both 
CSF and brain Aβ.  A relevant observation is the fact that probably encouraged by the 
expectations raised by these results, the mentioned investigators requested a patent of the 
described procedure, in the name of the investigators themselves for the United States and in 
the name of the New York State Office of Mental Health for the rest of the world (WO 
03/051374 A3). 
Recently, Cleary et al.10 have demonstrated that the soluble oligomers of Aβ that go on to 
form part of the amyloid plaques are already neurotoxic before the fibrillar forms are 
produced; as a result, they would play a relevant role in the early forms of AD. 
1.1.3 The Role of Plasma exchange with Albutein® 5% in Alzheimer’s disease 
The amyloid precursor protein (APP) and Aβ itself are secreted during normal cell 
metabolism, with small amounts of both being found in CSF and plasma.  In both 
compartments, Aβ is associated to proteins3 that may contribute to maintain the solubility of 
Aβ.  One such protein is albumin, which is the most abundant protein in both blood and CSF.  
In this sense, albumin is able to bind to and transport a range of small molecules, including 
peptides and drugs.  Only 40% of body albumin is contained in plasma; the remaining 60% is 
found in the extracellular fluids.  The great majority of Aβ circulating in blood (89%) is 
bound to albumin in 1:1 proportion4, and only 5% is bound to high density lipoproteins 
(apoenzyme E, ApoE and apoenzyme J, ApoJ)26,27.  It has been shown that albumin is one of 
the most important binding proteins, and one of the most potent inhibitors of Aβ 
polymerization4. 
Plasma exchange is a process used to eliminate patient plasma and replace it with another 
solution maintaining normal volemia and osmotic balance.  To this effect, albumin or other 
colloids have been used, as well as fresh frozen plasma (FFP) and crystalloids.  The purpose 
of this procedure is to eliminate toxic substances from patient plasma, such as: autoantibodies, 
alloantibodies, immune complexes, proteins, or toxins28.  The clinical efficacy of plasma 
exchange depends on many factors, including the volume exchanged, the number and 
frequency of sessions, the nature of the replacing solution, and the separation technique 
employed.  Data obtained in animal studies have shown human albumin to be neuroprotective 
 
Protocol IG1002 
Page 20 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
in models of acute ischemic infarction, improving neuron function and reducing both infarct 
volume and brain edema29. 
Plasma exchange is widely used in treatment of different pathologies.   Specifically, the 
procedure has been applied to the following disorders: Guillain-Barré syndrome (acute 
treatment)30, 
multiple 
sclerosis 
(chronic 
treatment)28, 
inflammatory 
demyelinating 
polyradiculoneuropathy31, acute inflammatory demyelinating disease of the CNS32 and other 
peripheral neurological alterations33.  Since 2004, the Banc de Sang i Teixits (BST) 
(Barcelona, Spain) has carried out 401 plasma exchange procedures and over 5000 aphereses.  
In comparison with this study, all perform a greater number of replacements, or alternatively 
the volume replaced is greater or the sessions are performed more frequently.  
On the other hand, in the clinical investigation of AD, methods more aggressive than plasma 
exchange have been used, such as ventriculoperitoneal shunting, which is a method involving 
implantation of a catheter connecting the brain ventricles with the peritoneal space for the 
drainage of CSF34,35. 
Albutein® 5% has been marketed in USA since 1978, though albumin had already been in use 
in different countries since the 1940s.  Since then the product has been continuously used in 
application to different clinical conditions, and is even employed as placebo in many clinical 
trials.  
1.1.4 Previous Clinical Studies of Plasma exchange with Albutein® 5% in Alzheimer’s 
disease 
In order to evaluate the effects of plasma exchange with Albutein® 5% in patients with mild to 
moderate AD, Grifols S.A. in 2005 started a pilot study directed by Dr. M. Boada of the 
Service of Neurology of Vall d’Hebron Hospital and of the Fundació ACE in Barcelona, 
Spain.  Ten patients were recruited, of which seven were subjected to plasma exchange, two 
received no treatment, and one was removed from the study upon personal request.  Of the 
seven subjects treated, three underwent five plasma exchanges, two patients received four 
exchanges, and two underwent three exchanges during a period of three weeks.  The 
participants were subsequently followed-up on for a period of 12 months. 
The most important variables recorded were the following:  
• 
changes in the levels of Aβ1-40 and Aβ1-42 in plasma,  
• 
changes in the levels of Aβ1-40 and Aβ1-42  in CSF,  
• 
changes in the neuropsychological test results (MMSE and ADAS-Cog), and 
• 
changes in the neuroimaging studies (MRI and SPECT). 
Results showed a consistent pattern of Aβ mobilization as well as a trend to stabilization in 
the MMSE and ADAS-Cog65.  
Based on these results a phase II clinical trial was conducted in 4 sites, 2 in Spain and 2 in the 
USA, with 42 patients recruited. The trial was a randomized, controlled, single-blind study in 
which 3 different plasma-exchange schedules were assessed: 1) 6 plasma exchanges in 3 
weeks, 2) 6 plasma exchanges in 6 weeks and 3) 6 plasma exchanges in 12 weeks. Therefore, 
patients that completed all cycles underwent a total of 18 plasma exchanges. The control 
group underwent sham (simulations) procedures that mimicked the actual procedures. Interim 
results have recently been published and they show a consistent pattern of Aβ mobilization as 
well as an improvement of the MMSE and ADAS-Cog of 2.5 and 5.5 points, respectively, at 9 
months of follow-up. In terms of Aβ mobilization, the schedule of 6 plasma exchanges in 6 
weeks seemed to be more effective than 6 plasma exchanges in 12 weeks and of similar 
 
Protocol IG1002 
Page 21 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
effectiveness as 6 plasma exchanges in 3 weeks65. Thus, 6 plasma exchanges in six weeks 
were selected as a potential load treatment for future trials. 
1.1.5 The role of intravenous immunoglobulin in Alzheimer’s disease 
In 2004 IVIG was used for the first time in a pilot study of Alzheimer’s disease66. The study 
included 5 patients and the results showed an improvement in the ADAS-Cog scale but not in 
the MMSE. The first randomized clinical trial of IVIG in Alzheimer’s disease was performed 
on 8 patients67 during a follow up of 18 months and the results showed plasma Aβ 
mobilization after each IVIG administration as well as a trend to cognitive stabilization. A 
second randomized clinical trial involving 24 patients has been completed68 and the 
preliminary results presented in the American Academy of Neurology 2010 meeting showed a 
statistical significant improvement of 6 points in the ADAS-Cog scores. In addition, a phase 
III study involving 360 patients is currently ongoing69.  
On the other hand, Grifols S.A. has conducted a pilot study of IVIG in 4 patients that had 
previously participated in the pilot study mentioned in section 1.1.4 and the preliminary 
results showed a similar pattern of plasma Aβ mobilization as compared to that observed in 
the plasma-exchange study. 
1.1.6 Potential role of a combination of plasma exchange with Albutein® with 
Flebogamma®DIF 
Taking into consideration the results of the clinical studies mentioned above, it can be 
concluded that both approaches, plasma exchange with albumin and IVIG infusion, act on the 
peripheral Aβ pool, as seen through the plasma Aβ mobilization observed, and that both 
approaches show a trend to cognitive improvement. Therefore, it seems reasonable to search 
for a synergy between the two treatments using lower doses of each of them which will also 
imply less concern about safety issues. In fact, for selected neurologic diseases, this 
combination approach has already been used70, 71. 
We propose here a combination of monthly low-volume plasma exchanges (similar to regular 
plasma donation plasmaphereses) with IVIG every four months. Previously, there will be a 
load treatment with six plasma exchanges in six weeks to assure the baseline results obtained 
in previous studies. Albutein® and Flebogamma®DIF, two approved products, will be used as 
albumin and IVIG, respectively. 
 
2. 
STUDY PURPOSE AND OBJECTIVES 
Primary objective 
The primary objective of this study is to evaluate the changes in the cognitive, functional, 
behavioral and global domains based on the different applicable psychometric batteries and 
scales. 
Secondary objectives:  
The secondary objectives of this study are: 
• 
To determine the changes in the concentration of beta-amyloid peptide in plasma and 
cerebrospinal fluid (CSF) in the treatment group of patients with Alzheimer’s disease 
(AD) 
• 
To evaluate the structural changes in volume of the hippocampus, posterior cingulate 
area, and other associated areas based on neuroimaging studies with MRI (variations 
versus baseline).  
 
Protocol IG1002 
Page 22 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
• 
To determine functional brain changes through FDG-PET (fluordeoxyglucose-PET). 
• 
To determine whether plasma exchange with human albumin combined with IVIG is 
safe, taking into account the following factors:  
- 
Type, severity and frequency of adverse reactions during and after the procedure 
and infusions. 
- 
Changes in vital signs and clinically relevant changes, according to the laboratory 
test findings. 
- 
Control of episodes of cerebrovascular accidents with MRI. 
 
3. 
INVESTIGATIONAL PLAN 
3.1 
Global Study Design/Developmental Phase 
The trial comprises a multicenter, randomized, controlled design.  The subjects included in 
the study will be controlled from the first screening visit up to fourteen months after. Then, 
the maximum study duration for a given subject will be approximately one year and two 
months.  There will be two weeks for screening and randomization of both groups (treatment 
and control).  After these two weeks the treatment period will proceed as follows:  
• One month and a half (six weeks) of intensive treatment with one full plasma 
exchange per week (all the three groups). 
• Two of the three groups will follow 12 months of maintenance treatment with one 
low-volume plasma exchange every month combined with IVIG every 4 months 
administered at the end of the corresponding plasmapheresis instead of albumin (that 
is, 9 plasmaphereses with Albumin replacement and 3 plasmaphereses with IVIG 
replacement). During this year patients will follow one of the two different pre-
allocated treatment arms: 1) with the doses of albumin and IVIG needed to replace 
those removed during the plasmapheresis, 2) with half of the doses of albumin and 
IVIG. 
• One of the three groups will follow the same schedule as the above two groups but 
with half of the doses of albumin alone (without IVIG), that is, 12 plasmaphereses 
with half-dose albumin alone. 
Patients in the control group will undergo sham procedures mimicking plasmaphereses but 
with neither fluid exchange nor albumin or IVIG administration (See Appendix 8). 
There will be sites in Spain and USA. 
The site of the Coordinating Investigator (Fundació ACE/Hospital Vall d’Hebron, Barcelona, 
SPAIN) will be the first site to be included. The rest of the sites will be incorporated 
progressively after the first site. Several months can elapse between the inclusion of the 
Spanish sites and the rest of sites. 
3.2 
Randomization and Treatment Assignment 
After the screening period, the subjects will be randomized to one of the 3 treatment groups or 
the control group according to a [1:1:1:1] scheme. 
 
Protocol IG1002 
Page 23 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
3.3 
Type of Control 
Control group: the subjects will be AD patients involving the same inclusion and exclusion 
criteria as the treated subjects but will undergo sham procedures mimicking plasmaphereses 
but with neither fluid exchange nor albumin or IVIG administration. 
3.4 
Blinding Techniques 
The control group will be subjected to simulated full plasma exchanges through a non-
invasive procedure. Specifically, the tip of a cut catheter will be stitched to an adhesive gauze 
dressing (acting as a “second skin”) which will be placed on the subclavicular or jugular 
region. Then, a second adhesive gauze will cover the one with the catheter tip stitched to it. 
The cut catheter will be of characteristics similar to the catheters used in the treatment group. 
Also simulated low-volume plasma exchanges will be performed. Likewise, these subjects 
will receive the same visits as the patients in the treatment group. 
This study is blind for patients, caregivers and raters. 
The study Sham manual guideline describes all the sham procedures throughout the study 
(Appendix 9).  
3.5 
Screening Period (Pre-Randomization or Pharmacological Washout) 
There will be a two-week period for screening before the six weeks of intensive treatment. At 
the end of the screening period subjects will be randomized to one of the three treatment 
groups or to the sham group. 
 
4. 
SELECTION OF STUDY POPULATION 
4.1 
Inclusion and Exclusion Criteria 
4.1.1 Inclusion Criteria 
In order to be eligible for participation in the trial, the patients must meet the following 
requirements: 
1. 
Males or females between 55-85 years of age at the time of signing of the informed 
consent document. 
2. 
A diagnosis of Alzheimer’s disease (NINCDS-ADRDA criterion), and MMSE score 
between ≥18 and ≤26. 
3. 
Current stable treatment with AchEIs and/or memantine for the previous three months. 
4. 
The patient and a close relative or the legal representative must read the patient 
information sheet, agree to participation in the trial, and then sign the informed 
consent document (the patient personally and the close relative/legal representative). 
5. 
The patient must be able to follow the study protocol, receive the treatment in the 
established time period, and continue during the follow-up interval.  
6. 
A brain CAT or MRI study obtained in the 12 months prior to screening, showing the 
absence of cerebrovascular disease, should be available. Nevertheless, it is mandatory 
to use the MRI obtained during the screening period to rule out any cerebrovascular 
disease such as microhemorrages, infarction, hematoma, stroke, meningioma or other 
finding that could affect patient safety. 
7. 
A stable care taker must be available, and must attend the patient study visits. 
 
Protocol IG1002 
Page 24 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
4.1.2 Exclusion Criteria 
Patients meeting any of the following criteria will not be able to participate in the trial:  
1. Any contraindication for plasma exchange due to behavioral disorders or abnormal 
coagulation parameters, such as for example: 
• 
Hypocalcemia (Ca++ < 8.7 mg/dL). 
• 
Thrombocytopenia (<100,000/µL). 
• 
Fibrinogen <1.5 g/L. 
• 
Prothrombin time (Quick) p<60% versus control (INR>1.5). 
• 
Beta-blocker treatment and bradycardia <55/min. 
• 
Treatment with ACEIs (increased risk of allergic reactions). 
2. Hemoglobin < 10 g/dL 
3. Difficult venous access precluding plasma exchange. 
4. A history of frequent adverse reactions (serious or otherwise) to blood products. 
5. Hypersensitivity to albumin or allergies to any of the components of Albutein® 5%. 
6. History of immunoglobulin A (IgA) deficiency. 
7. Known allergies to Flebogamma® DIF components such as sorbitol. 
8. History of thromboembolic complications of intravenous immunoglobulins. 
9. Plasma creatinine > 2 mg/dl.  
10. Uncontrolled high blood pressure (systolic blood pressure of 160 mmHg or higher 
and/or diastolic blood pressure of 100 mmHg or higher despite regular treatment 
during the last 3 months). 
11. Liver cirrhosis or any liver problem with GPT > 2.5 x ULN, or bilirubin > 2 mg/dL. 
12. Heart diseases as evidenced by myocardial infarction, severe or unstable angina, or 
heart failure (New York Heart Association Class II, III or IV) in the past 12 months. 
13. Participation in other clinical trials, or the receipt of any other investigational drug in 
the three months prior to the start of the study. 
14. Any condition complicating adherence to the study protocol (illness with less than one 
year of expected survival, known drugs or alcohol abuse, etc.). 
15. Pregnant or nursing women or women not using effective contraceptive methods for at 
least one month after plasma exchange. 
16. Fewer than six years of education (exclusion criteria under medical criterion). 
17. Less than three months with stable treatment for behavioral disorders including 
insomnia. 
18. Patients being treated with anticoagulants or antiplatelet therapy (antiaggregants) 
should not be recruited in the study. 
4.2 
Disease Diagnostic Criteria 
Probable mild to moderate Alzheimer’s disease, according to NINCDS-ADRDA criteria 2, 
with stable AChEI treatment and an MMSE score of ≥18 and ≤26. 
 
Protocol IG1002 
Page 25 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
4.3 
Planned Number of Subjects 
A sample size of 312 subjects (78 per each of the 4 groups) will make it possible to detect 
with nearly 92% power for the first of the co-primary efficacy variable (the changes from 
baseline of the ADAS -Cog scores) a difference in the mean of 3 points between any of the 
treatment groups and the control group, assuming the common standard deviation (SD) to be 
5.55 (according to the data obtained in the phase II study65), with a level of significance of 
5%. This same sample size provides over 98% power for second of the co-primary endpoint 
variables (the changes from baseline of the ADCS-ADL inventory scores) a difference in the 
mean of 6.69 points between any of the treatment groups and the control group, assuming the 
common standard deviation (SD) to be 10.0 (according to the data obtained in the phase II 
study), with a level of significance of 5%. 
The study will have joint power for these co-primary endpoints of at least 90% (0.92*0.98 = 
0.90). The calculation makes the conservative assumption that these endpoints are 
independent. Since these endpoints may be positively correlated 90% should serve as a lower 
bound on power. 
Assuming a global dropout rate of approximately 15%, the study would have to enroll 364 
subjects to obtain 312 subjects for evaluation. 
4.4 
Withdrawal Criteria and Planned Analyses of Withdrawals and Dropouts 
The subject will be withdrawn from the study if:  
• 
Prior to the first plasma exchange session, no plasma sample has been collected for 
possible future assays. 
• 
Any serious adverse event is recorded, advising removal of the subject. 
• 
The subject or his/her legal representative wishes to abandon the study and continue 
follow-up and normal treatment in the center. 
• 
The investigator is of the opinion that treatment continuation is contraindicated.  
• 
The subject fails to adhere to the study protocol. 
The reason for withdrawal of the subject will be documented, and a final visit will be 
scheduled to obtain blood samples and to complete the pertinent tests.  Whenever possible, 
these tests will be made on the same day as the final visit.  No subject can be re-enrolled into 
the study after having been withdrawn from the study. 
4.5 
Treatment of Pre-Randomization Losses, Entry Reclassification 
Subjects withdrawn in the screening phase will not be able to participate in the trial.  As 
discussed above, no subject will be re-enrolled into the study after having been withdrawn 
from the study. 
4.6 
Estimated Duration of the Recruitment Period 
The planned trial recruitment period will last approximately 12 months. 
 
5. 
TREATMENT OF SUBJECTS 
5.1 
Treatment Regimen 
5.1.1 Study Treatment Procedure 
After the screening visits, the subject will receive the following treatment: 
 
Protocol IG1002 
Page 26 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
• 
One month and a half (6 weeks) of intensive treatment with one full plasma exchange per 
week (all the three groups) 
• 
Two of the three groups will follow 12 months of maintenance treatment with one low-
volume plasma exchange every month combined with IVIG every 4 months administered 
at the end of the corresponding plasmapheresis instead of albumin (that is, 9 
plasmaphereses with Albumin replacement and 3 plasmaphereses with IVIG 
replacement). During this year patients will follow one of the two different pre-allocated 
treatment arms: 1) with the doses of albumin and IVIG needed to replace those removed 
during the plasmapheresis, 2) with half of the doses of albumin and IVIG.(See Appendix 
8). 
• 
One of the three groups will follow the same schedule as the above two groups but with 
half of the doses of albumin alone (without IVIG), that is, 12 plasmaphereses with half-
dose albumin alone. 
 
Albutein® 5% (an approved medicinal product) will be used during the intensive period (full 
plasma exchanges). 
Albutein® 20% (an approved medicinal product) will be used during the maintenance period 
(low-volume plasma exchanges), together with Flebogamma® DIF (an approved medicinal 
product). 
5.1.2 Dosage and Treatment Regimen 
The six full replacement sessions of the intensive treatment period will be completed in six 
weeks (one session per week) 
The volume of each full plasma exchange will be approximately that of one plasma volume of 
the patient as calculated from body weight, height and hematocrit (approximately 35-45 
mL/kg, corresponding to a volume of 2500-3000 mL).  
The 12 low-volume plasma exchange sessions (9 with albumin 20% and 3 with IVIG) of the 
maintenance treatment period will be completed in12 months (one session per month). 
The volume of each plasmapheresis during the low-volume plasma exchange period will be 
between 690 and 880 mL of plasma (depending on the patient body weight, following the 
nomogram for plasma donation used in the USA. (See Appendix 3). 
5.1.3 Method of Application 
Full plasma exchanges (Intensive treatment period) 
Full plasma exchanges (FPE) can be carried out via peripheral access or centrally, according 
to the individual characteristics of the subject.  In the latter case, and before the first 
replacement session, a double-lumen catheter must be placed in the subclavian or jugular 
vein.  Implantation and maintenance will be carried out according to the standard procedures 
used in each center but it will be mandatory to perform a chest X-ray to confirm the correct 
placement of the catheter.  Removed plasma volume will be replaced with the same volume of 
Albutein® 5% during the procedure. 
The removed and replaced plasma volume will depend on patient’s characteristics (sex, 
height, weight and hematocrit). It will be approximately 35-45 mL/kg, corresponding to a 
volume of 2500-3000 mL. This volume is calculated automatically by the device or manually 
by the operator depending on the device used.  
 
Protocol IG1002 
Page 27 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
For blinding the control group, adhesive gauze dressing will be placed on the subclavicular or 
jugular region, stitching a catheter of characteristics similar to the catheters used in the 
treatment group (see Appendix 9). 
The central catheter has the advantage of increased convenience for the subject during the 
process, since it allows greater flows and thus shorter session times and obviates the need in 
each session to perform two peripheral venipunctures. The central line access also facilitates 
subject mobility during the procedure.  
Each session is carried out at a rate of 60-100 mL/min., provided replacement is possible 
through a double-lumen catheter placed in the subclavian vein, with a continuous-flow cell 
separator.  Each of these sessions will last approximately two to three hours. The control 
group will be subjected to simulated (sham) plasma exchanges during the same time as the 
subjects in the treatment group. 
Each subject must remain in the facility throughout the procedure and then for as long as 
necessary to ensure a safe return home. 
These details refer to the plasma exchange procedure performed through centrifugation (the 
most commonly used) although the procedure through filtration is also permitted. 
Albutein® 5% will be used according to the instructions of the Full Prescribing Information 
(Appendix 1).  The solution is normally clear to slightly opalescent.  Do not use the product 
if the solution is cloudy or has precipitated.  The product must be at body temperature before 
use.  Do not dilute with water for injections.  Once the container is open, the contents must be 
administered immediately.  Unused contents must be discarded.  No remaining product in an 
opened container can be stored in the refrigerator and used at a later time. 
The vital signs of each subject (blood pressure, heart rate, respiratory rate, and body 
temperature) are to be monitored 15-30 minutes before replacement, during and again 15-30 
minutes after the procedure, and as often as considered opportune by the investigator.  The 
coagulation parameters must also be controlled, particularly fibrinogen concentration.  In the 
case of any relevant alteration in the coagulation parameters, replacement must be suspended 
and no further sessions will be carried out until the parameters return to adequate levels (see 
sections 5.2.1 and 5.2.2). 
Low-volume plasma exchanges (Maintenance treatment period)  
In all sites where the low-volume replacement session will be performed, a device based on 
regular plasma donation (Auto-C, Fenwal, Illinois, USA with FDA PMA approval  # 
BP850001 or Aurora, Fenwal, Illinois, USA with FDA 510(k) clearance # BK110072) will be 
tested (see Appendix 3 for device protocol). The Auto-C (FDA PMA approval # BP850001) 
or Aurora (FDA 510(k) clearance # BK110072) based devices are used with the objective of 
offering the patient a procedure that is similar to a conventional plasma donation with the 
difference that albumin or IVIG will be infused at the end of the plasmapheresis.  
Low volume plasma exchange (LVPE) will be carried out through a peripheral line. The 
removed plasma volume will be similar to that of a plasma donation (690 to 880 mL) and will 
depend on patient’s weight. 
The control group will undergo simulated (sham) low volume plasma exchange which will 
last approximately the same time as the subjects in the treatment group. 
 
 
 
Protocol IG1002 
Page 28 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
Albumin 
Albutein® 20% will be infused at the end of the corresponding plasmapheresis using Auto-C 
(FDA PMA approval # BP850001) or Aurora (FDA 510(k) clearance # BK110072) based 
devices. During the Maintenance period the dosing will be as follows:  
• 
1st arm: 200 mL (40 g, 9 plasmaphereses) 
• 
2nd arm: 100 mL (20 g, 9 plasmaphereses) 
• 
3rd arm: 100 mL (20 g, 12 plasmaphereses) 
 
Therefore, after the LVPE (690 to 880 mL of plasma removal), Albutein® 20% is infused 
depending also on patient’s weight and treatment arm (200 to 80 mL).  Due to the difference 
in volume (removed/infused), it is advised to infuse saline solution to avoid the risk of 
hypotension related events (see Appendix 10 for guidance).  
The main characteristics of the product can be found in the Full Prescribing Information 
(Appendix 1).  The solution is normally clear to slightly opalescent.  Do not use the product 
if the solution is cloudy or has precipitated.  The product must be at body temperature before 
use.  Do not dilute with water for injections.  Once the container is open, the contents must be 
administered immediately. Unused contents must be discarded.  No remaining product in an 
opened container can be stored in the refrigerator and used at a later time. 
Intravenous immunoglobulin infusions 
Flebogamma® DIF will be infused at the end of the corresponding plasmapheresis during the 
Maintenance period following the instructions of the Full Prescribing Information 
(Appendix 2). At the discretion of the investigator, patients can be premedicated with 
paracetamol and antihistamines. 
During the Maintenance period the dosing of IVIG will be as follows:  
• 
1st arm: 20 g 
• 
2nd arm: 10 g 
• 
3rd arm: None (only albumin) 
 
5.2 
Criteria for Treatment Modification or Interruption 
5.2.1 Criteria for Modifying Regimens 
In the case of any relevant alteration in the coagulation parameters, full plasma replacement 
(Intensive period) is to be suspended and no further sessions will be carried out until the 
parameters return to adequate levels. 
Replacement is to be postponed 24 hours if fibrinogen <1 g/L or the prothrombin time 
(Quick) <60% of the control value.  
Platelet depletion to below 100,000/µL is also an indication for replacement suspension. 
Relevant alterations of coagulation parameters are not expected to occur with the low-volume 
plasma exchanges (Maintenance period). 
If any adverse event occurs during the infusion of Flebogamma® DIF one of the following 
actions will be carried out taking into account the nature and severity of the event: 
- 
To stop the infusion. 
- 
To reduce progressively the infusion rate until the symptoms disappear. 
 
Protocol IG1002 
Page 29 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
After re-evaluation the adverse event, it can be proceed as follows: 
- 
To restart the infusion or to increase as of a tolerated rate (once the symptoms 
have disappear) or 
- 
To definitely stop the infusion. 
If a patient presents an adverse event two times with the same infusion rate, the following 
doses will be administered at the maximum tolerated rate. 
5.2.2 Special Warnings and Precautions for Use 
Full plasma exchange is a safe technique that may induce very well-known and therefore 
preventable and controllable, adverse reactions, according to the guidelines provided below.  
In any case, and considering the special vulnerability of the patients studied, a number of 
precautions (in addition to the habitual measures) have been taken to minimize the risks of the 
procedure: 
1. Plasma exchange will be carried out by specialized nursing personnel, under direct and 
continuous supervision by the specialists.  
2. Subjects will be required to remain in the center before and after the procedure for 
longer periods of time than usual.  
3. Vital signs and laboratory test parameters will be monitored more frequently than 
usual. 
4. The treatment suspension / postponement criteria are clearly established. 
5. The person accompanying the subject should be present and/or in proximity before, 
during and after the procedure but not in the same room in order to maintain the blind. 
Exceptionally, agitated patients could be accompanied by the caregiver during the 
procedure in the same room to ease patient’s anxiety. In this case it is mandatory the 
subject is scheduled for the treatment a different day than the rest of the patients. 
The patient will have direct, 24-hour access to the specialist (by mobile phone) in both 
the replacement phase and during subsequent follow-up.  In the case of any incident, 
the physician will decide the actions to take. 
Adverse effects (AEs) may be observed during the replacement procedure, due to the process 
of apheresis, the replacement fluid used, or as a result of the patient disease or idiosyncrasy.  
These AEs include hypocalcemia, hypotension, allergic reaction, coagulation disorders, 
adverse events related to vascular access, and other AEs such as headache, nausea and 
anxiety. 
The information contained in this and the following sections is also valid for plasma removal 
(plasmapheresis) during the low-volume plasma exchange period but the expected AE rate is 
much lower. In fact, the plasmaphereses performed within this period will be very similar to 
those performed for regular plasma donations (e.g., Grifols performs between 12,000 and 
15,000 plasmaphereses for plasma collection daily in the US). 
On the other hand, Albutein® and Flebogamma® DIF are safe products that are widely used 
worldwide. For special warnings and precautions see the corresponding Full Prescribing 
Information (Appendix 1 and 2). 
5.2.2.1 Hypocalcemia 
The great majority of side effects associated with plasma exchange apheresis is due to the 
administration of citrate and are related to diminish ionic calcium availability. Although some 
 
Protocol IG1002 
Page 30 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
adverse reactions not explainable in terms of hypocalcemia, or not resolved by calcium 
dosing, may be attributable to citrate interaction with magnesium (of characteristics similar to 
those of calcium). 
When volume replacement is performed with 5% albumin, the risk of hypocalcemia is 
considerably lower than when plasma is used for replacement (seen historically in 
approximately 7.8% of sessions), and no important toxicity is detected. 
The factors predisposing to hypocalcemia may be patient-related (hypoalbuminemia, vitamin 
D deficiency (malnutrition, malabsorption), hypomagnesemia, hyperphosphatemia, altered 
liver or kidney function or hypoparathyroidism) or related to the procedure (duration of citrate 
infusion >120 minutes, respiratory alkalosis generally induced by tachypnea). 
All plasma exchanges produce transient hypocalcemia that is usually well tolerated by the 
patient.  Occasionally, the decrease in ionic calcium levels can increase nerve cell membrane 
excitability, resulting in symptoms. 
The symptoms and signs of hypocalcemia to be assessed are:  
• 
paresthesias  
• 
headache  
• 
vision alterations (glinting)  
• 
nausea  
• 
cramps 
• 
chest oppression 
The degree of hypocalcemia is rated from 0 to 4 as follows: 
Level 
Symptoms 
Treatment 
0 
None  
None 
1 
Reported by patient, and tolerable 
Calcium p.o. (Sandosten Calcium)  
2 
Cause discomfort 
Infusion of CaCl2 i.v.  
3 
Important discomfort 
Reduce flow 20% 
Infusion of CaCl2 i.v. 
4 
Unbearable 
Stop procedure 
Infusion of CaCl2 i.v. 
Treatment is with a calcium chloride infusion, which may cause arrhythmias.  The calcium 
chloride formulation must be infused diluted in physiological saline solution, at a maximum 
concentration of 2 mg/mL. 
As each infused milliliter of acid citrate-dextrose A (ACD-A) neutralizes 0.5 mg of calcium, 
the calcium chloride dose will be equal to the milliliters of ACD-A infused in the last hour 
multiplied by 0.5 and by the calcium chloride concentration of the dilution employed (2 
mg/mL), using the following formula:  
Volume of calcium chloride = Volume of ACD-A (last hour) / 4 
The formulation is administered via drip through the return catheter, in 10-15 minutes.  This 
rate may vary according to whether the symptoms improve or not. 
If the patient shows Level 2 symptoms from the start or before the first 120 minutes of 
replacement, prophylactic blood calcium treatment should be provided.  A 0.2 mg/mL 
calcium chloride solution is prepared and infused through the return catheter.  To calculate the 
infusion rate, the following must be applied:  
 
Protocol IG1002 
Page 31 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
• Correcting factor of the amount of ACD-A/ml citrated blood 
• Proportion of ACD-A / blood 
• Access flow 
 
Protocol IG1002 
Page 32 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
Table 1 below specifies the calcium chloride infusion rate (concentration 2 mg/mL) when administered prophylactically on a continuous basis according to the separator inlet 
flow, the proportion ACD-A / blood, and the correction factor. 
Administration of CaCl2 
CaCl2 infusion rate in ml/hour (concentration 2 mg/ml) according to inflow rate and ACD-A: blood ratio 
 
Flow (ml/min) 
Ratio 
15 
20 
25 
30 
35 
40 
45 
50 
55 
60 
65 
70 
75 
80 
85 
90 
95 
100 
105 
110 
115 
120 
125 
130 
1:30 
7 
9 
12 
14 
16 
19 
21 
23 
26 
28 
30 
32 
35 
37 
39 
42 
44 
46 
49 
51 
53 
56 
58 
60 
1:29 
7 
10 
12 
14 
17 
19 
22 
24 
26 
29 
31 
34 
36 
38 
41 
43 
46 
48 
50 
53 
55 
58 
60 
62 
1:28 
7 
10 
12 
15 
17 
20 
22 
25 
27 
30 
32 
35 
37 
40 
42 
45 
47 
50 
52 
55 
57 
60 
62 
65 
1:27 
8 
10 
13 
15 
18 
21 
23 
26 
28 
31 
33 
36 
39 
41 
44 
46 
49 
52 
54 
57 
59 
62 
64 
67 
1:26 
8 
11 
13 
16 
19 
21 
24 
27 
29 
32 
35 
37 
40 
43 
45 
48 
51 
54 
56 
59 
62 
64 
67 
70 
1:25 
8 
11 
14 
17 
19 
22 
25 
28 
31 
33 
36 
39 
42 
45 
47 
50 
53 
56 
58 
61 
64 
67 
70 
72 
1:24 
9 
12 
14 
17 
20 
23 
26 
29 
32 
35 
38 
41 
43 
46 
49 
52 
55 
58 
61 
64 
67 
70 
72 
75 
1:23 
9 
12 
15 
18 
21 
24 
27 
30 
33 
36 
39 
42 
45 
48 
51 
54 
57 
60 
64 
67 
70 
73 
76 
79 
1:22 
9 
13 
16 
19 
22 
25 
28 
32 
35 
38 
41 
44 
47 
51 
54 
57 
60 
63 
66 
70 
73 
76 
79 
82 
1:21 
10 
13 
17 
20 
23 
26 
30 
33 
36 
40 
43 
46 
50 
53 
56 
60 
63 
66 
70 
73 
76 
79 
83 
86 
1:20 
10 
14 
17 
21 
24 
28 
31 
35 
38 
42 
45 
49 
52 
56 
59 
63 
66 
70 
73 
77 
80 
83 
87 
90 
1:19 
11 
15 
18 
22 
26 
29 
33 
37 
40 
44 
48 
51 
55 
59 
62 
66 
70 
73 
77 
81 
84 
88 
92 
95 
1:18 
12 
15 
19 
23 
27 
31 
35 
39 
43 
46 
50 
54 
58 
62 
66 
70 
73 
77 
81 
85 
89 
93 
97 
100 
1:17 
12 
16 
20 
25 
29 
33 
37 
41 
45 
49 
53 
57 
61 
65 
70 
74 
78 
82 
86 
90 
94 
98 
102 
106 
1:16 
13 
17 
22 
26 
30 
35 
39 
43 
48 
52 
57 
61 
65 
70 
74 
78 
83 
87 
91 
96 
100 
104 
109 
113 
1:15 
14 
19 
23 
28 
32 
37 
42 
46 
51 
56 
60 
65 
70 
74 
79 
83 
88 
93 
97 
102 
107 
111 
116 
121 
1:14 
15 
20 
25 
30 
35 
40 
45 
50 
55 
60 
65 
70 
75 
79 
84 
89 
94 
99 
104 
109 
114 
119 
124 
129 
1:13 
16 
21 
27 
32 
37 
43 
48 
54 
59 
64 
70 
75 
80 
86 
91 
96 
102 
107 
112 
118 
123 
128 
134 
139 
1:12 
17 
23 
29 
35 
41 
46 
52 
58 
64 
70 
75 
81 
87 
93 
99 
104 
110 
116 
122 
128 
133 
139 
145 
151 
1:11 
19 
25 
32 
38 
44 
51 
57 
63 
70 
76 
82 
89 
95 
101 
107 
114 
120 
126 
133 
139 
145 
152 
158 
164 
Protocol IG1002 
Page 33 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
5.2.2.2 Hypotension 
Hypotension, presents as paleness and perspiration, with lowered blood pressure and 
bradycardia.  This AE appears as a result of a vasovagal response secondary to hypothalamic 
stimulation, and is very rarely attributable to volemia if the separator used is of the continuous 
flow type (seen historically in approximately 2.6% of all processes).  
The predisposing factors may be patient-related (low body weight, a history of vasovagal 
reactions, or a low hematocrit) or related to the procedure (equipment fatigue or 
extracorporeal volume >20% of patient volemia). 
The initial symptoms and signs include:  
• perspiration  
• bradycardia 
• hypotension  
The progressive manifestations comprise:  
• nausea   
• vomiting  
• syncope  
• involuntary defecation 
• seizures 
Treatment of hypotension consists of interrupting the process, opening the serum access, 
placing the patient horizontal or in the Trendelenburg position, recording blood pressure and 
pulse, and waiting for recovery while investigating the cause (disconnect in case of equipment 
leakage; if other cause is involved, assess continuation). Recommendations for preventing 
hypotension related events in low-volume plasma exchange procedures have been captured in 
a study guideline. Hypotension episodes can be avoided by infusing saline solution and 
adjusting the removed plasma volume in low-weight patients (see Appendix 10). 
5.2.2.3 Allergic reaction 
Allergic reactions are generally associated with the blood components and albumin, though 
they may also be due to ethylene oxide or other medication. 
The signs and symptoms include: 
• urticaria  
• dyspnea  
• wheezing  
• hypotension  
• tachycardia  
• facial reddening 
• palpebral edema 
In case the patient suffers from an allergic reaction the site should follow their standard 
procedures to manage the situation. As a recommendation, mild allergic reactions could be 
controlled with antihistamines (diphenhydramine 25-50 mg i.v.). In case the reaction 
continues, or in the event of anaphylactic manifestations, it could be administered 0.3-0.5 mL 
of epinephrine 1:1000 s.c.  This dose may be repeated after 10-15 minutes if no response is 
elicited.  It is also possible to add methylprednisolone 100 mg i.v. 
Protocol IG1002 
Page 34 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
5.2.2.4 Coagulation disorders 
When the extracted plasma is replaced with albumin, coagulation disorders may develop due 
to dilution of the coagulation factors, mainly lowered blood fibrinogen, since its half-life is 72 
hours.  During daily plasma exchange sessions the fibrinogen concentration may drop to 
below 1 g/L, requiring the infusion of plasma or fibrinogen.  When replacement is performed 
every 72 hours, such measures are not necessary. 
Minor bleeding associated with severe thrombopenia has been observed (seen historically in 
approximately 2.2%). 
5.2.2.5 AEs Related to vascular access 
The central catheter has the advantage of increased convenience for the subject during the 
process, since it allows greater flows and thus shorter session times, obviating the need in 
each session to perform two peripheral venipunctures. 
As to the adverse effects if the catheter is placed in the subclavian vein, the risk of infection is 
minimal.  Thus, while the incidence of infections with all the catheters is <5 per 1000 days 
(<3% of all catheters), this incidence decreases considerably if only those placed in the 
subclavian vein are considered23,24.  Pneumothorax, hemothorax, bleeding at the time of 
placement and thrombosis in the case of indwelling catheters left in place for extended 
periods of time may be seen. The recommendations for the treatment and prevention of fever 
management and thromboembolic events have been captured in two study guidelines (see 
Appendix 11 and Appendix 12, respectively); nonetheless the sites should follow their local 
procedures.  
As to adverse events related to peripheral access, the most commonly expected are: pain, 
phlebitis, infiltration and extravasation. 
5.2.2.6 Other AEs and their treatment  
Other potential AEs include headache, nausea and anxiety. 
• Headache: administer paracetamol (acetaminophen) p.o. 1 g 
• Nausea: administer Primperan p.o. (Reglan) 5 mL 
• Anxiety: administer diazepam p.o. 5 mg (for body weight <55 kg) or 10 mg (weight > 
55 kg), or alprazolam at doses of 0.5 mg and 1 mg, respectively 
• IG levels decrease: A decrease in the IGs levels could occur during the FPE period. IG 
levels will recover their normal range at the end of the FPE period. Further 
investigations will be needed if the levels are not reestablished which may suggest an 
underlying pathology 
• Anemia: Although not frequently, it is expected to observe anemia in patients with 
haematocrit in the low normal range after the first FPEs. In these cases, oral or 
intravenous iron therapy is recommended depending on the severity of the anemia and 
the investigator assessment 
 
The recommendations to treat those AE are described above; nevertheless, the sites should 
follow their local procedures. 
 
5.2.2.7 Incidence of adverse reactions and mortality 
In a 1996 review of the adverse effects of plasma exchange in patients with Guillain-Barré 
syndrome, involving albumin replacements, a decrease in immediate adverse effects from 
Protocol IG1002 
Page 35 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
12% in 1986 to 7% in 1992 was recorded.  Allergic reactions and hypotension were the most 
frequent problems.  The estimated mortality was 1-2 deaths per 10,000 sessions, or two deaths 
per 2000 patients.  
As stated earlier, the expected rate of AEs during the plasmaphereses of the low-volume 
plasma exchanges (Maintenance period) is much lower than that expected during the full 
plasma exchanges (Intensive period). For the expected adverse reactions relative to Albutein® 
and Flebogamma® DIF see Section 9.1.3 and the corresponding Full Prescribing 
Information (Appendix 1 and 2). 
5.3 
Concomitant Treatment 
Subjects may continue to receive his/her usual medication.  In particular, the same 
acetylcholine esterase inhibitor (AChEI) and/or memantine treatment is to be continued, 
without modification during the study. If the subject develops adverse reactions related with 
the AChEI and/or memantine treatment, advising its withdrawal, the medication should be 
replaced by another drug of the same group at the end of all the plasma exchanges. 
Regarding IVIG administrations, the subject can be premedicated with paracetamol and 
antihistamines or corticosteroids at the discretion of the investigator. There are some sites that 
include corticosteroids administration during immunoglobulin infusion. 
Treatment with angiotensin-converting-enzyme inhibitors (ACEIs) is not allowed during the 
study. Principal Investigator may consider changing the medication to other antihypertensive 
drug at the screening visit and maintaining throughout the study. 
Any medication administered during the study (including any blood products) will be 
recorded on the case report form (CRF). 
5.4 
Special Guidelines for Study Drug Handling 
Albutein® and Flebogamma® DIF that are supplied for use in the trial are to be destined 
exclusively to the study.  Any unused material must be returned to the sponsor or at the 
discretion of the sponsor, may be destroyed at the center according to their SOPs.  
The investigator (or pharmacist) or designated team member is to keep all records of drug 
utilization.  The sponsor will provide specific forms to be completed by the investigator, 
pharmacist or designated team member, at the time of dispensation.  These forms can be 
replaced by proprietary forms of the study center, provided they meet the requirements of the 
sponsor.  
Once the forms have been completed, they must be signed and dated by the monitor and by 
the investigator to confirm their accuracy.  
5.4.1 Storage of Albutein® and Flebogamma® DIF 
Albutein® is to be stored at a temperature below 30ºC.  The shelf life is three years when 
maintained at this temperature. 
The product should not be frozen.  Once the container is open, the contents must be 
administered immediately.  Unused contents must be discarded according to the Center’s 
SOP.  No remaining product in an opened container can be stored in the refrigerator and used 
at a later time.  This product must not be used beyond the expiry date stated on the labeling.  
The solution is normally clear to slightly opalescent. Do not use the IP if the solution is 
cloudy or has precipitated.  
The product must be warmed to body temperature before use. 
Protocol IG1002 
Page 36 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
Access to the product must be strictly limited. 
Flebogamma® DIF is a liquid product and then reconstitution is not necessary. Flebogamma® 
DIF should be stored below 25°C, should not be frozen and has a shelf-life of two years when 
stored at this temperature. It must not be frozen and the unused contents of the vial should be 
kept separately until drug accountability has been completed. Vials must be inspected for 
particles and discoloration before administration. Solutions with evidence of turbidity should 
not be used because of the risk of bacterial contamination. Flebogamma® DIF must not be 
mixed with other pharmaceutical products or intravenous solutions, and a dedicated sterile 
infusion line should be used to ensure proper administration. Flebogamma® DIF must be 
brought to room temperature before infusion and administered intravenously through a 
separate infusion line. Mixing and administration of any other drug (including normal saline) 
with Flebogamma® DIF is strictly prohibited. 
5.5 
Measures to Assess Compliance 
Such measures are not applicable, since the procedure is carried out under the supervision of 
the principal investigator, and in the hospital setting. 
5.6 
Rescue Medication 
No rescue medication is being provided under the clinical trial.  The principal investigator is 
responsible for follow-up of the medical needs of the subject.  During the treatment phase, the 
physician supervising the plasma exchanges will propose the adequate measures according to 
the condition of the subject. 
6. 
TRIAL CONDUCT AND RESPONSE ASSESSMENT 
6.1 
Study Variables 
6.1.1 Primary Efficacy Variable 
Change from baseline in the cognitive scores as measured by ADAS-Cog (6 measurements: 
weeks -3, -2 or -1 and 7-8; months 6, 9, 12 and 14) within the 3 treatment arms. 
Change from baseline in the ADCS-ADL inventory (6 measurements: weeks -3, -2 or -1 and 
7-8; months 6, 9, 12 and 14) within the 3 treatment arms. 
Since it has been suggested that systemic infections can have a detrimental effect on cognitive 
scores, monitoring of subjects for number and type of bacterial infections requiring antibiotics 
will be performed. 
6.1.2 Secondary Efficacy Variables 
a) Change from baseline in the cognitive, functional and neuropsychiatric scores and overall 
development as measured by MMSE, NPS battery, NPI, CDR-Sb, ADCS-CGIC, CSDD 
and C-SSRS. (6 measurements: week -3, -2 or -1 and 7-8; months 6, 9, 12 and 14) and 
QoL-AD, RUD-Lite® (5 measurements: weeks -3, -2 or -1; months 6, 9, 12 and 14). 
Moreover the optional questionnaires like OAS and ABS could be used at any visit in case 
any sign of aggression or restlessness. 
b) Variation in levels of Aβ1−40 and Aβ1-42 in CSF in the period between baseline lumbar 
puncture (before the start of the Intensive treatment period) and lumbar puncture 
immediately after the end of the last low-volume plasmapheresis (whenever this may be) 
c) Variation in the levels of Aβ1−40 and Aβ1−42  in CSF between the finalization and 
beginning of each of the 2 treatment periods. 
d) Levels of Aβ1−40 , Aβ1−42, T-tau   and P-tau in CSF throughout the study. 
Protocol IG1002 
Page 37 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
e) Plasma levels of Aβ1−40 and Aβ1−42 before and after each plasma exchange for both 
treatment periods. 
f) Structural changes in volume of the hippocampus, posterior cingulate area, and other 
associated areas by MRI. Five measurements will be made (weeks -3, -2 or -1 and 7-8; 
months 6, 9 and 14). 
g) Variation in FDG-PET patterns (4 measurements: weeks -3, -2 or -1 and 7-8; months 9 
and 14). 
6.1.3 Safety Variables 
The primary criterion of safety will be the percentage of plasma exchanges (full and low-
volume exchanges, including the infusion of albumin and IVIG) associated with at least one 
adverse event that may be related to the study procedure (adverse reactions).  In addition, 
consideration globally will be made of the percentage plasma exchanges (full and low-volume 
exchanges, including the infusion of albumin and IVIG) involving some adverse event, 
whether or not related to the procedure. 
Vital signs (blood pressure, heart rate, respiration rate, and body temperature) will be 
recorded before, during and after each plasma exchange session, where required. Evaluation 
will also be made (where required) of the different laboratory test parameters (blood cell 
counts, platelet count, prothrombin time (Quick), aPPT, fibrinogen, total proteins, and 
calcium). 
During the treatment periods (before each plasma exchange) and on the days when there is no 
replacement, anxiety and restlessness tests will be made based on the Overt Aggression Scale 
(OAS) and the Agitated Behavior Scale (ABS), whenever considered opportune. 
According to the criterion of the investigator, all the clinically important changes in vital 
function, laboratory test parameters and neuroimaging findings will be evaluated. 
 
6.2 
Conduction of the Trial. Study Procedures. 
See Appendix 8 for the Study Summary Table and for the Study Flow Chart. 
6.2.1 Screening Visits (Weeks -3, -2 and -1) 
After obtaining informed consent, there will be screening period of up to 3 weeks which could 
consist of multiple visits.  During the screening visit, all demographic data will be collected.  
Documentation will also include vital signs (axillary temperature, heart and respiration rate, 
and blood pressure) and physical examinations with ECG and a sample of blood for genetic 
markers determination.  
Also at the screening visit, the subject’s medical history, including AD, will be recorded 
together with the medication used in the preceding month.  The CRF will also register a brief 
history of AD and the prior treatments received.  However, on subsequent visits, recording 
will be limited to the abnormal conditions observed during the previous visit, along with the 
concomitant medication and any adverse event that may have been detected. 
Sufficient blood will be collected for all the laboratory tests, and a plasma sample will be 
stored at -70ºC for any possible future analysis.  
The following parameters will also be evaluated: biomarkers of AD (Aβ−40, Aβ−42, β-
secretase, γ-secretase, cholesterol, LDL, HDL, VLDL, C-reactive protein, rheumatoid factor, 
IL-1b, IL-6, ferritin, ΤΝF-α), coagulation factors (prothrombin time (Quick), aPPT, calcium 
Protocol IG1002 
Page 38 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
and fibrinogen), proteinogram (total proteins, albumin, α1-globulina, α2-globulina, β-
globulina, γ-globulina and IgG), other liver or kidney biochemical markers (AST, ALT, 
bilirubin, LDH and creatinine), troponin and serology (anti-HIV and HCV antibodies, and 
HBsAg antigen).  In addition, a blood cell count will be performed, including: hematocrit, 
hemoglobin and erythrocytes, platelets and leukocytes (if an abnormal leukocyte count is 
recorded, it will be obligate to specify neutrophils, basophils, eosinophils, lymphocytes and 
monocytes).  
All the inclusion criteria are to be confirmed again after obtaining the laboratory test results. 
If the inclusion criteria are not met, or if some exclusion criterion proves applicable, the 
patient may not be entered into the study. 
During the study period between week -3 and the first plasma exchange (week 0), MRI and 
FDG-PET will be performed. 
At the same time, during this study period (from week -3 to week 0), the following tests will 
be administered to measure cognition, functionality, behavior, global evolution, impression 
and depression : MMSE, ADAS-Cog, NPS battery, ADCS-ADL, NPI, CDR-Sb, ADCS-
CGIC, CSDD, CSSRS, QoL-AD and RUD-Lite® which are to be administered as indicated in 
the corresponding section.  Likewise, anxiety and restlessness tests will be made based on the 
Overt Aggression Scale (OAS) and the Agitated Behavior Scale (ABS), whenever considered 
opportune. 
If the subject is to receive full plasma exchanges through a central venous access, a double-
lumen catheter will be placed in the subclavian or jugular vein before the full plasma 
exchange period. It is advisable to place the catheter a few days before the first plasma 
exchange session. For the low-volume exchanges peripheral access will be used. 
Furthermore, it is obligatory to perform lumbar puncture before the first plasma exchange, to 
collect CSF samples and assess the levels of Aβ−40, Aβ-42, P-tau, T-tau, β-secretase, γ-
secretase, cholesterol, LDL, HDL, VLDL, C-reactive protein, IL-1b, IL-6, ferritin, TNF-α) 
and to perform standard CSF tests (cell counts, glucose, proteins and albumin). Time 
collection for the CSF must be between 8am and 12am.  If these procedures are not carried 
out in the days preceding plasma exchange, they will have to be done on the day of first 
plasma exchange with the subject remaining at rest until indication by the investigator that 
plasma exchange can be carried out.  These evaluations are considered to be the baseline data.  
6.2.2 Weeks 1 to 6 - Intensive plasma exchange period 
Full Plasma Exchange (Window range +/- 1 day) 
Plasma samples will be collected from the subject before and 15-30 minutes after each 
procedure, to allow the pertinent tests.  Additional plasma samples will be collected each time 
for storage at -70ºC and possible future assays.  
The following tests will be made before each procedure: biomarkers of AD (Aβ−40, Aβ−42, 
β-secretase, γ-secretase, cholesterol, LDL, HDL, VLDL, C-reactive protein, rheumatoid 
factor, IL-1b, IL-6, ferritin and TNF-α), coagulation factors (prothrombin time (Quick), 
aPPT, calcium and fibrinogen) and proteinogram (total proteins, albumin, α1-globulina, α2-
globulina, β-globulina, γ-globulina and IgG). In addition, a cell count will be made including 
hematocrit, hemoglobin and erythrocytes, platelets and leukocytes (if an abnormal leukocyte 
count is recorded, it will be obligate to specify neutrophils, basophils, eosinophils, 
lymphocytes and monocytes).  The samples obtained after plasma exchange will be used to 
evaluate the biomarkers of AD, cell count, platelets, coagulation factors (prothrombin time 
Protocol IG1002 
Page 39 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
(Quick), aPPT, calcium), proteinogram, fibrinogen and troponin, as well as other 
biochemistry parameters (AST, ALT, LDH and creatinine). 
A maximum of six full plasma exchange sessions will be made during this period: one per 
week.  
The subject will remain in the center throughout the procedure and then for as long as needed 
to ensure a safe return home, under conditions similar to before plasma exchange.  
Before plasma exchange, a physical examination will be made, with the recording of any 
anomalies.  Concomitant medication is also to be registered, together with any adverse event 
detected since the last visit or since the last plasma exchange session.  The anxiety and 
restlessness tests, if necessary, will be performed before each plasma exchange process, and 
between 15-30 minutes after replacement.  These tests will be carried out by the same patient 
supervisor. 
Vital signs (axillary temperature, heart and respiration rate, and blood pressure) will be 
determined 15-30 minutes before replacement during and again 15-30 minutes after the 
procedure, and as often as considered opportune by the investigator.  
Any adverse event during or after the procedure, will be recorded. 
Control group 
The control group will undergo simulated (sham) full plasma exchanges and will follow the 
same schedule of assessments including the lumbar puncture. 
6.2.3 Weeks 7 to 8 – Intermediate visit (Window range +/- 2 days) 
Plasma samples will be collected from the subjects (control and full plasma exchange group) 
to allow the pertinent tests.  Additional plasma samples will be collected each time for storage 
at -70ºC and possible future assays.  
The following tests will be made: biomarkers of AD (Aβ−40, Aβ−42, β-secretase, γ-secretase,  
cholesterol, LDL, HDL, VLDL, and C-reactive protein, rheumatoid factor, IL-1b, IL-6, 
ferritin, ΤΝF-α) and plasma IgG.  
During the visit medical history will be checked with the recording of any anomalies.  
Concomitant medication is also to be registered, together with any adverse event detected 
since the last visit or since the last plasma exchange session.   
Central catheter will be also extracted during this intermediate visit. 
After the intensive plasma exchange period (weeks 1 to 6) and before Maintenance period, 
lumbar puncture will be performed to assess the levels of Aβ−40, Aβ−42, P-tau, T-tau and 
other Alzheimer’s disease biomarkers together with standard tests (cell counts, glucose, 
proteins and albumin).  Time collection for the CSF must be between 8am and 12am.   
During this intermediate visit (weeks 7 to 8) the following cognitive impairment and 
behavioral tests will be made: ADAS-Cog, MMSE, NPS battery, ADCS-ADL, NPI, CDR-Sb, 
ADCS-CGIC, CSDD and CSSRS.  Likewise, anxiety and restlessness tests will be made 
based on the Overt Aggression Scale (OAS) and the Agitated Behavior Scale (ABS), if 
considered opportune. 
During the study period between week 7 and 8, a FDG-PET and an MRI will be also carried 
out. 
Control group 
Protocol IG1002 
Page 40 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
The control group will undergo simulated (sham) central catheter removal and will follow the 
same schedule of assessments as the treated groups 
6.2.4 Months 3 to 14 - Maintenance Period 
Treatment Groups: Maintenance Period (Plasmaphereses + albumin or IVIG) (Window 
range +/- 5 days) 
At months 6, 9, 12 and 14, the following cognitive impairment and behavioral tests will be 
made: ADAS-Cog, MMSE, NPS battery, ADCS-ADL, NPI, CDR-Sb, ADCS-CGIC, CSDD, 
CSSRS, QoL-AD and RUD-Lite®. Likewise, anxiety and restlessness tests will be made 
based on the Overt Aggression Scale (OAS) and the Agitated Behavior Scale (ABS), 
whenever considered opportune. 
The plasma samples of the patient will be collected before and 15-30 minutes after each 
procedure, to allow the pertinent tests.  These plasma samples collected before and after the 
procedure will be stored at -70ºC for possible future assays.  
The following tests will be made before each procedure: biomarkers of AD (Aβ−40, Aβ−42, 
β-secretase, γ-secretase, cholesterol, LDL, HDL, VLDL, C-reactive protein, rheumatoid 
factor, IL-1b, IL-6, ferritin, TNF-α), coagulation factors (prothrombin time (Quick), aPTT, 
calcium and fibrinogen), and proteinogram (total proteins, albumin, α1-globulina, α2-
globulina, β-globulina, γ-globulina and IgG). In addition, a cell count will be made including 
hematocrit, hemoglobin and erythrocytes, platelets and leukocytes (if an abnormal leukocyte 
count is recorded, it will be obligate to specify neutrophils, basophils, eosinophils, 
lymphocytes and monocytes). The samples obtained after plasma exchange will only be used 
to evaluate the biomarkers of AD and, if necessary, to assess coagulation factors. A more 
intense monitoring is not considered mandatory since in this period the procedure is similar to 
a plasma donation plasmapheresis. However, the investigator can decide to assess other 
parameters for safety reasons. Other liver or kidney biochemical markers (AST, ALT, 
bilirubin, LDH, creatinine and troponin), and serology (anti-HIV and HCV antibodies, and 
HBsAg antigen) will be also done.. 
There will be 3 treatment groups. A maximum of 12 plasmaphereses will be performed, one 
plasmapheresis per month. In the first treatment group there will be 9 plasmaphereses with 
infusion of albumin 20% (200 mL, 40 g) at months 4, 5, 6, 8, 9, 10, 12, 13 and 14 and 3 
plasmaphereses with infusion of IVIG (20 g) at months 3, 7 and 11. In the second treatment 
group, the schedule will be the same as previous but with half of the dose of albumin 20% 
(100 ml, 20 g) and IVIG (10 g). The third treatment group will follow the same schedule but 
only half-dose albumin (100 ml, 20 g) will be administered in each of the 12 plasmaphereses, 
that is, this group will not receive IVIG. The plasma removed and the albumin infused after 
the procedure depends on patient’s weight (see Table 1, Appendix 10). 
The subject will remain in the center throughout the procedure and then for as long as needed 
to ensure a safe return home, under conditions similar to before the procedure. 
Before each plasmapheresis, a physical examination will be made, with the recording of any 
anomalies. Concomitant medication is also to be registered, together with any adverse event 
detected since the last visit or since the last plasma exchange session.  
The anxiety and restlessness tests, if necessary, will be performed before each plasmapheresis, 
and between 15-30 minutes after the administration of albumin or IVIG.  These tests will be 
carried out by the same patient supervisor. 
Protocol IG1002 
Page 41 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
Vital signs (axillary temperature, heart and respiratory rate, and blood pressure) will be 
determined 15-30 minutes before plasmapheresis, during and again 15-30 minutes after the 
administration of albumin or IVIG and as often as considered opportune by the investigator.  
Any adverse event during or after the procedure, will be recorded. 
A FDG-PET will be carried out at months 9 and an MRI also will be carried out at months 6, 
and 9. 
Control group 
The control group will undergo simulated (sham) low-volume plasma exchanges but will 
follow the same schedule of assessments. 
6.2.5 Final Visit (Month 14) 
During the final visit medical history will be checked with the recording of any anomalies.  
Concomitant medication is also to be registered, together with any adverse event detected 
since the last visit or since the last plasma exchange session.   
Plasma samples will be collected from the subjects (control and treatment group) to allow the 
pertinent tests. Additional plasma samples will be collected each time for storage at -70ºC and 
possible future assays. 
The following parameters will also be evaluated: biomarkers of AD (Aβ−40, Aβ−42, β-
secretase, γ-secretase, cholesterol, LDL, HDL, VLDL, C-reactive protein, rheumatoid factor, 
IL-1b, IL-6, ferritin, ΤΝF-α), coagulation factors (prothrombin time (Quick), aPTT, calcium 
and fibrinogen), proteinogram (total proteins, albumin, α1-globulina, α2-globulina, β-
globulina, γ-globulina and IgG), other liver or kidney biochemical markers (AST, ALT, 
bilirubin, LDH and creatinine), troponin and serology (anti-HIV and HCV antibodies, and 
HBsAg antigen).  In addition, a blood cell count will be performed, including: hematocrit, 
hemoglobin and erythrocytes, platelets and leukocytes (if an abnormal leukocyte count is 
recorded, it will be obligate to specify neutrophils, basophils, eosinophils, lymphocytes and 
monocytes).  
During the final visit a MRI and a FDG-PET will also be performed. 
The following tests will be performed to measure cognition, functionality, behavior, global 
evolution, impression and depression: ADAS-Cog, MMSE, NPS battery, ADCS-ADL, NPI, 
CDR-Sb, ADCS-CGIC, CSDD, CSSRS, QoL-AD and RUD-Lite® which are to be 
administered as indicated in the corresponding section.  Likewise, anxiety and restlessness 
tests will be made based on the Overt Aggression Scale (OAS) and the Agitated Behavior 
Scale (ABS), whenever considered opportune. 
Furthermore, it is obligatory to perform lumbar puncture, to collect CSF samples and assess 
the levels of Aβ−40, Aβ−42, P-tau, T-tau, β-secretase, γ-secretase, cholesterol, LDL, HDL, 
VLDL, C-reactive protein, IL-1b, IL-6, ferritin, TNF-α) and to perform standard CSF tests 
(cell counts, glucose, proteins and albumin).  
These evaluations are considered to be the final data. 
Control group 
The control group will undergo the same schedule of assessments. 
In case the final visit is conducted before completing the study, some assessments could be 
avoided. It will be decided case by case and depending on when the last assessments have 
been done. 
Protocol IG1002 
Page 42 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
6.2.6 Description of the Response Evaluation Methods 
Medical history will be performed according to usual practice.  Physical examination likewise 
will be performed according to the practice of the investigator.  The investigator will carry out 
a general evaluation of the body systems, together with a full physical examination during the 
initial visit and again at the end of follow-up.  The vital signs will be measured according to 
standard practice of the investigator. 
Blood samples will be drawn according to standard practice of the center for the obtainment 
of blood, plasma and serum.  
The amount of blood and CSF to be collected for all the tests will correspond to the amount 
needed for the assays in each visit or procedure.  The precise amount of each sample will be 
established according to the requirements of the specific laboratory performing the analysis.  
As a recommendation, the minimum amounts are: 
• 
Plasma samples for frozen back-up (-70oC): 10 mL of blood which, once processed, 
will be divided into three equal plasma aliquots in three cryopreservation tubes. 
• 
From the plasma bag corresponding to each plasma exchange (FPE and LVPE), six 
samples will be obtained, with a maximum volume of two ml each, at each of the 
following time points: 30 minutes after starting replacement, after one hour, and at the 
end of the procedure. Thus, 18 plasma samples will also be obtained in each 
replacement session. The removed plasma bag from the FPE and LVPE will also be 
collected. These samples will be collected in some selected sites. 
• 
Aβ and P-tau: 10 mL of blood (to obtain 5 mL of plasma) with EDTA (collection in 
polypropylene tubes is needed, since Aβ adheres to glass). In addition, 10 mL of blood 
with EDTAK2 will be obtained separately to assess Aβ in blood. 
• 
Genetic markers: 4 mL of blood (approximately 2 mL of plasma) with EDTA. 
• 
Coagulation parameters: 5 mL of blood (collected according to standard practice of 
the laboratory). 
• 
Hematological tests: 5 mL of blood (collected according to standard practice of the 
laboratory). 
• 
Proteinogram, biochemistry (kidney and liver function), and serology: 10 mL of blood 
(collected according to standard practice of the laboratory).  
• 
CSF: At least a minimum of 5 mL and a maximum of 10 mL of CSF will be obtained 
according to the standard technique employed in the center.  The sample will be 
divided into three aliquots: 3 mL for general tests (cell count, glucose, proteins and 
albumin), 3 mL for Aβ and P-tau (collected in polypropylene tubes), and 4 mL for 
frozen back-up (-70oC), stored in cryopreservation tubes.  
The CSF aliquot destined for general testing should not be frozen but kept at room 
temperature, with immediate analysis.  The other two aliquots can be immediately 
frozen, however, future testing cannot be done if >10 erythrocytes are detected.  To 
avoid rejection of the sample, these aliquots may be centrifuged and the clarified CSF 
saved to eliminate any possible residual cells.  
In the event of insufficient blood or plasma sample volume, priority should center on the 
measurements of Aβ and P-tau, then reserving three mL for frozen back-up, and the rest for 
testing according to the course of the study and investigator criterion (e.g., during the 
Intensive treatment phase the coagulation parameters are a greater priority than the 
Protocol IG1002 
Page 43 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
proteinogram; in contrast, during screening or the final visit, serology is the most important 
aspect).  
In the event of insufficient CSF volume, priority is to center on the Aβ and P-tau 
measurements, then reserving two mL for frozen back-up, and the rest for general testing 
(particularly cell counts). 
During the visits, and after blood collection, processing of the samples to obtain the plasma 
and/or serum is to be made within two hours.  The blood and plasma and/or serum samples 
will be collected and taken immediately to the site laboratory for processing.  
The serum and/or plasma samples can be analyzed on the same day (depending on the 
standard practice of the laboratory and test involved), or stored at -20ºC for analysis within no 
more than two months after collection. 
The routine hematological tests are to be made within a maximum of 12 hours after blood or 
CSF collection.  Prior to analysis, the samples can be kept at 2-8ºC, with the exception of the 
CSF samples, which must be kept at room temperature. 
The plasma and CSF samples collected for possible future assays will be stored at -70ºC. 
Hematological, coagulation, and kidney and liver function tests will be performed by the 
standard practices of the laboratory.  
 
7. 
SPECIFIC METHODOLOGY 
7.1 
Behavioral and cognitive impairment scales and tests  
The cognitive measurement instruments used are mainly those sensitive to change, in regard 
to the nature of the study (pre-post condition).  Specifically, the following tests are will be 
performed (see Appendix 7): 
 
7.1.1 Gold standards for the study of dementia  
Screening: Mini-Mental Status Examination (MMSE)36.  This test is widely used to assess 
cognitive alterations, and is the most commonly used brief screening test.  The score ranges 
from 0 to 30, and is obtained by summing the points corresponding to each answer.  Results 
below 26 points may indicate cognitive impairment.  The test performed on occasion of the 
selection visit will serve as criterion for inclusion in the study. The subject is required to yield 
a score of ≥18 and ≤26 points. 
For the evaluation of cognitive function in AD: Alzheimer’s Disease Assessment Scale-
Cognitive (ADAS-Cog)37.  This is an instrument specifically designed to evaluate the severity 
of the fundamental alterations in cognitive and behavioral function that are characteristic of 
patients with AD.  The instrument consists of two parts (ADAS-Cog and ADAS-no Cog): the 
first measures cognitive function and the second (not to be applied in the present study) 
assesses non-cognitive (behavioral) function.  The first part comprises 11 subtests that explore 
different areas: spoken language skills, test instructions recall, difficulty finding words, 
following instructions, naming objects, construction of figures, ideation praxis, orientation, 
recall and recognition of words.  Scoring is by errors, and the total score ranges from 0 (no 
impairment) to 70 (maximum impairment). 
7.1.2 Specific neuropsychological battery (NPS battery)  
a) Processing speed 
Protocol IG1002 
Page 44 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
i. 
Symbol Digit Modalities Test (SDMT)38: developed principally for examining 
visual attention and tracking, concentration and psychomotor speed.  The correct 
symbol-number pairs during 90 seconds are counted.  Maximum score = 110. 
b) Language (global measures)  
i. 
Semantic and phonetic verbal fluency (animals per minute)39,40: allowing 
voluntary access to a certain vocabulary assessing reduction in verbal spontaneity 
and fluency difficulties. 
ii. 
Boston Naming Test (BNT)41 reduced to 15 words:  This is an essential test for the 
assessment of semantic memory in dementia evaluation protocols.  The total score 
is the sum of the correct answers given spontaneously, together with the correct 
answers after a semantic cue.  The first incorrect item is also reflected in the last 
section. 
c) Verbal memory (immediate/delayed) - Rey Auditory Verbal Learning Test 
(RAVLT)42:  This is a test of 5 learning series of 15 words presented in the same order 
that the subject listens and must remember and repeat at the end of each series. Next, a 
new series of 15 different words is administered as interference. Again, the subject is 
asked to remember the initial series. Finally, after 30 minutes, the subject is asked to 
the words from the initial list (deferred memory).  Scoring is based on the number of 
words recognized. 
In addition, the following instruments are included for the measurement of other variables: 
Functional ability 
Activities of daily living: Alzheimer’s Disease Cooperative Study - Activities of Daily Living 
(ADCS-ADL)43:  This offers detailed descriptions of each activity and requests the informer to 
describe the actions or behaviors observed.  The evaluator describes ability to carry out a 
series of activities of daily life (e.g., personal hygiene, using the phone, leaving home, etc.). 
The total sum is not calculated, though increased autonomy is associated with higher scores.  
Neuropsychiatric disorders 
Neuropsychiatric Inventory (NPI)44:  This evaluates the most frequent neuropsychiatric 
manifestations of dementia and also determines their frequency and intensity.  Generally, the 
NPI is used to evaluate the changes in patient behavior that have appeared in the course of a 
given period of time.  The NPI comprises 12 domains: delusions, hallucinations, dysphoria, 
apathy, euphoria, disinhibition, aggressivity and restlessness, irritability, anxiety, aberrant 
motor behavior, appetite and eating disorders, and nocturnal behavior.  Each domain 
comprises an exploratory question, where an affirmative answer is followed by a series of 
seven to nine follow-up questions relating to symptoms present or not in that particular 
domain.   
Frequency is scored as follows: 0 = none; 1 = occasional [less than once a week]; 2 = often 
[more or less once a week]; 3 = frequent [several times a week]; 4 = very frequent [daily or 
continuously].   
Severity is scored as 1 = mild; 2 = moderate [if possible to reconduct by care taker]; 3 = 
severe [if not possible to reconduct]. 
The NPI thus evaluates response to therapy; the total score of the NPI is obtained by adding 
the scores (frequency x severity) of all the inventory domains.  The score on the stress scale is 
not included in the total NPI score. 
Protocol IG1002 
Page 45 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
Measurement of depression in dementia: Cornell Scale for Depression in Dementia 
(CSDD)45.  This scale evaluates the signs and symptoms of major depression in patients with 
dementia.  The information is obtained from two semistructured interviews - one with the 
caretaker and the other with the patient.  Each item is scored for intensity (0 = none; 1 = mild 
or intermittent; 2 = severe). 
Clinical grading of dementia, global evolution: Clinical Dementia Rating – Sum of boxes 
(CDR-Sb)46,47. This is a clinical test validated in patients with AD.  Impairment is scored as 
follows: 0 = normal; 0.5 = slight cognitive impairment or questionable dementia; 1 = slight 
dementia; 2 = moderate dementia; 3 = severe dementia. Six categories are contemplated: 
memory, orientation, judgment and problem solving, social and occupational activities, 
domestic activities and hobbies, and personal care. 
Clinical global impression of change: Alzheimer’s Disease Cooperative Study – Clinical 
Global Impression of Change (ADCS-CGIC)48.  This instrument offers a method for the 
reliable assessment of global change in a clinical trial from baseline, using a 7-point Likert 
scale.  It is administered to the caretaker and to the patient.  
7.2 
Method of Behavioral and Cognitive Testing   
The established order in each visit will be as follows: 
With the patient: 
Rater 1 
a) MMSE (when stated by the protocol) 
b) ADAS-Cog 
c) NPS battery 
i. 
RAVLT (Parts 1, 2, 3, 4 and 5) 
ii. 
RAVLT (Part 6: interference) 
iii. 
RAVLT (Part 6B: evocation) 
iv. 
BNT (15 items) 
v. 
SDMT 
vi. 
Semantic and phonetic verbal fluency 
vii. 
CSDD (includes the 30 minutes for differed memory) 
viii. 
RAVLT (Part 7: differed memory 30 minutes after part 6B) 
ix. 
RAVLT (Part 8: differed recognition) 
d) QoL-AD 
e) C-SSR (only once rater 1 has administered scales to caretaker) 
Rater 2 
Next, the global impairment and clinical impression scales are administered by the 
second evaluator: 
 
a) CDR-Sb 
b) ADCS-CGIC 
With the care taker: 
Protocol IG1002 
Page 46 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
The second evaluator, while the evaluator 1 is administering the above mentioned battery, will 
administer the global impairment and clinical impression scale to the care taker in the 
following order: 
a) CDR-Sb 
b) ADCS-CGIC 
The first evaluator, once he has finished the NPS battery, will interview the care taker to 
evaluate the subject functionality and behavior: 
• 
NPI  
• 
ADCS-ADL 
• 
CSDD  
• 
QoL-AD 
• 
RUD-Lite 
Evaluators are blinded to patient treatment.  Importantly, the evaluators of the 
neuropsychological tests will not have access to any kind of information allowing them to 
identify patient assignment to treatment.   
An evaluator will administer all the neuropsychological battery scales: MMSE, ADAS-Cog, 
NPS Battery, behavior scales NPI and CSDD and the functional scale  ADCS-ADL.  
The second evaluator, also on a blind basis, will administer the CDR-Sb and ADCS-CGIC.  
Results from previous evaluations will remain unknown for both evaluators and they must not 
comment any result to each other or to other study members and they will be considered 
blinded evaluators and will sign a document to the effect.  
Anxiety and restlessness tests (during the replacement phase):  
In case any sign of aggression or restlessness during the procedure, the following instruments 
will be used: 
Measurement of overt aggression: Overt Aggression Scale (OAS)49. This instrument measures 
patient aggression and provides a global score as the sum of the scores assigned to each of the 
different items.  Increased severity is associated with higher scores.  
Measurement of restlessness: Agitated Behavior Scale (ABS)50. This includes 14 items 
grouped into three factors (disinhibition, and liability). The global score is obtained from the 
sum of the scores assigned to the different items. Increased severity is associated with higher 
scores.  
Columbia-Suicide Severity Rating Scale (C-SSRS): 
The scale is currently being used in a variety of settings from clinical trials to clinical practice. 
The Columbia–Suicide Severity Rating Scale (C-SSRS) was designed to quantify the severity 
of suicidal ideation and behaviour. 
The primary outcomes to evaluate are: suicidal behaviour categorical rating, suicidal ideation 
categorical rating and to estimate the rate of suicidality.  
We are going to use two versions of the scale that are currently being used in clinical trials: 
- The Baseline version of the scale assesses lifetime suicidal ideation and behavior. 
This version is suitable as part of a patient’s first interview in a private practice or as 
part of a clinical study.  
Protocol IG1002 
Page 47 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
- The Since Last Visit version of the scale assesses suicidality since the patient’s last 
visit. This version is meant to assess patients who have completed at least one initial 
C-SSRS assessment, and should be used in every subsequent visit. The ‘Since Last 
Visit’ version of the C-SSRS is asking about any suicidal thoughts or behaviors the 
patient/participant may have had since the last time you have administered the C-
SSRS.  
Quality of Life AD Measure (QoL-AD): 
The QoL-AD is a brief, 13-item measure designed specifically to obtain a rating of the 
patient's Quality of Life from both the patient and the caregiver. It was developed for 
individuals with dementia, based on patient, caregiver, and expert input, to maximize 
construct validity, and to ensure that the measure focuses on quality of life domains thought to 
be important in cognitively impaired older adults. It uses simple and straightforward language 
and responses & includes assessments of the individual's relationships with friends and 
family, concerns about finances, physical condition, mood, and an overall assessment of life 
quality. 
Caregivers complete the measure as a questionnaire about their patients’ QoL, while patients 
complete it in interview format about their own QoL. The measure consists of 13 items, rated 
on a four point scale, with 1 being poor and 4 being excellent. Total scores range from 13 to 
52. It generally takes caregivers about 5 minutes to complete the measure about their patients; 
for patients, the interview takes about 10 to 15 minutes to administer. Detailed instructions for 
interviewer administration are available.  
Scoring is straightforward - the sum of all items; patient and caregiver reports can be 
evaluated separately and/or combined into a single score if desired. Patients with MMSE 
scores of 10 or higher can usually complete it with no problem; below that caregivers can 
continue to complete it as proxies indefinitely. 
Resource Utilization in Dementia (RUD-Lite©) Questionnaire: 
The Resource Utilization in Dementia (RUD) Questionnaire was developed as a 
comprehensive tool to assess the amount of resource use among demented patients, which in a 
further step can be calculated into costs. It has been used in pharmacoeconomical studies and 
it has proven to be a useful tool in the evaluation of dementia care. RUD Lite© has been 
developed as a new shorter version of the instrument RUD. 
RUD  assesses  both  formal  and  informal  resource  use of  patients  and  the  primary  
caregiver,  making  it possible  to  calculate  costs  from  a  societal  perspective.  It consists of 
two parts with a similar content, but the wording is adapted to a baseline situation or follow-
up situation(s).  The questionnaire is divided in two parts, the first one is about the patients’ 
and the second one is about the caregivers’ health status and resource use. 
7.3 
Method of Biochemical Marker Testing  
Aβ in plasma, CSF and withdrawn plasma and P-tau and T-tau in CSF: These determinations 
will be carried out using ELISA as detailed below: 
• 
Determination of plasma and CSF Aβ1−40 (The Genetics Company) and Aβ1−42 
(Innogenetics and The Genetics Company)  
• 
Determination of P-tau and T-tau in CSF using the Innotest P-tau and Innotest T-tau 
(Innogenetics) 
• 
Determination of Aβ1−40 and Aβ1−42 pool in blood (Araclon Biotech). 
Protocol IG1002 
Page 48 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
• 
Determination of other biomarkers will be assessed from plasma removed samples. 
The plasma-EDTA samples will be collected in the course of the study and will be stored 
frozen. The assays will be performed at the same time and in parallel with pre-treatment 
(baseline) samples and post-treatment samples (coded), to avoid modifications related to day 
variations. 
7.4 
Method of Neuroimaging Studies  
FDG-PET  
This study will be carried out according to the standard operation procedures of this study. 
The images will be sent to a central vendor for interpretation. 
Four FDG-PET studies per patient will be made. A comparison between control and treatment 
groups will be performed. Qualitative and quantitative evaluation will be made by an 
experienced specialist. 
MRI  
MRI will be performed with a 1.5 Tesla magnet with a real-time acquisition system (Real-
time fMRI). LX 9.1 M4 software will be used.  The gradient amplitude will be 40 mT/m, with 
a slew rate of 150 T/m/s.  A schematic representation of the process is provided.  
The MRI scans will be examined by the central vendor clinical neuroradiologist, who in turn 
will issue a safety report for each subject. Any imaging anomaly will be communicated to the 
investigating team. 
Once all the study MRI scans have been obtained, they will be analyzed using a visual scale 
with the CVHS standards, based on adequate software (3D-SPGR), including: 
• 
Brain reconstruction in the axial plane, aligning with a standard reference image 
(MNT T1 matrix) 
• 
Normal tracing of the hippocampus and of the anterior cingulate region using standard 
software 
• 
Analysis of the volume of the hippocampus and of the anterior cingulate region using 
the LOWI system51. 
 
 
Protocol IG1002 
Page 49 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
Series 1 - Sagittal T1 Scout 
Plane 
Mode 
PSD 
TE 
TR 
FOV 
Slice/Gap 
#sli 
Matrix 
NEX 
Freq Dir 
Auto Shim 
Time 
Sagittal 
2D 
SE 
MF 
400 
20 
5/inter L50-
R50 
21 
256 x 192 
1 
SI 
Y 
2:46 
 
Series 2 – Axial T1  
Plane 
Mode 
PSD 
TE 
TR 
FOV 
Options 
Slice/Gap 
#sli 
Matrix 
NEX 
Freq Dir 
Auto Shim 
Time 
Axial 
2D 
SE 
MF 
400 
20 
VBw=15.
63 
5/1 
24 
256 x 192 
1 
AP 
Y 
2:49 
 
Series 3 – Axial fse PD 
Plane 
Mode 
PSD 
TE 
TR 
ETL 
FOV 
Options 
Slice/Gap 
#sli 
Matrix 
NEX 
Freq Dir 
Auto Shim 
Time 
Axial 
2D 
fse 
17 
2000 
4 
20 
VBw=15
.63 FC 
5/1 
24 
256 x 192 
1 
AP 
Y 
1:40 
 
Series 4– Axial fse T2 
Plane 
Mode 
PSD 
TE 
TR 
ETL 
FOV 
Options 
Slice/Gap 
#sli 
Matrix 
NEX 
Freq Dir 
Auto Shim 
Time 
Axial 
2D 
fse 
102 
2500 
8 
20 
Vbw=15.
63 FC 
5/1 
24 
256 x 
192 
1 
AP 
Y 
2:10 
 
Series 5 – Coronal 3D SPGR 
Plane 
Mode 
PSD 
TE 
TR 
Flip 
FOV 
Slice 
Matrix 
NEX 
Freq Dir 
Auto Shim 
Time 
Cor 
3D 
SPGR 
5 
25 
40 
24x18 
3/4 PFOV 
124 
256 x 192 
1 
SI 
Y 
7:44 
 
Series 6 - Axial FLAIR 
Plane 
Mode 
PSD 
TE 
TR 
TI 
FOV 
Options 
Slice/Gap 
#sli 
Matrix 
NEX 
Freq Dir 
Auto Shim 
CV’s 
Time 
Ax 
2D 
FLAIR 
ir 
156 
10000 
2200 
20 
Vbw=3
1.25 
5/1 
24 
256 
x192 
1 
AP 
Y 
Min Acq =1 
3:20 
Protocol IG1002 
Page 50 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
 
8. 
ASSESSMENT OF EFFICACY 
The first co-primary efficacy endpoint is to compare the changes to baseline of the cognitive 
scores as measured by ADAS-Cog between each of the three treatment arms and the control 
group and between the three treatment arms themselves. The second of the co-primary 
efficacy endpoints is to compare the changes to baseline of the ADCS-ADL inventory scores 
between each of the three treatment arms and the control group and between the three 
treatment arms themselves. 
The secondary efficacy endpoint is to assess the variations in other cognitive scores, AD 
biomarkers and other biochemical parameters. 
8.1 
Efficacy variables 
 
Change from baseline in the cognitive scores as measured by ADAS-Cog (6 measurements: 
weeks -3, -2 or -1, and 7-8, months 6, 9, 12 and 14). 
Change from baseline in the ADCS-ADL inventory (6 measurements: weeks -3, -2 or -1 and 
7-8; month 6, 9, 12 and 14). 
8.2 
Secondary efficacy variables  
• 
Change from baseline in the cognitive, functional and neuropsychiatric scores and overall 
development as measured by MMSE, NPS battery, NPI, CDR-Sb, ADCS-CGIC, CSDD, 
C-SSRS. (6 measurements: weeks -3, -2 or -1 and 7-8, month 6, 9, 12 and 14) and QoL-
AD, RUD-Lite® (5 measurements: weeks -3, -2 or -1; months 6, 9, 12 and 14). Moreover 
the optional questionnaires like OAS and ABS could be used at any visit in case any sign 
of aggression or restlessness. 
• 
Variation in levels of Aβ1−40 and Aβ1-42 in CSF in the period between baseline lumbar 
puncture (before the start of the intensive treatment period) and lumbar puncture 
immediately after the end of the last plasma exchange (whenever this may be). 
• 
Variation in the levels of Aβ1−40 and Aβ1−42  in CSF between the finalization and 
beginning of each of the 2 treatment periods. 
• 
Levels of Aβ1−40 , Aβ1−42, T-tau   and P-tau in CSF throughout the study. 
• 
Plasma levels of Aβ1−40 and Aβ1−42 before and after each plasma exchange for both 
treatment periods. 
• 
Structural changes in volume of the hippocampus, posterior cingulate area, and other 
associated areas by MRI. Five measurements will be made (weeks -3, -2 or -1 and 7-8; 
months 6, 9 and 14). 
• 
Variation in FDG-PET patterns (4 measurements: weeks -3, -2 or -1 and 7-8; months 9, 
and 14). 
8.3 
Safety variables 
The primary criterion of safety will be the percentage of plasma exchanges (full and low-
volume exchanges, including the infusion of albumin and IVIG) associated with at least one 
adverse event that may be related to the study procedure (adverse reactions) within 72 hours 
after infusion completion (or after the infusion stops).  In addition, consideration globally will 
be made of the percentage plasma exchanges (full and low-volume exchanges, including the 
infusion of albumin and IVIG) involving some adverse event, whether or not related to the 
procedure. 
Protocol IG1002 
Page 51 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
Vital signs (blood pressure, heart rate, respiration rate and body temperature) will be recorded 
before, during and after each plasma exchange session, where required. Evaluation will also 
be made (where required) of the different laboratory test parameters (blood cell counts, 
platelet count, troponin, prothrombin time (Quick), aPPT, fibrinogen, total proteins, and 
calcium). 
During the treatment periods (before each plasma exchange) and on the days when there is no 
replacement, anxiety and restlessness tests will be made based on the Overt Aggression Scale 
(OAS) and the Agitated Behavior Scale (ABS), whenever considered opportune. 
According to the criterion of the investigator, all the clinically important changes in vital 
function, laboratory test parameters and neuroimaging findings will be evaluated. 
 
9. 
ASSESSMENT OF SAFETY 
9.1 
Adverse Events 
9.1.1 Information to specify 
Descriptions/Definitions: 
- Adverse Event (AE) is any untoward medical occurrence in a patient or clinical trial subject 
administered a medicinal product and which does not necessarily have a causal relationship 
with this treatment.  
- Adverse Reaction (AR) is all untoward and unintended responses to an investigational 
medicinal product related to any does administered.  
- Serious Adverse Event (SAE) or Serious Adverse Reaction (SAR) is any untoward medical 
occurrence or effect that at any dose results in death, is life-threatening, requires 
hospitalization or prolongation of existing hospitalization, results in persistent or significant 
disability or incapacity, or is a congenital anomaly or birth defect. 
Likewise, medical criterion will decide whether an event is serious in other situations such as 
those requiring intervention to prevent some of the aforementioned consequences. 
Medical and scientific criteria will decide whether other situations that have not led to the 
outcomes listed in the above definitions should be notified as SAE. 
By life-threatening event, it is understood a situation which according to the investigator 
opinion, would have led to the patient death in the absence of a timely therapeutic 
intervention.  
- Unexpected Adverse Event: any adverse experience of a nature or severity that does not 
correspond to the information available in reference to the investigational procedure or study 
drug. Once the adverse event has been evaluated and reasonable bases are established for 
suspecting a causal relation to the study procedure and the SPC for the study drugs, the event 
is to be classified as an adverse reaction to the procedure or to the drug. 
Detection and recording: 
 - Method of Detection: The AEs will be daily collected from a careful clinical observation of 
the patient, laboratory analyses, spontaneous communication from the patient and also 
through and open questioning from the investigator 
- Adverse events recording: All adverse events and serious adverse events will be recorded in 
the patient’s medical records and in the CRF (Adverse Events Form). In addition, the adverse 
Protocol IG1002 
Page 52 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
events related to the Auto-C (FDA PMA approval # BP850001) or Aurora (FDA 510(k) 
clearance # BK110072) based devices used in the low-volume plasma exchanges 
(Maintenance period) will be recorded in the specific form attached to the Auto-C (FDA PMA 
approval # BP850001) or Aurora (FDA 510(k) clearance # BK110072) clinical protocols 
(Appendix 3). 
In the context of this clinical trial, all incidents clearly related to progression of the disease 
will not be considered as adverse events, and will not be necessary to include them in the 
CRF.   
All adverse events occurring during the study are should be included in the CRF of the 
corresponding patient. The minimum information to be supplied comprises the nature of the 
event, its time of appearance in relation to the administration, its duration, dose, seriousness, 
intensity, causality, the actions taken, and the course. If it is a preexisting AE that gets worse 
regarding intensity or frequency it should be indicated. 
Adverse events will be classified according to severity, depending on the intensity of the 
event, as follows: 
 
Mild, when well tolerated by the patient, causing only minimal discomfort, and without 
interfering with the activities of daily living (ADL) 
Moderate, when interfering with activities of daily living 
Intense or severe, when impeding activities of daily living 
Severity must be distinguished from seriousness, which is based on the consequence of the 
adverse event.  For example, a headache may be mild, moderate or severe, though rarely is it 
serious.  
9.1.2 Imputability criteria 
To analyze the possible relation cause-effect, it will be considered the temporal relationship 
between drug administration and the AE, possible alternative causes, evolution (complete 
remission, partial recovery, death and sequelae), persistence or not after drug discontinuation, 
reappearance with drug re-administration, or the previous knowledge of the event matching 
up with the known or expected response pattern of the study drug. 
The following definitions will be used to establish cause-effect relationships: 
Definitive: the adverse event occurs after a reasonable time sequence related to the study drug 
administration or study procedure, with a known response model, but cannot be explained by 
the patient clinical condition and other treatments provided, confirmed by improvement after 
interrupting or diminishing treatment dose, and with relapse after reintroducing treatment. 
Probable: the adverse event occurs after a reasonable time sequence related to the study drug 
administration or study procedure, with a known response model, confirmed by improvement 
after interrupting treatment, and that cannot be explained by the patient clinical condition or 
other treatments provided. 
Possible: the adverse event occurs after a reasonable time sequence related to the study drug 
administration or study procedure, with a known response model, but can be explained by the 
patient clinical condition and other treatments provided. 
Unlikely: the adverse event occurs after a reasonable time sequence related to the study drug 
administration or study procedure, not following a known response model, and that cannot be 
explained by the patient clinical condition or other treatments provided. 
Protocol IG1002 
Page 53 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
Unrelated: Any other adverse event. 
9.1.3 Expected adverse events 
There are a series of expected adverse events attributable to the plasma exchange procedure, 
with others that are inherent to the replacement fluid used (human albumin).  Lastly, other 
events are a consequence of patient disease or idiosyncrasy. 
The expected adverse events of plasma exchange are the following: hypocalcaemia 
(manifesting as paresthesias, headache, vision alterations, nausea, cramps and chest 
oppression), anaemia and coagulation disorders secondary to coagulation factor dilution 
(mainly hypofibrinogenemia, with possible minor bleeding associated to severe 
thrombopenia).  Hypotension may occur (accompanied by paleness, perspiration, bradycardia, 
nausea, vomiting, syncope, sphincter relaxation and seizures); though the risk is minimal, 
since the infusion amount is equivalent to the extracted amount.  Allergic reactions are also 
possible, with urticaria, dyspnea, wheezing, hypotension, tachycardia, facial reddening and 
palpebral edema.  Other events may be of psychological origin or may be inherent to the 
process, such as for example pain after remaining immobile for several hours.  
As indicated by the Full Prescribing Information (Appendix 1), the Albutein® specific 
adverse events are mild reactions such as reddening, urticaria, fever and nausea. Such 
reactions are rare and normally subside when the perfusion rate is reduced or perfusion is 
suspended. Anaphylactic shock may be observed in isolated cases. In such situations, 
perfusion is to be suspended immediately with the provision of adequate treatment. 
Albutein® is obtained from human plasma. The controls applied in the centers where the 
plasma is obtained, and in the fractionation plant, as well as the validated infectious agent 
inactivation/elimination procedures included in the production process, are all designed to 
minimize the risk of transmission of infectious disease. In any case, when dealing with blood 
products it is not possible to fully rule out possible transmission of infectious agents. This also 
refers to the possible transmission of unknown pathogens. 
In a 1996 review of the adverse effects of plasma exchange in patients with Guillain-Barré 
syndrome involving albumin replacements, a decrease in immediate adverse effects from 12% 
in 1986 to 7% in 1992 was recorded. Allergic reactions and hypotension were the most 
frequent problems. The estimated mortality was 1-2 deaths per 10,000 sessions, or two deaths 
per 2000 patients. 
With regard to Flebogamma®DIF (see Full Prescribing Information, Appendix 2) Adverse 
reactions such as chills, headache, fever, vomiting, allergic reactions, nausea, arthralgia, low 
blood pressure and moderate low back pain may occur occasionally. Rarely human normal 
immunoglobulins may cause a sudden fall in blood pressure and, in isolated cases, 
anaphylactic shock, even when the patient has shown no hypersensitivity to previous 
administration. Cases of reversible aseptic meningitis, isolated cases of reversible haemolytic 
anaemia/haemolysis and rare cases of transient cutaneous reactions, have been observed with 
human normal immunoglobulin. Increase in serum creatinine level and/or acute renal failure 
have been observed. Very rarely: Thromboembolic reactions such as myocardial infarction, 
stroke, pulmonary embolism, deep vein thromboses. 
In addition, there may be adverse events related to the concomitant medication provided. 
Thus, acetilcolinesterase inhibitors have been associated with diarrhea, muscle cramps, 
fatigue, nausea, vomiting, insomnia, headache, pain, accidents, common cold, gastrointestinal 
problems and dizziness. There have also been sporadic reports of syncope, bradycardia, 
sinoatrial block, atrioventricular block, seizures, liver dysfunction, psychiatric problems 
Protocol IG1002 
Page 54 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
(hallucinations, restlessness and aggressive behavior), anorexia, gastric and duodenal ulcers, 
gastrointestinal bleeding, extrapyramidal symptoms, and a small increase in serum muscle 
creatine kinase (CK). 
9.2 
Procedures for the immediate notification of serious adverse events 
Immediate notification of serious adverse events (expected or unexpected) by the 
investigator: 
The Principal Investigator must report immediately to United BioSource Corporation Safety 
Team (CRO) all serious adverse events (SAEs) regardless of the study drug causality. The 
notification deadline (whether expected or unexpected) will be 24h from the moment the 
investigator first receives news of the event.. 
The initial submission of the SAE (whether expected or unexpected) must be done in less than 
24h by email to United BioSource Corporation Safety Team (Contact email: 
AMBARSAFETY@unitedbiosource.com, fax number: 0800 24 25 26 27). 
Moreover, this information must be subsequently completed within a maximum of 3 days 
using the Serious Adverse Event Notification form. The form will be preferably sent via email 
or by fax to the above mentioned numbers.  
In case of SAE (expected or unexpected), the investigator should provide to United BioSource 
Corporation Safety Team all the information related to the event (additional laboratory tests, 
discharge report, etc). 
In case of death, the investigator should provide to United BioSource Corporation Safety 
Team and to the Ethics Committee/Institutional Review Board involved, all the additional 
information requested. 
Serious and unexpected adverse events potentially related to the study drug will be promptly 
reported to the Ethics Committee/Institutional Review Board involved and to the Health 
Authorities in accordance with the applicable legislation. All adverse events will be reported 
tabulated in the final clinical trial report. 
 
10. 
STATISTICAL METHODS  
10.1.1 Analytical Populations 
All subjects included in the study and subjected to at least one plasma exchange session (i.e., 
randomized and treated) during the intensive treatment phase (the six first weeks of treatment) 
will form part of the efficacy population.  
Control group subjects will also be included (without the plasma exchange) if they attended at 
least 1 of the 6 intensive treatment phase visits. 
A second efficacy analysis will also be carried out (per protocol analysis) with the patients 
who complete the treatment without major breaches in the study protocol.  
10.1.2 Missing Data 
Subjects with missing values for a given efficacy value at baseline of at the time point 
analyzed will be treated as missing rather than using imputed values.  More details regarding 
handling of missing data will be provided in the statistical analysis plan (SAP). 
 
Protocol IG1002 
Page 55 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
10.1.3 Demographic and Baseline Characteristics 
The demographic and baseline characteristics of the study patients will be presented in table 
form by treatment group and center.  The results will also be expressed in total. 
All continuous variables will be reported using standard statistical measures, i.e. number of 
observations, mean, standard deviation, minimum and maximum, median, and first and third 
quartiles.  
All categorical variables will be summarized by frequency tables. 
Equality of the baseline characteristics between the treatment groups will be assessed by 
descriptive methods. 
10.2 
Assessment of Efficacy 
10.2.1 General 
In general, the statistical tests will be performed with a 5% significance level and will be two-
sided. In addition to the tests, two-sided 95% confidence intervals (95% CI) will be reported.  
Specifically, the null hypothesis for all inferential analyses, including the primary endpoint, is 
that all three treatment groups are equal to placebo. Specific doses will be considered different 
from placebo if statistically significant following the Hochberg procedure described below. 
The study is considered positive if at least one dose group differs from placebo in the primary 
analysis. Subsequently, secondary endpoints are considered positive if at least one dose group 
differs from placebo. 
More details will be provided in the statistical analysis plan (SAP). 
10.2.2 Primary Endpoint 
The co-primary endpoints, changes from baseline of the ADAS-Cog scores and change from 
baseline in the ADCS-ADL inventory, will be assessed with the principal analytical objective 
being to determine whether there are differences between each of the 3 treatment groups and 
the control group. In addition, a comparison between the 3 treatment groups will be 
performed. 
Success of the study is determined by the change from baseline in the Total ADAS-Cog score 
at 14 months and the change from baseline in the ADCS-ADL inventory score ADAS-Cog 
and ADCS-ADL scores at remaining time points are considered to be secondary to the scores 
at month 14. Missing 
The mean change from baseline in both the ADAS-Cog and ADCS-ADL scores will be 
analyzed using analysis of covariance (ANCOVA) with adjustment for respective baseline as 
the covariate to compare the difference between each treatment group and the placebo group 
in the efficacy population.   
If the data distribution assumptions are significantly violated, a non-parametric analysis will 
be used. If the test for either normality of error terms or equality of error variances fails at the 
significance level of 0.01, the rank ANCOVA procedure will be applied.  The standardized 
ranks for both covariate and the response variable will be produced for each stratum.  Then 
linear regression models will be performed on ranked data by stratum to generate the 
residuals.  Finally the stratified mean score test using the value of the residuals as scores will 
compare the treatment groups using the Cochran-Mantel-Haenszel procedure. 
 
Protocol IG1002 
Page 56 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
Because the endpoints are co-primaries, both must be statistically significant for the study to 
provide evidence of efficacy. Therefore, no multiplicity adjustment is needed to adjust for the 
co-primary endpoints. However, to account for the three dose group comparisons to placebo 
and to maintain the overall significance level of 0.05, adjustment for α will be made for 
multiple dose groups according to the Hochberg procedure. The Hochberg procedure will be 
implemented as follows: For each endpoint the three dose group comparisons versus placebo 
will be ordered according to the p-value from the largest to the smallest.  If the largest p-value 
is < 0.05 then all comparisons to placebo will be declared significant. Otherwise, if the second 
largest p-value is < 0.025 (0.05/2) then this dose and all doses with smaller p-values will be 
declared significant. Otherwise if the smallest p-value is < 0.0167 (0.05/3) then this dose will 
be declared significant. Otherwise, no dose is considered significantly different from placebo. 
This procedure has been demonstrated to control the overall Type I error at 0.05. Both co-
primary endpoints must be significant at a given dose to provide evidence of efficacy for that 
dose. 
A supportive analysis will be performed in per protocol analysis set for the primary efficacy 
endpoint applying the same respective methodologies, but without adjusting for Type I error. 
10.2.3 Secondary Endpoints 
All continuous secondary endpoints (Section 8.2) will be tested in a manner identical to the 
primary analysis, with the corresponding baseline used as the covariate. 
10.3 
Evaluation of Tolerability 
The analysis of tolerability will be based on description of the safety variables according to 
their nature. In addition, a comparison of Adverse Drug Reactions between the treatment and 
the control groups will be performed. 
The adverse reactions will be coded according to the adverse events classification of the 
World Health Organization (WHO) (MeDRA current version), and will be described by a 
synonym (Lowest Level Term) and the affected organ / system, the intensity, causality and 
seriousness. 
10.4 
Intermediate Analysis and Stopping Rules 
A descriptive analysis is planned once half of the subjects are undergoing low-volume plasma 
exchanges. 
Serious adverse events related to full plasma exchanges (performed during the first six 
weeks), AEs leading to withdrawal of the study and additional safety measures if required will 
be monitored by the independent DMC on a regular basis. Special focus will be put on those 
SAEs considered as related to the therapeutic procedure or Investigational Product(s) by the 
Principal Investigator as defined in the protocol. Additional common side effects might also 
be analyzed if significantly higher proportions are found in any of the treatment arms. 
Under the following circumstances the independent DMC will recommend to halt the trial 
partly (stopping a specific treatment arm) temporarily (until modifications to the protocol are 
completed) or wholly (abandon all study activities):  
- 
If more than 30% of patients undergoing full plasma exchanges experience an 
SAE as defined by the protocol labeled “Definitively related to the therapeutic 
procedure” or “Probably related to the therapeutic procedure” or “Possibly 
related to the therapeutic procedure” and not attributable to the Investigational 
Products, as judged by the principal investigator.    
Protocol IG1002 
Page 57 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
- 
If more than 30% of patients undergoing full plasma exchanges experience an 
SAE as defined by the protocol labeled “Definitively related to the 
Investigational Product(s)” or “Probably related to the Investigational 
Product(s)” or “Possibly related to the Investigational Product(s)” and not 
attributable to the therapeutic procedure or technique of application, as judged 
by the principal investigator. 
 
10.5 
Conduction of the Statistical Analysis 
The statistical analysis will be carried out by the Biometrics Department of UBC (United 
Biosource Corporation). 
 
11. 
CHANGES TO THE PROTOCOL 
Any attached document or document related to the present study protocol must be considered 
as part of the latter. 
After protocol review and signing, neither the investigators nor the sponsor may introduce 
modifications or alterations without written approval from both parties.  
Any modification or alteration of the protocol after signing of the latter must be jointly 
discussed and approved by the principal investigator and sponsor, and must be signed by both.  
Protocol amendments are to be incorporated as part of the original protocol. The Institutional 
Review Board (IRB) must be informed of all protocol amendments that may affect the safety 
of the participating subjects or conduction of the trial. Amendment approval must be 
requested if considered necessary. 
 
12. 
ETHICS 
12.1 
General Considerations 
The ethical standards adopted by the XVIII World Medical Assembly Declaration of 
Helsinki (and subsequent revisions) will be strictly observed (Appendix 5).  The trial 
likewise will be performed in compliance with European Union standards of Good Clinical 
Practice (GCP) relating to trials involving drug products64 (see Appendix 6 for the 
responsibilities of the sponsor, monitor and investigator). 
The study cannot begin until an Institutional Review Board (IRB) or Ethics Committee and 
the health authorities (if necessary) have approved the protocol, the informed consent 
document, and the patient information sheets.  The study file is to include a letter of approval 
of the Institutional Review Board or Ethics Committee before the trial is started.  The 
Institutional Review Board or Ethics Committee must be informed of all protocol 
amendments that may affect the safety of the participating subjects or conduction of the trial.  
All serious or unexpected adverse reactions and other information that may alter the study 
design or entail patient risk must be reported to the Committee. The study file must also 
contain a list of the members of the Institutional Review Board or Ethics Committee, 
indicating those who participated in the discussion. 
An individual code will be used for the identification of patients. A subject information sheet 
is to be elaborated and filed at the center. 
Protocol IG1002 
Page 58 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
Lastly, and considering the particular vulnerability of the subjects to be included in the trial, 
mention should be made of some of the ethical particulars specifically related to this study. 
The informed consent document takes into account the opinion of the relative or legal 
representative, who ultimately has the capacity to decide patient participation in the study.  
The subject will not be able to participate unless both he/she and the relative or legal 
representative sign the consent form. 
The informed consent document is elaborated in such a way that at least the relative / care 
taker is able to understand all the implications of patient participation in the study. 
According to the experts, since only mild-moderate disease cases are involved in the study, it 
is very likely that the patients themselves will have no difficulties understanding the 
implications of participation in the study. 
If the study hypothesis is confirmed, direct clinical benefit for the subject may be expected. 
The method explored is warranted by extensive experience in other applications. 
12.2 
Written Informed Consent and Information 
The study characteristics will be duly described to all subjects amenable to participation in the 
trial (or to the legal representatives in the case the patient is unable) - followed by the request 
for free and voluntary authorization.  The subject and the accepted legal representative of the 
subject will be informed of the nature, purpose and procedures of the study, with a description 
of the possible risks involved. 
The subject (and representative) will be informed of the voluntary nature of participation, and 
of the right to withdraw from the study at any time, without this implying any negative 
consequences for the patient.  They must also be informed that the sponsor, its 
representatives, and the supervising authorities may have access to the subject’s information. 
If the subject (and relative/legal representative) agrees to participation in the study, the 
consent document must be signed accordingly, and filed by the investigator in the study 
archives.  If the subject is unable, the legal representative must sign the consent form.  The 
subject should also do so as far as possible.  The subject will not be able to participate until 
he/she (and/or the legal representative) sign the consent form.  
Informed consent must also be signed by one patient relative or by one legal 
representative (when patient’s relative is not available), who will serve as witness. This 
relative must receive the same information as the subject.  
 The investigator or the study personnel obtaining consent (if different from the investigator) 
will also sign and date the consent form, thus reflecting that informed consent has been 
obtained, and that the subject (and his/her representative) has had the opportunity to ask 
questions, and has received adequate answers. 
The subject and relative/legal representative will receive a copy of the informed consent form 
and of the subject information sheet.  The original will be filed along with the study 
documentation. 
12.3 
Confidentiality of Subject Records 
All data related to the procedure, medications, patents, scientific information and other data 
on materials will be considered confidential, and are the property of the sponsor. 
Protocol IG1002 
Page 59 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
The study protocol and other important documents must be submitted to the Institutional 
Review Board or Clinical Research Ethics Committee and regulatory authorities to obtain 
approval for conducting the study.  
There will be a file for each subject participating in the trial, where the investigator is to 
include all the information relating to the patient and the treatment. Data will be collected 
using specifically designed case report forms (CRF) that will be in an electronic version. The 
personal information of each subject needed for the study (age, sex, health data, etc.) is 
confidential, and the identity of the subject will not be disclosed except for the purposes of the 
study and in the event of a medical emergency or if required by law.  The personal 
information obtained will be kept and processed by a computer system ensuring 
confidentiality. 
The investigator accepts that the sponsor may use the results of the clinical trial, including 
CRF database or their copies, or reports with or without comments, and with or without 
analyses, to submit them to the authorities in charge of granting the license, and may reveal 
them if need be to other investigators.  To allow use of the information obtained in the clinical 
trial, the investigator understands that he/she is obliged to supply the sponsor with full results 
of the tests and all the information developed during the study. 
12.4 Institutional Review Board and Data Monitoring Committee (DMC) 
The present protocol and all the required documentation will be subject to evaluation by the 
corresponding Institutional Review Board or Clinical Research Ethics Committee, in order to 
obtain the required authorization before starting the study. 
An independent Data Monitoring Committee (DMC) will be established for this trial in order 
to monitor its progress and enhance the safety of trial participants. Review of unblinded 
interim data will include comparison of adverse event rates occurring in each treatment arm 
and the control group with special attention given to serious events in order to perform a 
risk/benefit assessment. The committee will be responsible for making recommendations to 
the sponsor regarding continuation, early termination or modification of study activities based 
on the analysis of accumulating outcome data.  Aspects of study conduct such as protocol 
adherence, patient withdrawal, and timeliness of data submission, eligibility rates and reasons 
for ineligibility will also be monitored by the DMC.  
12.5 Responsibilities of the Participants in the Clinical Trial, and Applicable 
Regulations 
The regulations applicable to the clinical trial will be the following, together with any other 
applicable norms in accordance to national law in the participating countries: 
Declaration of Helsinki (Helsinki, 1964) and subsequent revisions  
ICH. Note for guidance on good clinical practice. CPMP/ICH/135/95, 1996. 
Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 
on the approximation of the laws, regulations and administrative provisions of the 
Member States relating to the implementation of good clinical practice in the conduct 
of clinical trials on medicinal products for human use.  
Spanish Royal Decree 223/2004, of February 6, regulating clinical trials with drugs. 
United States Food and Drug Administration (FDA) Code of Federal Regulations. 
 
Protocol IG1002 
Page 60 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
13. 
QUALITY CONTROL AND QUALITY ASSURANCE 
13.1 
Audits and Inspections by the Health Authorities 
A person designated by the sponsor will monitor the study to ensure that all the required 
documentation is available, and that the collected data precisely reflect the data of the CRF.  
Access to the history and clinical course of the subjects will be required. 
When the study is completed, or at some other time, a trial quality assurance audit may be 
conducted. 
The health authorities and/or authorities from the Food and Drug Administration may inspect 
the centers where the study is carried out, as well as any analytical laboratory involved. 
14. 
DATA HANDLING AND RECORD KEEPING 
14.1 
Handling of the Principal Study File 
14.1.1 Documents Required Before the Start of the Study 
• 
Investigator acceptance to participate in the clinical trial following the duly signed 
protocol 
• 
Updated curriculum vitae of the investigators implicated in the study 
• 
Institutional Review Board or Ethics Committee approval 
• 
Sample of the informed consent approved by the Institutional Review Board or Ethics 
Committee 
• 
Approval from the authorities, if required 
• 
Normal laboratory values/ranges for all tests required in the study and laboratory 
certifications 
14.1.2 Study File 
The essential documents are to be filed for at least two years from the last authorization of the 
procedure and until there is no pending or contemplated registry process in any country, or 
until two years have elapsed from formal discontinuation of the clinical development of the 
investigational procedure.  If so required by the corresponding regulatory authorities, these 
documents are to be retained for a longer period of time. Before the investigator destroys 
material related to the clinical trial, written approval must be obtained from the Sponsor. 
The investigator is to keep a file including the full name and address of each subject, and all 
the signed informed consent documents, for no less than 15 years after conclusion of the 
study.  Any original information related to the study allowing verification of the inclusion and 
exclusion criteria, including the case history, a copy of all CRFs database and the documents 
on the use of the investigational product are to be filed for the maximum period of time 
allowed by the center. 
At the request of the monitor, auditor, Institutional Review Board or Ethics Committee or 
regulatory authorities, the investigator will provide direct access to all requested documents 
related to the trial. 
The following study documents are to be filed: 
• 
Signed final version of the protocol and any subsequent amendments  
• 
Institutional Review Board or Ethics Committee approval 
• 
Approval from the authorities, if required 
 
Protocol IG1002 
Page 61 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
• 
Informed consent of each subject 
• 
A full copy of the case report form and of the distribution of the product 
• 
Normal values/ranges for medical, laboratory or technical procedures 
• 
Correspondence between the investigator and the Institutional Review Board or Ethics 
Committee or sponsor 
• 
Reports from the monitoring visits 
• 
Clinical trial report 
• 
Audit certificate (if available) 
• 
Reporting of serious adverse events to the authorities or regulatory authorities 
14.1.3 Data Handling, Processing and Correction 
All case report forms will be completed electronically. 
The investigator must sign and date electronically each of the eCRF forms once completed. 
All the original documentation (laboratory test results, treatment forms, etc.) will be filed by 
the investigator.  The investigator also must file subject’s medical records, together with the 
informed consent and the other study documents, for possible future auditing. 
14.1.4 Identification of the Clinical Research Samples and Persons Responsible for Their 
Supply and Storage. Labeling of Samples 
The albumin and IVIG destined for use in the trial will come from batches - the largest of 
which is to be available on the market.  Each vial and corresponding box will have a label 
stating the protocol number, and specifying that the product is only to be used in the clinical 
trial. 
 
15. 
PUBLICATION POLICY 
The sponsor will prepare a report summarizing the results of the study, based on the statistical 
analysis of the results, and on any other relevant additional information. The study will 
include a description of the methods, materials and plans.  The investigator will express 
conformity by signing it. 
The investigators are free to publish the results after signing the final report, reflecting as co-
authors all persons who have significantly participated in the project.  In the event several 
papers are published, each will be prepared mainly by the investigator with most experience 
in the field, which moreover will appear as first signing author.  The rest of co-authors will 
appear in the order considered opportune by the principal investigators.  The sponsor will 
receive a copy of the manuscript for review at least 30 days prior to submission for 
publication or presentation of the Abstract at some scientific meeting. 
 
16. 
LIABILITIES AND INSURANCE 
16.1 
Trial Budget Contents 
A contract will be developed by common agreement with the investigators and the respective 
centers, detailing the costs and economical funding for conduction of the study procedures, 
for each participating subject and for each visit.  The Institutional Review Board or Ethics 
Committee may review and approve the economical memoranda associated to these contracts.  
Protocol IG1002 
Page 62 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
16.2 
Insurance / Compensation 
The sponsor will contract an insurance to cover possible damage to the patient resulting from 
application of the study procedure, in accordance with applicable legislation; such coverage 
will be renewed periodically for the full duration of the study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol IG1002 
Page 63 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
LITERATURE REFERENCES 
1. 
Andreasen N. Biomarkers for Alzheimer disease in the cerebrospinal fluid: tau, 
hyperphosphorilated tau and amyloid beta protein. Brain Aging. 2003;3:7-14. 
2. 
Andreasen N, Sjogren M, Blennow K. CSF markers for Alzheimer's disease: total tau, 
phospho-tau and Abeta42. World J Biol Psychiatry. Oct 2003;4(4):147-155. 
3. 
Tapiola T. Biological narkers for Alzheimer's disease, with special emphasis on 
cerebrospinal fluid beta-amyloid and tau [Doctoral dissertation]. Kuopio, Finland: 
Deparment of Neurology, University of Kuopio; 2001. 
4. 
Kuo YM, Kokjohn TA, Kalback W, et al. Amyloid-beta peptides interact with plasma 
proteins and erythrocytes: implications for their quantitation in plasma. Biochem 
Biophys Res Commun. Feb 24 2000;268(3):750-756. 
5. 
Knopman D. The necessity of human trials of putative therapies for Alzheimer's disease. 
Neurobiol Aging. Sep-Oct 1989;10(5):633-634; discussion 648-650. 
6. 
Miller CC, Anderton BH. Alzheimer's disease: transgenic models to test new chemicals 
and pharmaceuticals. Curr Opin Biotechnol. Dec 1992;3(6):683-686. 
7. 
Lemere C, Spooner E, LaFrancois J, et al. A-beta immunization of PS/APP mice leads 
to decreased cerebral A-beta and a corresponding increase in serum A-beta. Soc 
Neurosci Abstr. 2002;27:687.610. 
8. 
DeMattos RB, Bales KR, Cummins DJ, Dodart JC, Paul SM, Holtzman DM. Peripheral 
anti-A beta antibody alters CNS and plasma A beta clearance and decreases brain A beta 
burden in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. Jul 17 
2001;98(15):8850-8855. 
9. 
Sigurdsson E, Frangione B, Wisniewski T. Immunization for Alzheimer's disease. Drug 
Dev Res. 2002;56:135-142. 
10. Cleary JP, Walsh DM, Hofmeister JJ, et al. Natural oligomers of the amyloid-beta 
protein specifically disrupt cognitive function. Nat Neurosci. Jan 2005;8(1):79-84. 
11. Ghersi-Egea JF, Gorevic PD, Ghiso J, Frangione B, Patlak CS, Fenstermacher JD. Fate 
of cerebrospinal fluid-borne amyloid beta-peptide: rapid clearance into blood and 
appreciable accumulation by cerebral arteries. J Neurochem. Aug 1996;67(2):880-883. 
12. Ji Y, Permanne B, Sigurdsson EM, Holtzman DM, Wisniewski T. Amyloid beta40/42 
clearance across the blood-brain barrier following intra-ventricular injections in wild-
type, apoE knock-out and human apoE3 or E4 expressing transgenic mice. J Alzheimers 
Dis. Feb 2001;3(1):23-30. 
13. Mackic JB, Weiss MH, Miao W, et al. Cerebrovascular accumulation and increased 
blood-brain barrier permeability to circulating Alzheimer's amyloid beta peptide in aged 
squirrel monkey with cerebral amyloid angiopathy. J Neurochem. Jan 1998;70(1):210-
215. 
14. Maness LM, Banks WA, Podlisny MB, Selkoe DJ, Kastin AJ. Passage of human 
amyloid beta-protein 1-40 across the murine blood-brain barrier. Life Sci. 
1994;55(21):1643-1650. 
15. Martel CL, Mackic JB, McComb JG, Ghiso J, Zlokovic BV. Blood-brain barrier uptake 
of the 40 and 42 amino acid sequences of circulating Alzheimer's amyloid beta in guinea 
pigs. Neurosci Lett. Mar 15 1996;206(2-3):157-160. 
16. Poduslo JF, Curran GL, Haggard JJ, Biere AL, Selkoe DJ. Permeability and residual 
plasma volume of human, Dutch variant, and rat amyloid beta-protein 1-40 at the blood-
brain barrier. Neurobiol Dis. 1997;4(1):27-34. 
Protocol IG1002 
Page 64 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
17. Poduslo JF, Curran GL, Sanyal B, Selkoe DJ. Receptor-mediated transport of human 
amyloid beta-protein 1-40 and 1-42 at the blood-brain barrier. Neurobiol Dis. Jun 
1999;6(3):190-199. 
18. Shibata M, Yamada S, Kumar SR, et al. Clearance of Alzheimer's amyloid-ss(1-40) 
peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. J Clin 
Invest. Dec 2000;106(12):1489-1499. 
19. Zlokovic BV, Ghiso J, Mackic JB, McComb JG, Weiss MH, Frangione B. Blood-brain 
barrier transport of circulating Alzheimer's amyloid beta. Biochem Biophys Res 
Commun. Dec 30 1993;197(3):1034-1040. 
20. Kawarabayashi T, Younkin LH, Saido TC, Shoji M, Ashe KH, Younkin SG. Age-
dependent changes in brain, CSF, and plasma amyloid (beta) protein in the Tg2576 
transgenic mouse model of Alzheimer's disease. J Neurosci. Jan 15 2001;21(2):372-381. 
21. Kuo YM, Crawford F, Mullan M, et al. Elevated A beta and apolipoprotein E in A 
betaPP transgenic mice and its relationship to amyloid accumulation in Alzheimer's 
disease. Mol Med. May 2000;6(5):430-439. 
22. DeMattos RB, Bales KR, Cummins DJ, Paul SM, Holtzman DM. Brain to plasma 
amyloid-beta efflux: a measure of brain amyloid burden in a mouse model of 
Alzheimer's disease. Science. Mar 22 2002;295(5563):2264-2267. 
23. Gandy S, Walker L. Toward modeling hemorrhagic and encephalitic complications of 
Alzheimer amyloid-beta vaccination in nonhuman primates. Curr Opin Immunol. Oct 
2004;16(5):607-615. 
24. Goni F, Sigurdsson EM. New directions towards safer and effective vaccines for 
Alzheimer's disease. Curr Opin Mol Ther. Feb 2005;7(1):17-23. 
25. Matsuoka Y, Saito M, LaFrancois J, et al. Novel therapeutic approach for the treatment 
of Alzheimer's disease by peripheral administration of agents with an affinity to beta-
amyloid. J Neurosci. Jan 1 2003;23(1):29-33. 
26. Galeazzi L, Galeazzi R, Valli MB, Corder EH, Giunta S. Albumin protects human red 
blood cells against Abeta25-35-induced lysis more effectively than ApoE. Neuroreport. 
Nov 15 2002;13(16):2149-2154. 
27. Biere AL, Ostaszewski B, Stimson ER, Hyman BT, Maggio JE, Selkoe DJ. Amyloid 
beta-peptide is transported on lipoproteins and albumin in human plasma. J Biol Chem. 
Dec 20 1996;271(51):32916-32922. 
28. Meca-Lallana JE, Rodriguez-Hilario H, Martinez-Vidal S, et al. [Plasmapheresis: its use 
in multiple sclerosis and other demyelinating processes of the central nervous system. 
An observation study]. Rev Neurol. Nov 16-30 2003;37(10):917-926. 
29. Suarez JI, Shannon L, Zaidat OO, et al. Effect of human albumin administration on 
clinical outcome and hospital cost in patients with subarachnoid hemorrhage. J 
Neurosurg. Apr 2004;100(4):585-590. 
30. Bambauer R, Arnold A. Plasmapheresis with a substitution solution of human serum 
protein (5%) versus plasmapheresis with a substitution solution of human albumin (5%) 
in patients suffering from autoimmune diseases. Artif Organs. Dec 1999;23(12):1079-
1087. 
31. Dyck PJ, Litchy WJ, Kratz KM, et al. A plasma exchange versus immune globulin 
infusion trial in chronic inflammatory demyelinating polyradiculoneuropathy. Ann 
Neurol. Dec 1994;36(6):838-845. 
32. Weinshenker BG, O'Brien PC, Petterson TM, et al. A randomized trial of plasma 
exchange in acute central nervous system inflammatory demyelinating disease. Ann 
Neurol. Dec 1999;46(6):878-886. 
Protocol IG1002 
Page 65 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
33. Mazzi G, Raineri A, Zucco M, Passadore P, Pomes A, Orazi BM. Plasma-exchange in 
chronic peripheral neurological disorders. Int J Artif Organs. Jan 1999;22(1):40-46. 
34. Pratico D YY, Rokach J, Mayo M, Silverberg GG, McGuire D. . Reduction of brain 
lipid peroxidation by CSF drainage in Alzheimer's disease patients. J Alzheimers Dis. . 
2004 6(4):385-389; discussion 443-389. 
35. Silverberg GD, Levinthal E, Sullivan EV, et al. Assessment of low-flow CSF drainage 
as a treatment for AD: results of a randomized pilot study. Neurology. Oct 22 
2002;59(8):1139-1145. 
36. Folstein MF, Folstein SE, McHugh PR. "Mini-mental state". A practical method for 
grading the cognitive state of patients for the clinician. J Psychiatr Res. Nov 
1975;12(3):189-198. 
37. Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer's disease. Am J 
Psychiatry. Nov 1984;141(11):1356-1364. 
38. Smith A. Symbol Digits Modality Test. Los Angeles: Western Psychological Services; 
1973. 
39. Benton A, Hamsher K. Multilingual aphasia examination. 2nd ed ed. Iowa City: ASA 
Associates; 1983. 
40. Morris JC, Heyman A, Mohs RC, et al. The Consortium to Establish a Registry for 
Alzheimer's Disease (CERAD). Part I. Clinical and neuropsychological assessment of 
Alzheimer's disease. Neurology. Sep 1989;39(9):1159-1165. 
41. Kaplan E, Goodglass H, Weintraub S. The Boston naming test. 2nd ed ed. Philadelphia: 
Lea & Febiger; 1983. 
42. Rey A. L'examen clinique en psychologie. Paris, France: Presses Universitaires de 
France; 1964. 
43. Galasko D, Bennett D, Sano M, et al. An inventory to assess activities of daily living for 
clinical trials in Alzheimer's disease. The Alzheimer's Disease Cooperative Study. 
Alzheimer Dis Assoc Disord. 1997;11 Suppl 2:S33-39. 
44. Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. The 
Neuropsychiatric Inventory: comprehensive assessment of psychopathology in 
dementia. Neurology. Dec 1994;44(12):2308-2314. 
45. Alexopoulos GS AR, Young RC, Shamoian CA. Cornell Scale for Depression in 
Dementia. Biol Psychiatry. . 1988;23(3):271-284. 
46. Berg L. Clinical Dementia Rating (CDR). Psychopharmacol Bull. 1988;24(4):637-639. 
47. Morris JC MDJ, Fulling K, Torack RM, Berg L. . Validation of clinical diagnostic 
criteria for Alzheimer's disease. Ann Neurol. 1988;24(1):17-22. 
48. Schneider LS OJ, Doody RS, Clark CM, Morris JC, Reisberg B, Schmitt FA, Grundman 
M, Thomas RG, Ferris SH. . Validity and reliability of the Alzheimer's Disease 
Cooperative Study-Clinical Global Impression of Change. The Alzheimer's Disease 
Cooperative Study. Alzheimer Dis Assoc Disord. 1997;11(Suppl 2):22-32. 
49. Yudofsky SC, Silver JM, Jackson W, Endicott J, Williams D. The Overt Aggression 
Scale for the objective rating of verbal and physical aggression. Am J Psychiatry. Jan 
1986;143(1):35-39. 
50. Corrigan JD. Development of a scale for assessment of agitation following traumatic 
brain injury. J Clin Exp Neuropsychol. Mar 1989;11(2):261-277. 
51. Thompson PM, Hayashi KM, De Zubicaray GI, et al. Mapping hippocampal and 
ventricular change in Alzheimer disease. Neuroimage. Aug 2004;22(4):1754-1766. 
Protocol IG1002 
Page 66 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
52. Directive 2001/20/EC of the European Pariliament and of the Council of 4 April 2001 
on the approximation of the laws, regulations and administrative provisions of the 
Members States relating to the implementation of good clinical practice in the conduct 
of clinical trials on medicinal products for human use. In: Union TEPatCotE, ed. Vol 
2001/20/EC: Official Journal of the European Communities; 2001. 
53. Real Decreto 223/2004, de 6 de febrero, por el que se regulan los ensayos clínicos con 
medicamentos. Vol BOE 233: Ministerio de Sanidad y Consumo; 2004:5429-5443. 
54. Karch FE, Lasagna L. Adverse drug reactions. A critical review. Jama. Dec 22 
1975;234(12):1236-1241. 
55. Simon T. Coagulation Disorders with plasma exchange. Plasma Ther Transfus Technol. 
1982;3:147-152. 
56. Straves R, McLeold B. Adverse reactions to therapeutic apheresis. In: Popousky M, ed. 
Transfusion reactions. Bethesda: AABB Press; 1996:281-300. 
57. Rodnitzky RL, Goeken JA. Complications of plasma exchange in neurological patients. 
Arch Neurol. Jun 1982;39(6):350-354. 
58. Domen RE, Kennedy MS, Jones LL, Senhauser DA. Hemostatic imbalances produced 
by plasma exchange. Transfusion. Jul-Aug 1984;24(4):336-339. 
59. Hazards of apheresis. Lancet. Nov 6 1982;2(8306):1025-1026. 
60. Burgstaler EA, Pineda AA. Therapeutic cytapheresis: continuous flow versus 
intermittent flow apheresis systems. J Clin Apher. 1994;9(4):205-209. 
61. Huestis DW. Risks and safety practices in hemapheresis procedures. Arch Pathol Lab 
Med. Mar 1989;113(3):273-278. 
62. Uldall P, Dyck R, Woods F, Merchant N, Martin G, Cardella C. A subclavian cannula 
for temporary vascular access for hemodialysis or plasmapheresis. Dial Transplant 
1979;8:963-968  
63. Ficha técnica de Aricept® (donepezilo clorhidrato), comprimidos de 5 y 10 mg (números 
de la autorización de comercialización: 61869 y 61870). Pfizer; 2003. 
64. Note for guidance. Good Clinical Practice. CPMP/ICH/135/95. In: ICH, ed; 1996. 
65. Boada M, Ortiz P, Anaya F et al. Use of human Albumin in plasma exchange as a novel 
approach for Abeta mobilization. Drug News Perpect. 2009; 22(6):325-339 
66. Dodel, R.C., Depboylu, C. et al. Intravenous immunoglogulins containing antibodies 
against 
beta-amyloid 
for 
the 
treatment 
of 
Alzheimer’s 
disease.  
J. Neurol. Neurosurg. Psychiatry 2004; 75: 1472-1474 
67. Relkin, N.R., Szabo, P. et al. 18-month study of intravenous immunoglobulin for 
treatment of mild Alzheimer disease. Neurobiol Aging 2009;30(11):1728-1736 
68. U.S. National Institutes of Health (2011) [on line]. Phase II study of intravenous 
immunoglobulin 
(IVIg) 
for 
Alzheimer’s 
disease. 
Available 
from 
: 
http://clinicaltrials.gov/ct2/show/NCT00299988?term=baxter+AND+alzheimer&rank=2 
69.  U.S. National Institutes of Health (2011) [on line]. A Phase 3 Study Evaluating Safety 
and Effectiveness of Immune Globulin Intravenous (IGIV 10%) for the Treatment of 
Mild 
to 
Moderate 
Alzheimer´s 
Disease. 
Available 
from 
: 
http://clinicaltrials.gov/ct2/show/NCT00818662?term=baxter+AND+alzheimer&rank=1 
70. Lehmann HC, Hartung HP. Plasma exchange and intravenous immunoglobulins: 
Mechanism of action in immune-mediated neuropathies. J Neuroimmunol. 2011; 231(1-
2):61-69 
Protocol IG1002 
Page 67 of 68 
Version 5.0 (IND version) / February 2018 
 

Confidential 
 
 
71. Ludwig KP, Thiesset HF, Gayowski TJ et al. Plasmapheresis and Intravenous Immune 
Globulin Improve Neurologic Outcome of Central Pontine Myelinolysis Occurring Post 
Orthotopic Liver Transplant. Ann. Pharmacother. 2011; 45 (Feb 8, Epub ahead of print). 
 
Protocol IG1002 
Page 68 of 68 
Version 5.0 (IND version) / February 2018 
 





















APPENDIX  1 




FULL PRESCRIBING INFORMATION 
(Albutein®) 





















APPENDIX  2 




FULL PRESCRIBING INFORMATION  
(Flebogamma® DIF) 

HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use FLEBOGAMMA 5% DIF safely and effectively. See 
full prescribing information for FLEBOGAMMA 5% DIF.
FLEBOGAMMA 5% DIF (immune globulin intravenous [human]), solution for intravenous administration
Initial U.S. Approval: 2006
WARNING: THROMBOSIS, RENAL DYSFUNCTION, and ACUTE RENAL FAILURE
See full prescribing information for complete boxed warning.
•  Thrombosis may occur with immune globulin products, including FLEBOGAMMA 5% DIF. Risk factors may 
include: advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial 
thrombosis, use of estrogens, indwelling vascular catheters, hyperviscosity, and cardiovascular risk factors. 
• For patients at risk of thrombosis administer FLEBOGAMMA 5% DIF at the minimum dose and infusion rate 
practicable. Ensure adequate hydration in patients before administration. Monitor for signs and symptoms of 
thrombosis and assess blood viscosity in patients at risk of hyperviscosity.
• Renal dysfunction, acute renal failure, osmotic nephrosis and death may occur with the administration 
of human immune globulin intravenous (IGIV) products, particularly those products that contain sucrose. 
FLEBOGAMMA 5% DIF does not contain sucrose.
• For patients at risk of renal dysfunction or failure, administer FLEBOGAMMA 5% DIF at the minimum dose and 
infusion rate practicable. (5.2)
 
-------------------------------------------------RECENT MAJOR CHANGES---------------------------------------------------
Warnings and Precautions: Hereditary Fructose Intolerance (5.12) 
 
                   
           7/2017
-------------------------------------------------INDICATIONS AND USAGE---------------------------------------------------
Flebogamma 5% DIF is an immune globulin intravenous (human), indicated for treatment of primary (inherited) immunodeficiency 
(PI) in adults and pediatric patients 2 years of age and older. (1)
----------------------------------------------DOSAGE AND ADMINISTRATION------------------------------------------------
For Intravenous Use Only
Indication
Dose
Initial Infusion Rate
Maintenance Dose Rate (if tolerated)
PI
300-600 mg per kg
every 3-4 weeks
0.01 mL per kg per minute 
(0.5 mg per kg per min)
Increase to 0.10 mL per kg per minute 
(5 mg per kg per min)
 
• For patients at risk of renal dysfunction or thrombosis, administer Flebogamma 5% DIF at the minimum dose and 
infusion rate practicable. (5.2, 5.4)
• Ensure that patients with pre-existing renal insufficiency are not volume-depleted and discontinue Flebogamma 5% DIF 
if renal function deteriorates. (5.2)
---------------------------------------------DOSAGE FORMS AND STRENGTHS------------------------------------------------
Solution for intravenous injection containing 5% IgG (50 mg per mL). (3)
--------------------------------------------------CONTRAINDICATIONS------------------------------------------------------
• History of anaphylactic or severe systemic reactions to human immunoglobulin. (4)
• IgA-deficient patients with antibodies against IgA and a history of hypersensitivity. (4)
----------------------------------------------WARNINGS AND PRECAUTIONS-------------------------------------------------
• IgA-deficient patients with antibodies to IgA are at greater risk of developing severe hypersensitivity and anaphylactic 
reactions. (5.1) 
• Monitor renal function, including blood urea nitrogen, serum creatinine, and urine output in patients at risk of 
developing acute renal failure. (5.2)
• Hyperproteinemia, increased serum viscosity, and hyponatremia may occur in patients receiving Flebogamma 5% DIF 
therapy. (5.3) 
• Thrombosis may occur. Monitor patients with known risk factors for thrombosis and consider baseline assessment of 
blood viscosity for those at risk of hyperviscosity. (5.4)
• Aseptic meningitis syndrome (AMS) may occur in patients receiving Flebogamma 5% DIF therapy, especially with high 
doses or rapid infusion. (5.5)
• Hemolysis, either intravascular or due to enhanced red blood cell sequestration, can develop subsequent to 
Flebogamma 5% DIF treatments. Risk factors include high doses and non-O blood group. Monitor patients for 
hemolysis and hemolytic anemia. (5.6)
• Monitor patients for pulmonary adverse reactions (transfusion-related acute lung injury, TRALI). (5.7)
• Patients receiving Flebogamma 5% DIF for the first time or being restarted on the product after a treatment hiatus 
of more than 8 weeks may be at a higher risk for development of fever, chills, nausea, and vomiting. (5.8)
• Flebogamma 5% DIF is made from human plasma and may contain infectious agents, e.g., viruses, the variant 
Creutzfeldt-Jakob disease (vCJD) agent and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. (5.9)
• Passive transfer of antibodies may confound serologic testing. (5.11)
•  Flebogamma 5% DIF contains sorbitol. The presence of sorbitol presents a risk to those with hereditary fructose 
intolerance (HFI). (5.12)
----------------------------------------------------ADVERSE REACTIONS----------------------------------------------------
The most common adverse reactions (reported in at least 5% of clinical trial adult subjects) were headache, pyrexia/fever, 
pain, infusion site reactions, diarrhea, rigors or chills, urticaria, and infusion site inflammation. (6)
The most common adverse reactions (reported in at least 5% of clinical trial pediatric subjects) were headache, pyrexia, 
hypotension, tachycardia, diastolic hypotension, nausea, abdominal pain, diarrhea, pain, and vomiting. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Grifols Biologicals at 1-888-GRIFOLS (1-888-474-3657) or FDA at 
1-800-FDA-1088 or www.fda.gov/medwatch.
---------------------------------------------------DRUG INTERACTIONS-----------------------------------------------------
Passive transfer of antibodies may transiently interfere with the immune response to live virus vaccines, such as measles, 
mumps, and rubella. (7)   
----------------------------------------------USE IN SPECIFIC POPULATIONS-----------------------------------------------
• Pregnancy: No human or animal data. Use only if clearly needed. (8.1)
• Geriatric: In patients over age 65 or in any patient at risk of developing renal insufficiency, do not exceed the 
recommended dose, and infuse Flebogamma 5% DIF at the minimum dose and infusion rate practicable and at less 
than 0.06 mL per kg per minute (3 mg per kg per min). (8.5)
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 7/2017
Flebogamma® 5% DIF
Immune Globulin Intravenous (Human)
For intravenous administration, 5% Liquid Preparation
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: THROMBOSIS, RENAL DYSFUNCTION, and ACUTE RENAL FAILURE
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Dosage  
2.2 Preparation and Handling    
2.3 Administration
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Hypersensitivity
5.2 Renal Dysfunction/Failure
5.3  Hyperproteinemia, Increased Serum Viscosity, and Hyponatremia
5.4 Thrombosis
5.5 Aseptic Meningitis Syndrome (AMS)
5.6 Hemolysis
5.7 Transfusion-Related Acute Lung Injury (TRALI)
5.8 Infusion Reactions
5.9 Transmissible Infectious Agents
5.10 Monitoring: Laboratory Tests
5.11 Interference with Laboratory Tests
5.12 Hereditary Fructose Intolerance   
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Postmarketing Experience
7 DRUG INTERACTIONS
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.4 Pediatric Use
8.5 Geriatric Use
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenicity, Mutagenesis, Impairment of Fertility
13.2 Animal Toxicology and/or Pharmacology  
14 CLINICAL STUDIES
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
* Sections or subsections omitted from the full prescribing information are not listed.
FULL PRESCRIBING INFORMATION
WARNING: THROMBOSIS, RENAL DYSFUNCTION, and ACUTE RENAL FAILURE
• Thrombosis may occur with immune globulin products, including FLEBOGAMMA 5% DIF. Risk factors may 
include: advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial 
thrombosis, use of estrogens, indwelling central vascular catheters, hyperviscosity, and cardiovascular risk 
factors. Thrombosis may occur in the absence of known risk factors. (see Warnings and Precautions [5.4] and 
Patient Counseling Information [17])
• For patients at risk of thrombosis, administer FLEBOGAMMA 5% DIF at the minimum dose and infusion rate 
practicable. Ensure adequate hydration in patients before administration. Monitor for signs and symptoms of 
thrombosis and assess blood viscosity in patient at risk for hyperviscosity. (see Dosage and Administration 
[2.3] and Warnings and Precautions [5.4])
• Renal dysfunction, acute renal failure, osmotic nephrosis, and death1 have been related to intravenous 
immune globulin (IGIV) products. Patients predisposed to acute renal failure include patients with any 
degree of pre-existing renal insufficiency, diabetes mellitus, age greater than 65, volume depletion, sepsis, 
paraproteinemia, or patients receiving known nephrotoxic drugs. 
• Administer FLEBOGAMMA 5% DIF at the minimum dose and rate of infusion practicable in patients at risk for 
renal dysfunction or failure.
• Reports of renal dysfunction and acute renal failure occur more commonly in patients receiving IGIV 
products containing sucrose as a stabilizer. They account for a disproportionate share of the total number of 
reported cases of renal dysfunction and acute renal failure. FLEBOGAMMA 5% DIF does not contain sucrose. 
(see Dosage and Administration [2.3] and Warnings and Precautions [5.2])
1 INDICATIONS AND USAGE
Flebogamma 5% DIF is an immune globulin intravenous (human) solution indicated in adults and pediatric patients 2 years of 
age and older for the treatment of primary immunodeficiency (PI), including the humoral immune defects in common variable 
immunodeficiency, x-linked agammaglobulinemia, severe combined immunodeficiency, and Wiskott-Aldrich syndrome. 
2 DOSAGE AND ADMINISTRATION
For Intravenous Use Only  
2.1 Dosage 
Treatment of Primary Immunodeficiency (PI)
Dose
Initial Infusion Rate
Maintenance Dose Rate 
(if tolerated)
300-600 mg per kg body weight (6.0-12.0 mL 
per kg) administered every 3-4 weeks
0.01 mL per kg per minute (0.5 mg 
per kg per min)
Increase to 0.10 mL per kg per 
minute (5 mg per kg per min)
As there are significant differences in the half-life of IgG among patients with PI, the frequency and amount of 
immunoglobulin therapy may vary from patient to patient. Adjust the dose according to the clinical response.
Adjust the dosage over time to achieve the desired trough IgG levels and clinical responses. No randomized controlled trial data 
are available to determine an optimum target trough serum IgG level.
2.2 Preparation and Handling 
• Inspect Flebogamma 5% DIF visually for particulate matter and color prior to administration. Do not use the vial if 
particles are detected. Do not use if turbid. 
• Several vials of Flebogamma 5% DIF may be pooled into an empty sterile solution container by using aseptic 
technique, if large doses are to be administered.
• Do not dilute with intravenous fluids. Do not inject other medications into intravenous tubing being used for 
Flebogamma 5% DIF.
• Infuse Flebogamma 5% DIF through a separate intravenous line. Do not add any medications or intravenous fluids 
to the Flebogamma 5% DIF infusion container. Do not mix IGIV products of different formulations or from different 
manufacturers.
• Discard unused contents and administration devices after use.
• Use promptly any vial that has been entered.
• Discard partially used vials. Do not save for future use because the solution contains no preservative. 
• Do not use solution that has been frozen.
2.3 Administration
The recommended initial infusion rate of Flebogamma 5% DIF is 0.01 mL per kg body weight per minute (0.5 mg per kg per min). 
If the infusion is well-tolerated during the first 30 minutes, the rate may be gradually increased to a maximum of 
0.10 mL per kg per minute (5 mg per kg per min).
Monitor patient vital signs throughout the infusion. Slow or stop infusion if adverse reactions occur. If symptoms subside 
promptly, the infusion may be resumed at a lower rate that is comfortable for the patient.
3 DOSAGE FORMS AND STRENGTHS
Flebogamma 5% DIF is a liquid preparation containing 5% IgG (50 mg per mL).
4 CONTRAINDICATIONS 
• Flebogamma 5% DIF is contraindicated in patients who have had a history of anaphylactic or severe systemic 
hypersensitivity reactions to the administration of human immune globulin. 
• Flebogamma 5% DIF is contraindicated in IgA-deficient patients with antibodies to IgA and a history of hypersensitivity. 
(see Warnings and Precautions [5.1]) 
5 WARNINGS AND PRECAUTIONS
5.1 Hypersensitivity  
Severe hypersensitivity reactions and anaphylactic reactions with a fall in blood pressure may occur, even in patients who 
had tolerated previous treatment with IGIV. (see Contraindications [4]) If hypersensitivity reaction develops, discontinue 
Flebogamma 5% DIF infusion immediately and institute appropriate treatment. 
Flebogamma 5% DIF contains trace amounts of IgA (less than 50 μg/mL). (see Description [11]) Patients with antibodies to 
IgA have a greater risk of developing potentially severe hypersensitivity and anaphylactic reactions. Flebogamma 5% DIF is 
contraindicated in patients with antibodies against IgA and a history of hypersensitivity reaction. (see Contraindications [4]) 
5.2 Renal Dysfunction/Failure
Acute renal dysfunction/failure, acute tubular necrosis, proximal tubular nephropathy, osmotic nephrosis, and death have 
been reported in patients receiving IGIV, particularly those products containing sucrose2. Flebogamma 5% DIF does not 
contain sucrose.
Ensure that patients are not volume-depleted before administering Flebogamma 5% DIF. For patients judged to be at risk 
for developing renal dysfunction, including patients with any degree of pre-existing renal insufficiency, diabetes mellitus, 
age greater than 65, volume depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic drugs, administer 
Flebogamma 5% DIF at the minimum dose and rate of infusion practicable3. (see Boxed Warning, Dosing and Administration [2.3]) 
Periodic monitoring of renal function and urine output is particularly important in patients judged to be at increased risk 
of developing acute renal failure1. Assess renal function, including measurement of blood urea nitrogen (BUN) and serum 
creatinine, before the initial infusion of Flebogamma 5% DIF and at appropriate intervals thereafter. If renal function 
deteriorates, consider discontinuation of the product. 
5.3 Hyperproteinemia, Increased Serum Viscosity, and Hyponatremia
Hyperproteinemia, increased serum viscosity, and hyponatremia may occur in patients receiving Flebogamma 5% DIF therapy. 
It is clinically critical to distinguish true hyponatremia from a pseudohyponatremia that is temporally or causally related 
to hyperproteinemia with concomitant decreased calculated serum osmolarity or elevated osmolar gap, because treatment 
aimed at decreasing serum free water in patients with pseudohyponatremia may lead to volume depletion, a further increase 
in serum viscosity, and a higher risk of thrombosis. 
5.4 Thrombosis
Thrombosis may occur following treatment with immune globulin products, including FLEBOGAMMA 5% DIF. Risk 
factors may include advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial 
thrombosis, use of estrogens, indwelling central vascular catheters, hyperviscosity, and cardiovascular risk factors. 
Thrombosis may occur in the absence of known risk factors.
Consider baseline assessment of blood viscosity in patients at risk for hyperviscosity, including those with cryoglobulins, 
fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies. (see Warnings 
and Precautions [5.10]) For patients at risk of thrombosis, administer FLEBOGAMMA 5% DIF at the minimum dose 
and infusion rate practicable. Ensure adequate hydration in patients before administration. Monitor for signs and 
symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity. (see Boxed Warning, Dosage 
and Administration [2.3], and Patient Counseling Information [17])
5.5 Aseptic Meningitis Syndrome (AMS)
AMS has been reported to occur following IGIV treatment. Discontinuation of IGIV treatment has resulted in remission 
of AMS within several days without sequelae4-7. The symptoms of AMS usually begin within several hours to 2 days 
following IGIV treatment.
AMS is characterized by the following signs and symptoms: severe headache, nuchal rigidity, drowsiness, fever, photophobia, 
painful eye movements, nausea, and vomiting. (see Patient Counseling Information [17]) Cerebrospinal fluid (CSF) studies 
frequently reveal pleocytosis up to several thousand cells per cubic millimeter, predominantly from the granulocytic series, 
and elevated protein levels up to several hundred mg/dL, but negative culture results. Conduct a thorough neurological 
examination to patients exhibiting such signs and symptoms, including CSF studies, to rule out other causes of meningitis.
AMS may occur more frequently following high-dose (e.g. over 1.0 g per kg body weight) or rapid infusion of IGIV.  
5.6 Hemolysis
Flebogamma 5% DIF may contain blood group antibodies that may act as hemolysins and induce in vivo coating of red blood 
cells (RBCs) with immunoglobulin, causing a positive direct antiglobulin test (DAT) (Coombs’ test) result and hemolysis8-11. 
Delayed hemolytic anemia can develop subsequent to IGIV therapy due to enhanced RBC sequestration and acute hemolysis, 
consistent with intravascular hemolysis, has been reported12. Cases of severe hemolysis-related renal dysfunction/failure or 
disseminated intravascular coagulation have occurred following infusion of IGIV. 
The following risk factors may be associated with the development of hemolysis following IGIV administration: high doses 
(e.g., at least 2 g per kg), given either as a single administration or divided over several days, and non-O blood group13. Other 
individual patient factors, such as an underlying inflammatory state (as may be reflected by, for example, elevated C-reactive 
protein or erythrocyte sedimentation rate), have been hypothesized to increase the risk of hemolysis following administration 
of IGIV14, but their role is uncertain. Hemolysis has been reported following administration of IGIV for a variety of indications, 
including ITP and PI11. Monitor patients for clinical signs and symptoms of hemolysis, particularly patients with risk factors 
noted above. Consider appropriate laboratory testing in higher risk patients, including measurement of hemoglobin or hematocrit 
prior to infusion and within 36 to 96 hours post infusion. If clinical signs and symptoms of hemolysis or a significant drop in 
hemoglobin or hematocrit have been observed, perform appropriate confirmatory laboratory testing. If transfusion is indicated 
for patients who develop hemolysis with clinically compromising anemia after receiving IGIV, perform adequate cross-matching 
to avoid exacerbating on-going hemolysis. (see Patient Counseling Information [17])
5.7 Transfusion-Related Acute Lung Injury (TRALI) 
Non-cardiogenic pulmonary edema has been reported in patients following IGIV treatment15. TRALI is characterized by 
severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever. Symptoms typically 
appear within 1 to 6 hours after transfusion. 
Monitor patients for pulmonary adverse reactions. (see Patient Counseling Information [17]) If TRALI is suspected, 
perform appropriate tests for the presence of antineutrophil antibodies and anti-HLA antibodies in both the product and 
patient serum. TRALI may be managed by using oxygen therapy with adequate ventilatory support. 
5.8 Infusion Reactions
Individuals receiving Flebogamma 5% DIF for the first time, or being restarted on the product after a treatment hiatus of 
more than 8 weeks, may be at a higher risk for the development of fever, chills, nausea, and vomiting. Careful monitoring 
of recipients and adherence to recommendations regarding dosage and administration may reduce the risk of these types 
of events. (see Dosage and Administration [2.3]) 
5.9 Transmissible Infectious Agents
Because Flebogamma 5% DIF is made from human plasma, it may carry a risk of transmitting infectious agents, 
e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent and, theoretically, the Creutzfeldt-Jakob disease (CJD) 
agent. This also applies to unknown or emerging viruses and other pathogens. No cases of transmission of viral diseases 
or CJD have been associated with the use of Flebogamma 5% DIF. All infections suspected by a physician possibly to have 
been transmitted by this product should be reported by the physician or other healthcare provider to Grifols Biologicals 
at 1-888-474-3657. 
Before prescribing or administering Flebogamma 5% DIF, the physician should discuss the risks and benefits of its use 
with the patient. (see Patient Counseling Information [17])
5.10 Monitoring: Laboratory Tests
• Periodic monitoring of renal function and urine output is particularly important in patients judged to be at increased 
risk of developing acute renal failure. Assess renal function, including measurement of BUN and serum creatinine, 
before the initial infusion of Flebogamma 5% DIF and at appropriate intervals thereafter. 
• Consider baseline assessment of blood viscosity in patients at risk for hyperviscosity, including those with 
cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies 
because of the potentially increased risk of thrombosis.
• If signs and/or symptoms of hemolysis are present after an infusion of Flebogamma 5% DIF, perform appropriate 
laboratory testing for confirmation.
• If TRALI is suspected, perform appropriate tests for the presence of antineutrophil antibodies and anti-HLA antibodies 
in both the product and patient serum. 
5.11 Interference with Laboratory Tests  
After infusion of IgG, the transitory rise of the various passively transferred antibodies in the patient’s blood may yield positive 
serological testing results, with the potential for misleading interpretation. Passive transmission of antibodies to erythrocyte 
antigens (e.g. A, B, and D) may cause a positive direct or indirect antiglobulin (Coombs’) test.
5.12   Hereditary Fructose Intolerance
Flebogamma 5% DIF contains sorbitol. The presence of sorbitol presents a risk to those with hereditary fructose intolerance (HFI). 
The incidence of HFI is estimated at 1 in 20,000 births and is usually diagnosed at the time of weaning when fructose or sucrose 
is introduced into the diet. Clinical symptoms include recurrent vomiting, abdominal pain and hypoglycemia. Flebogamma 5% DIF 
must not be administered to subjects with HFI. 
6 ADVERSE REACTIONS
The most common adverse reactions (reported in at least 5% of clinical trial adult subjects) were headache, pyrexia/fever, pain, 
infusion site reactions, diarrhea, rigors or chills, urticaria, and infusion site inflammation. 
The most common adverse reactions (reported in at least 5% of clinical trial pediatric subjects) were headache, pyrexia, 
hypotension, tachycardia, diastolic hypotension, nausea, abdominal pain, diarrhea, pain, and vomiting. 
To report SUSPECTED ADVERSE REACTIONS, contact Grifols Biologicals at 1-888-GRIFOLS (1-888-474-3657) or FDA at 
1-800-FDA-1088 or www.fda.gov/medwatch.
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical 
trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates 
observed in clinical practice.
Adverse reactions were reported in a study of 46 individuals with PI receiving infusions every 3 to 4 weeks of 300-600 mg per kg 
body weight. Thirty-one subjects (67.4%) had at least one adverse reaction at some time during the study that was 
considered product-related. None of the 46 subjects who participated in this study discontinued the study prematurely 
due to an adverse drug reaction. 
Adverse reactions that occurred with an incidence of at least 5% on a per-subject basis are summarized in Table 1.
Table 1. Adverse Reactions Occurring in at Least 5% of Subjects 
Adverse Reaction
Subjects (%) N=46
Number of Events
Headache
10 (21.7)
24
Pyrexiaa
9 (19.6)
12
Painb
7 (15.2) 
11
Injection site reaction
6 (13.0)
10
Diarrhea
4 (8.7)
5
Rigors
4 (8.7)
7
Urticaria
3 (6.5)
3
Infusion site inflammationc 
3 (6.6)
3
a.  include combined reported terms of pyrexia and body temperature increase.
b.  include combined reported terms of pain such as pain (not otherwise specified), injection site pain, back pain, abdominal 
pain (not otherwise specified), and abdominal pain upper.
c.  include combined reported terms of infusion site inflammation and others such as injection site oedema and injection site swelling.
Other common adverse drug reactions reported in fewer than 5% of the subjects included hypertension, sinusitis, 
nausea/vomiting, positive Coombs test, arthralgia, myalgia, dizziness, bronchitis, and hypotension.
The total number of adverse reactions reported whose onset were within 72 hours after the end of an infusion of 
Flebogamma 5% DIF was 94. There were a total of 709 infusions, resulting in a ratio of 0.13 temporally associated adverse 
reactions per infusion (the upper bound of the 1-sided 95% confidence interval = 0.18). Of the 709 total infusions, 70 (9.7%, 
1-sided 95% upper bound CI = 12.4%) were associated with at least one adverse reaction that began within 72 hours after 
the completion of an infusion. In this analysis, each infusion is only counted once, regardless of the number of adverse 
reactions that occurred during the infusion, when during the 72-hour period after the infusion the adverse reaction started, 
or the intensity of those adverse reactions.
Factoring adverse reaction intensity into the analysis of the 709 infusions shows that there were 58 infusions with at least 
one mild adverse reaction (8.2% [upper bound 95% CI=10.5%]), 25 infusions with at least one moderate adverse reaction 
(3.5% [upper bound 95% CI=5.2%]), and 1 infusion with a severe adverse reaction (0.1% [upper bound 95% CI=0.8%]). In 
this analysis, if a subject reported multiple events with different intensities during the same infusion (e.g., mild headache 
and moderate pyrexia), that infusion would be counted in all relevant categories. Therefore, the number of infusions counted 
is 84.
Three subjects (6.5%) experienced a treatment-emergent rise in AST (> 3x the upper-limit of normal), and 1 subject (2.2%) 
experienced a treatment-emergent rise in ALT (> 3x the upper-limit of normal). None of these abnormal lab values were 
long-lasting (i.e. they occurred at 1 or 2 infusions), and none of these subjects had a concomitant treatment-emergent rise 
in total bilirubin. 

A clinical study with Flebogamma 5% DIF for the treatment of PI was conducted in 24 pediatric subjects aged 2-16 years 
to determine whether they respond differently from adult subjects. Pediatric subjects received intravenous infusions of 
262-625 mg per kg body weight every 3-4 weeks. Twenty subjects (83.3%) had at least one adverse reaction at some time 
during the study that was considered product-related. There were no deaths or serious adverse reactions. 
In 317 infusions, 20 pediatric subjects reported 159 treatment-related adverse drug reactions (ADR). Treatment-related 
adverse reactions that occurred with an incidence of at least 5% on a per-subject basis included headache (42%), pyrexia 
(29%), hypotension (25%), tachycardia (25%), diastolic hypotension (21%), nausea (8%), abdominal pain (8%), 
diarrhea (8%), pain (8%), and vomiting (8%). Of these, 99 ADRs were mild, 54 were moderate, and 6 were severe in 
intensity. The most common severe ADR was headache. Tachycardia was defined as mild, moderate, or severe by ratio 
of heart rate over baseline of 1.2-1.4, 1.41-1.6, or >1.6, respectively. Two episodes of tachycardia were moderate and 
14 were mild, 1 mild case had the infusion interrupted and the rest had no action taken, and all resolved. Hypotension 
was defined as mild, moderate, or severe by the decrease in pressure below baseline of 10-15%, 16-25%, and >25%, 
respectively. Ten episodes of hypotension/diastolic hypotension were moderate and 29 were mild, one moderate case had 
the infusion interrupted and the rest had no action taken, and all resolved. None of the ADRs related to fluctuation in vital 
signs were severe, all resolved without sequelae, and none were considered clinically significant.
One subject (6.5%) experienced a treatment-emergent rise in ALT (over 2.5x the upper-limit of normal). This was considered 
a mild treatment-related AE and resolved without sequelae. All other lab values were within normal limits. One subject 
experienced one positive Coombs’ test result after baseline (experienced 14 days after the final infusion). No subjects 
experienced clinically significant abnormal lab values for LDH, bilirubin, serum creatinine. In addition, no subjects 
experienced positive test results for HBsAg, HCV, or HIV.
6.2 Post-marketing Experience
Because adverse reactions are reported voluntarily post-approval from a population of uncertain size, it is not always 
possible to reliably estimate their frequency or establish a causal relationship to product exposure. 
The following adverse reactions have been identified during the post-approval use of IGIV products16, 17, including 
Flebogamma 5% DIF. 
Infusion Reactions   
Hypersensitivity (e.g. anaphylaxis), headache, diarrhea, tachycardia, fever, fatigue, 
dizziness, malaise, chills, flushing, urticaria or other skin reactions, wheezing or 
other chest discomfort, nausea, vomiting, rigors, back pain, myalgia, arthralgia, and 
changes in blood pressure 
Renal  
Acute renal dysfunction/failure, osmotic nephropathy
Respiratory 
Apnea, Acute Respiratory Distress Syndrome (ARDS), Transfusion-Related Acute Lung 
Injury (TRALI), cyanosis, hypoxemia, pulmonary edema, dyspnea, bronchospasm
Cardiovascular 
Cardiac arrest, thromboembolism, vascular collapse, hypotension
Neurological 
Coma, loss of consciousness, seizures, tremor, aseptic meningitis syndrome
Integumentary 
Stevens-Johnson Syndrome, epidermolysis, erythema multiformae, dermatitis 
(e.g. bullous dermatitis)
Hematologic 
Pancytopenia, leukopenia, hemolysis, positive direct antiglobulin (Coombs) test
Musculoskeletal 
Back pain
Gastrointestinal 
Hepatic dysfunction, abdominal pain
General/Body as a Whole 
Pyrexia, rigors
7 DRUG INTERACTIONS
Passive transfer of antibodies may transiently impair the immune response to live attenuated virus vaccines, such as 
measles, mumps, and rubella. Inform the immunizing physician of recent therapy with Flebogamma 5% DIF so that 
appropriate measures can be taken (see Patient Counseling Information [17])
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
There are no studies of Flebogamma 5% DIF use in pregnant women. Animal reproduction studies have not been performed 
with Flebogamma 5% DIF. It is also not known whether Flebogamma 5% DIF can cause fetal harm when administered to 
a pregnant woman or can affect reproduction capacity. Immunoglobulins cross the placenta from maternal circulation 
increasingly after 30 weeks of gestation. Flebogamma 5% DIF should be given to a pregnant woman only if clearly needed.
8.2 Lactation
Risk Summary
There is no information regarding the presence of Flebogamma 5% DIF in human milk, its effects on the breastfed infant, 
or its effects on milk production. The developmental and health benefits of breastfeeding should be considered along 
with the mother’s clinical need for Flebogamma 5% DIF and any potential adverse effects on the breastfed infant from 
Flebogamma 5% DIF or from the underlying maternal condition.
8.4 Pediatric Use
Flebogamma 5% DIF was studied in a multicenter clinical trial for the treatment of PI in 24 subjects aged 2-16 years 
(seven were 2-5 years of age, seven were 6-11 years, and ten were 12-16 years), and found to be efficacious for the 
prevention of acute serious bacterial infections. No pediatric-specific dose requirements were necessary to achieve the 
desired serum IgG levels.
Twenty subjects (83.3%) had at least one adverse reaction at some time during the study that was considered product-related. 
There were no deaths or serious adverse reactions. Treatment-related adverse reactions that occurred with an incidence of at 
least 5% on a per-subject basis included headache (42%), pyrexia (29%), hypotension (25%), tachycardia (25%), diastolic 
hypotension (21%), nausea (8%), abdominal pain (8%), diarrhea (8%), pain (8%), and vomiting (8%).
Safety and efficacy of Flebogamma 5% DIF in pediatric patients below the age of 2 years have not been established. 
8.5 Geriatric Use
Limited information is available for the geriatric use of Flebogamma 5% DIF. Clinical studies of Flebogamma 5% DIF did not 
include sufficient numbers of subjects over the age of 65 to determine whether they respond differently from younger subjects. 
Use caution when administering Flebogamma 5% DIF to patients age 65 and over who are judged to be at increased risk for 
developing thrombosis or renal insufficiency. Do not exceed recommended dose, and administer Flebogamma 5% DIF at the 
minimum dose and infusion rate practicable, and at less than 0.06 mL per kg per minute (3 mg per kg per min). (see Boxed 
Warning, Warning and Precautions [5.2, 5.4], and Dosage and Administration [2.3])
10   OVERDOSAGE
Overdose may lead to fluid overload and hyperviscosity. Patients at particular risk of complications of fluid overload and 
hyperviscosity include elderly patients and patients with cardiac or renal impairment.
11   DESCRIPTION
Flebogamma 5% DIF is a ready to use, sterile, clear or slightly opalescent and colorless to pale yellow, liquid preparation 
of purified immunoglobulin (IgG) obtained from human plasma pools. The purification process includes cold ethanol 
fractionation, polyethylene glycol precipitation, ion exchange chromatography, low pH treatment, pasteurization, solvent 
detergent treatment, and Planova nanofiltration using 20 nanometer (nm) filters.
Flebogamma 5% DIF is a purified (at least 97% IgG), unmodified, human IgG. The distribution of the four IgG subclasses 
is approximately 66.6% IgG1, 28.5% IgG2, 2.7% IgG3, and 2.2% IgG4. Flebogamma 5% DIF contains trace amounts of IgA 
(typically less than 50 µg/mL) and trace amounts of sodium and IgM. 
Flebogamma 5% DIF contains 5 g human normal immunoglobulin and 5 g D-sorbitol (as stabilizer) in 100 mL of water for 
injection, and ) 3 mg/mL polyethylene glycol. There is no preservative in the formulation. The pH of the solution ranges from 
5 to 6 and the osmolality from 240 to 370 mOsm/kg, which is within the normal physiological range.
Screening against potentially infectious agents begins with the donor selection process and continues throughout plasma 
collections and plasma preparation. Each individual plasma donation used in the manufacture of Flebogamma 5% DIF 
is collected only at FDA-approved blood establishments and is tested by FDA-licensed serological test for hepatitis B 
virus (HBV) surface antigen (HBsAg), and for antibodies to human immunodeficiency virus (HIV-1/HIV-2) and hepatitis C 
virus (HCV) in accordance with U.S. regulatory requirements. As an additional safety measure, mini-pools of plasma are 
tested for the presence of HBV, HIV-1 and HCV by FDA-licensed nucleic acid testing (NAT) and found to be negative. In 
addition, plasma is tested by in-process NAT for hepatitis A virus (HAV) and parvovirus B19 (B19) on mini-pools and the 
viral load limit for B19 in the manufacturing pool is set not to exceed 104 IU/mL. NAT for the presence of HCV and HIV in 
the manufacturing plasma pool is also performed and found to be negative.
To further improve the margin of safety, three dedicated, independent virus inactivation/removal steps have been 
integrated into the manufacturing and formulation processes, namely pasteurization at 60 ºC, 10 hours, solvent-detergent 
treatment for 6 hours, and nanofiltration down to 20 nm Planova filters. 
In vitro virus spiking studies have been used to validate the capability of the manufacturing process to inactivate and 
remove viruses. To establish the minimum applicable virus clearance capacity of the manufacturing process, these virus 
clearance studies were performed on seven steps of the production process (pasteurization, solvent-detergent treatment, 
nanofiltration, Fraction I precipitation, Fraction II+III precipitation, 4% PEG precipitation, and pH treatment for 4 hours 
at 37 ºC). 
The viral reduction data (in log10) from these experiments are summarized in Table 2.
Table 2. Flebogamma 5% DIF: Viral Reduction Capacity of Combined Steps (log10)
Target virus
HIV-1, HIV-2
(env. RNA)
HBV Herpesvirus
(env. DNA)
HCV
(env. RNA)
WNV
(env. RNA)
HAV
(non-env. 
RNA)
Virus B19
(non-env. 
DNA)
Model virus
HIV-1
PRV 
IBR
BVDV
SINDBIS
WNV
EMC
PPV
Fraction I 
precipitation
< 1.00*
nd
nd
nd
nd
2.78
nd
< 1.00*
Ethanol incubation 
(Fraction II+III) 
1.48
nd
nd
nd
nd
< 1.00*
nd
nd
PEG precipitation
* 6.10
* 5.92
nd
* 5.78
nd
nd
* 6.41
6.35
Acid pH treatment  
2.47
* 5.32
nd
< 1.00*
nd
nd
1.36
na
Pasteurization 
* 5.64
* 4.96
* 6.33
* 4.69
* 6.49
* 5.42
* 5.56
4.08
Solvent Detergent 
* 4.61
* 6.95
nd
* 6.14
nd
* 5.59
na
na
Nanofiltration 
20 nanometer
* 4.81
* 4.63
nd
* 4.67
nd
* 3.63
* 5.92
4.61
Overall Reduction 
Capacity
* 25.11
* 27.78
* 6.33
* 21.28
* 6.49
* 17.42
* 19.25
15.04
* When the RF is < 1 log10, it is not taken into account for the calculation of the overall reduction capacity.
* is no residual infectivity detected; nd = not done; na = non-applicable, since the virus is theoretically resistant to this 
treatment.
Abbreviations: HIV = Human immunodeficiency virus; PRV = Pseudorabies virus; IBR = Infectious bovine 
rhinotracheitis virus; BVDV = Bovine viral diarrhea virus; SINDBIS = Sindbis virus; WNV = West Nile virus; 
EMC = Encephalomyocarditis virus; PPV = Porcine parvovirus.
Additionally, the manufacturing process was investigated for its capacity to decrease infectivity of an experimental agent 
of transmissible spongiform encephalopathy (TSE), considered as a model for the vCJD and CJD agents. Several individual 
production steps in the Flebogamma 5% DIF manufacturing process have been shown to decrease TSE infectivity of an 
experimental model agent. TSE reduction steps include 4% polyethylene glycol precipitation [at least 6.19 log10] and Planova 
nanofiltration using a 20 nanometer filter [at least 5.45 log10]. These studies provide reasonable assurance that low levels 
of CJD/vCJD agent infectivity, if present in the starting material, would be removed.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Flebogamma 5% DIF, immune globulin intravenous (human), is a replacement therapy for PI. It supplies a broad spectrum 
of opsonizing and neutralizing IgG antibodies against a wide variety of bacterial and viral agents. Flebogamma 5% DIF 
also contains a spectrum of antibodies capable of reacting with cells such as erythrocytes. The role of these antibodies 
and the mechanisms of action of IgG in Flebogamma 5% DIF have not been fully elucidated.
12.3 Pharmacokinetics 
In the clinical study assessing safety and efficacy in PI, Flebogamma 5% DIF was administered as an IV infusion 
(300-600 mg per kg) to subjects every 3 (n = 8) or 4 (n = 12) weeks for 12 months. The pharmacokinetics of total IgG 
was determined after the 7th infusion for the 3-week dosing interval and after the 5th infusion for the 4-week dosing 
interval (Table 3).
Table 3. Pharmacokinetic Variables of Total IgG in Subjects with PI
Variable
3-Week Dosing Interval (n = 8)
4-Week Dosing Interval (n = 12)
Mean [Range]
SD
Mean [Range]
SD
Cmax (mg/dL)
1,929 [1,300-2,420] 
441
2,069 [1,590-2,800]
338
AUC0 - last (day·mg/dL)
31,159 [20,458-40,104]
6,572
32,894 [27,650-41,814]
3,886
Clearance (mL/day)
139 [81-243]
57
109 [59-161]
33
Half-life (days)a
30 [19-41]
9
32 [25-39]
5
Trough IgG level (mg/dL)b
951.38
[773.17-1143.15]
132.42
899.89
[776.70-1,137.14]
92.03
a.  This half-life is an apparent value derived from a period of measurement of 28 days.
b.  For subjects on the 3-week schedule, the average of the trough levels from Infusion 7 to the end of the study was calculated; 
for those on a 4-week schedule, the average of the trough levels from Infusion 5 to the end of the study was calculated. The 
means of the subject means are presented in this table.
There were 3 adolescent (up to 16 years of age) subjects who underwent pharmacokinetic testing, all of whom were on the 
3-week infusion schedule. There were no clinically relevant differences among the adults and adolescents that were tested. 
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenicity, Mutagenesis, Impairment of Fertility  
No animal studies were conducted to evaluate the carcinogenic or mutagenic effect of Flebogamma 5% DIF or its effects 
on fertility.
13.2 Animal Toxicology and/or Pharmacology
Acute toxicity studies were performed in mice and rats at doses up to 2.5 g per kg body weight with infusion rates 
6-37 times higher than the maximum rates recommended for humans. The most common clinical observations in mice 
studies were piloerection, ptosis, ataxia, and increase in respiration all lasting 90 minutes or less. No relevant adverse 
effects could be confirmed affecting respiratory, circulatory, renal, autonomic and central nervous systems, somatomotor 
activity, and behavior of the treated mice and rats.
Five of the 25 rats treated with the highest dose, approximately 8 times the maximum infusion rate recommended for 
humans, showed a transient “reddish urine” sign which was not confirmed as a relevant toxicity-causing phenomenon 
after renal macroscopic and microscopic analysis. This phenomenon was ascribed to hemolysis when serum was 
analyzed, suggesting a possible relation to cross reactivity of rodent red cells with human antibodies. No “reddish urine” 
was detected in any mouse, a much smaller animal where the rate of infusion was comparatively much higher than in 
rats. The macroscopic inspection of all treated mice did not show any renal alteration.
14 CLINICAL STUDIES
A multicenter, open-label, historically controlled study was conducted in the United States to assess the efficacy, safety, 
and pharmacokinetics of Flebogamma 5% DIF in adult and pediatric subjects with PI. A total of 46 subjects aged 
15-75 years (63% male, 37% female) were enrolled and treated with Flebogamma 5% DIF at a dose of 300-600 mg per 
kg per infusion every 3-4 weeks for 12 months.
3048714
Instituto Grifols, S.A. Can Guasc, 2 - Parets del Vallès 08150 Barcelona - SPAIN
Since the subjects in the clinical study were assigned to two different treatment intervals (3-week vs. 4-week infusion 
schedules), the dosage had to be adjusted to ensure that the subjects received approximately the same dosage on an 
annualized basis. Therefore, subjects in the 3-week schedule received 75% of the monthly (4-week) dosage per infusion. 
This resulted in a mean annualized dosage of 451 mg per kg per month for subjects in the 3-week schedule (n=13, range 
288-588 mg per kg per month) and 448 mg per kg per month for subjects in the 4-week schedule (n=33, range 298-591 mg 
per kg per month).
During the study period, the annual rate of acute serious bacterial infection, defined as bacterial pneumonia, bacteremia 
or sepsis, osteomyelitis/septic arthritis, visceral abscess, and bacterial meningitis per subject per year, was 0.021 (with 
an upper 1-sided 98% confidence interval of 0.112). One subject had one episode of bacterial pneumonia and there were 
no other episodes of serious bacterial infections reported (Table 4). 
Table 4. Summary of Bacterial Infections (Intention-to-Treat Population, N = 46)
Infections
Subjects (N=46) N (%)
Episodes
Estimates a
98% CI b
Bacterial pneumonia
1 (2.2)
1
Bacteremia or sepsis
0 (0.0)
0
Osteomyelitis/septic arthritis
0 (0.0)
0
Bacterial meningitis
0 (0.0)
0
Total subjects 
1 (2.2)
1
0.021
(0.001-0.112)
a. Estimate = Total episodes/Total subject years.
b. The confidence interval is obtained by using a generalized linear model procedure for Poisson distribution.
The number of days of work/school missed, hospitalizations and days of each hospitalization, the number of visits to 
physicians or emergency rooms, other infections documented by positive radiographic findings and fever, and days on 
therapeutic and prophylactic oral/parenteral antibiotic use were also evaluated. These variables were annualized by using 
the subject-years exposure data of those subjects experiencing the events, but not the entire study cohort. With regard to 
the number of other validated infections, the mean rate was less than 2 days per subject per year (this calculation used all 
subjects, including those who had no infections). (Table 5)
Table 5. Summary of Annualized Efficacy Variables
Variable
Subjects 
Mean number of events, days or 
visits per subject per yeara
N
%
Work/school days missed
23
50.0
12.95
Days of normal activities missed
18
39.1
7.28
Days in hospital 
4
8.7
0.77
Visits to physician/ER
29
63.0
4.31
Number of other documented infectious episodes
33
71.7
1.96
Days of therapeutic oral antibiotic use
35
76.1
55.52
Days of therapeutic parenteral antibiotic use
2
4.3
0.14
Days of other therapeutic antibiotic use
16
34.8
44.30
Days of prophylactic oral antibiotic use
19
41.3
81.08
Days of prophylactic parenteral antibiotic use
1
2.3
0.02
Days of other prophylactic antibiotic use
0
0.0
0.00
a.  Days of work/school missed per subject year are derived as total days of work/school missed divided by total days in study 
multiplied by 365. If data are missing for a period (e.g. between Infusion 2 and Infusion 3), then number of days in this period 
is not counted in the denominator. All other endpoints are derived similarly.
A multicenter, open-label, historically controlled study was conducted in the United States to assess the efficacy of 
Flebogamma 5% DIF in pediatric subjects with PI. A total of 24 subjects aged 2-16 years (79% male, 21% female) 
were enrolled and treated with Flebogamma 5% DIF at a dose of 262-625 mg per kg per infusion every 3-4 weeks for 
12 months.
The annual rate of acute serious bacterial infections, defined as bacterial pneumonia, bacteremia or sepsis, 
osteomyelitis/septic arthritis, visceral abscess, and bacterial meningitis per subject per year, was 0.051 (with an upper 
1-sided 99% confidence limit of 0.53). One subject had one episode of bacterial pneumonia and there were no other 
episodes of serious bacterial infections reported.
15 REFERENCES
1. Cayco AV, Perazella MA, Hayslett JP. Renal insufficiency after intravenous immune globulin therapy: a report of two 
cases and an analysis of the literature. J Am Soc Nephrol 1997; 8:1788-94.
2. Winward DB, Brophy MT. Acute renal failure after administration of intravenous immunoglobulin: review of the 
literature and case report. Pharmacotherapy 1995; 15:765-72.
3. Tan E, Hajinazarian M, Bay W, et al. Acute renal failure resulting from intravenous immunoglobulin therapy. Arch 
Neurol 1993; 50:137-9.
4. Sekul EA, Cupler EJ, Dalakas MC. Aseptic meningitis associated with high-dose intravenous immunoglobulin therapy: 
frequency and risk factors. Ann Intern Med 1994; 121:259-62.
5. Kato E, Shindo S, Eto Y, et al. Administration of immune globulin associated with aseptic meningitis. JAMA 1988; 
259:3269-71.
6. Casteels-Van Daele M, Wijndaele L, Hanninck K, et al. Intravenous immune globulin and acute aseptic meningitis. 
N Engl J Med 1990; 323:614-5.
7. Scribner CL, Kapit RM, Phillips ET, et al. Aseptic meningitis and intravenous immunoglobulin therapy. Ann Intern Med 
1994; 121:305-6.
8. Copelan EA, Strohm PL, Kennedy MS, et al. Hemolysis following intravenous immune globulin therapy. Transfusion 
1986; 26:410-2.
9. Thomas MJ, Misbah SA, Chapel HM, et al. Hemolysis after high-dose intravenous Ig. Blood 1993; 15:3789.
10. Reinhart WH, Berchtold PE. Effect of high-dose intravenous immunoglobulin therapy on blood rheology. Lancet 1992; 
339:662-4.
11. Wilson JR, Bhoopalam N, Fisher M. Hemolytic anemia associated with intravenous immunoglobulin. Muscle Nerve 
1997; 20:1142-1145.
12. Kessary-Shoham H, Levy Y, Shoenfeld Y, et al. In vivo administration of intravenous immunoglobulin (IVIG) can lead 
to enhanced erythrocyte sequestration. J Autoimmune 1999; 13:129-35.
13. Kahwaji J, Barker E, Pepkowitz S, et al. Acute hemolysis after high-dose intravenous immunoglobulin therapy in highly 
HLA sensitized patients. Clin J Am Soc Nephrol 2009; 4:1993-1997.
14. Daw Z, Padmore R, Neurath D, et al. Hemolytic transfusion reactions after administration of intravenous immune 
(gamma) globulin: A case series analysis. Transfusion 2008; 48:1598-1601.
15. Rizk A, Gorson KC, Kenney L, et al. Transfusion-related acute lung injury after the infusion of IVIG. Transfusion 2001; 
41:264-8.
16. Pierce LR, Jain N. Risks associated with the use of intravenous immunoglobulin. Transfus Med Rev 2003; 17:241-51.
17. Orbach H, Katz U, Sherer Y, Shoenfeld Y. Intravenous immunoglobulin: adverse effects and safe administration. Clin 
Rev Allergy Immunol, 2005; 29:173-184.
16 HOW SUPPLIED/STORAGE AND HANDLING
Flebogamma 5% DIF is supplied in single-use, individually laser-etched vials containing the labeled amount of 
functionally active IgG. The following presentations of Flebogamma 5% DIF are available:
NDC Number
Size
Grams Protein
61953-0004-1
10 mL
0.5 g
61953-0004-2
50 mL
2.5 g
61953-0004-3
100 mL
5.0 g
61953-0004-4
200 mL
10.0 g
61953-0004-5
400 mL
20.0 g
Each vial has an integral suspension band and a label with two peel-off strips showing the product name and lot number.
Flebogamma 5% DIF may be stored at room temperature at 2 to 25 ºC (36 to 77 ºF) for 24 months, as indicated by the 
expiration date printed on the outer carton and container label. Discard after expiration date. Do not freeze. 
Keep Flebogamma 5% DIF in its original carton to protect it from light.
Not made with natural rubber latex.
17 PATIENT COUNSELING INFORMATION
Instruct patients to immediately report the following signs and symptoms to their physician:
• Decreased urine output, sudden weight gain, fluid retention/edema, and/or shortness of breath (see Renal Failure 
[5.2])
• Symptoms of thrombosis which may include: pain and/or swelling of an arm or leg with warmth over the affected 
area, discoloration of an arm or leg, unexplained shortness of breath, chest pain or discomfort that worsens on deep 
breathing, unexplained rapid pulse, numbness or weakness on one side of the body (see Thrombosis [5.4]) 
• Severe headache, neck stiffness, drowsiness, fever, sensitivity to light, painful eye movements, nausea, and vomiting 
(see Aseptic Meningitis Syndrome [5.5])
• Fatigue, increased heart rate, yellowing of the skin or eyes, and dark-colored urine (see Hemolysis [5.6])
• Trouble breathing, chest pain, blue lips or extremities, fever (see TRALI [5.7])
Inform patients that Flebogamma 5% DIF is made from human plasma and may contain infectious agents that 
can cause disease (e.g., viruses, the vCJD agent and, theoretically, the CJD agent). The risk of Flebogamma 5% DIF 
transmitting an infectious agent has been reduced by screening plasma donors for prior exposure, testing the donated 
plasma, and inactivating and/or removing certain viruses during manufacturing. (see Warnings and Precautions [5.8]) 
Instruct patients to report any symptoms that concern them and might be caused by infections.
Inform patients that Flebogamma 5% DIF may interfere with their immune response to live viral vaccines such as 
measles, mumps, and rubella. Inform patients to notify their health care professional of this potential interaction when 
they are receiving vaccinations. (see Drug Interactions [7])
Manufactured by:
INSTITUTO GRIFOLS, S.A.
BARCELONA - SPAIN
U.S. License No. 1181





















$33(1',;D




$872&&/,1,&$/35272&2/
dŚĞƵƚŽͲĚĞǀŝĐĞŵĞŶƚŝŽŶĞĚŝŶƚŚŝƐƉƌŽƚŽĐŽů
ĐŽƌƌĞƐƉŽŶĚƐƚŽ&WDĂƉƉƌŽǀĂůη
%3

	

 !!"!#$%& %'"%( 
 %
+
/&
"0		,(
1! 2%#
,
.3
2
"01,(

"%4+
/&
))
2%# 

2%#
' 2%#
' 

2%#" 2%#" 

86  86  

"% !  "% !
  


 
CONFIDENTIAL, 
 
 Page 1 of 15 
 
 
Protocol Number 931-PRO-010255 [7.0] 
 
 
 
 
 
Protocol Number:  
 
Title:  Evaluation of the Autopheresis-C Plasma Exchange Procedure within a Clinical Trial 
Proposed Completion Date: December 31, 2013 
Project: Auto-C Plasma Exchange 
Requesting Individual/Department: 
  
 
Project Management 
Additional Distribution (Original to Quality System Archives):   
 
Global Plasma Business 
 
Regulatory Affairs 
 
Regulatory Affairs 
 
Plasma Services 
 
 
 
APPROVALS:  Entire Document
Name 
Department 
Signature 
Date 
 
Author  
R&D Systems Engineering 
See Electronic Signature 
 
Clinical Affairs 
Technical Approver 
See Electronic Signature 
 
Quality Engineering 
See Electronic Signature 
 
Study must not begin until all approval signatures are obtained. 
 

Evaluation of the Autopheresis-C Plasma Exchange Procedure within a Clinical Trial 
 
 
CONFIDENTIAL,
. 
 Page 2 of 15 
 
 
Protocol Number 931-PRO-010255 [7.0] 
1. Purpose 
This protocol defines system evaluation for the Autopheresis-C Plasma Exchange Protocol, running complete 
procedures as part of a clinical trial conducted by Grifols SA.  The tests defined herein are intended to satisfy system 
performance requirements that cannot be fully tested on bagged blood procedures.  Additionally, this document will 
provide the data sheet to be used during the procedures outlined herein. 
The following are the purposes for this protocol: 
x To observe typical return rates for a mixture of blood and replacement fluid in Alzheimer’s patients, 
x To compare replacement fluid volume delivered to the programmed volume to show that the delivered volume of 
replacement fluid is within +/-10% of the programmed target volume for 90% of completed procedures, and 
x To provide a method for Grifols SA to communicate this data to Fenwal, Inc. 
 
The results of execution of this protocol are intended to satisfy, in part, 931-PLN-010004. 
 
2. Background 
The AUTOPHERESIS-C® (Auto-C™) system (Fenwal, Inc.) is an automated plasma collection system that has been 
in use in the United States since its Food and Drug Administration (FDA) clearance in March, 1986.  It was 
classified at that time as a Class III PMA device (BP850001).  In February 2003, automated blood cell separator 
devices operating by filtration principles intended for the routine collection of blood and blood components, 
including the Autopheresis-C, were re-classified by the FDA as Class II devices.  This modified their regulatory 
review pathway from PMA (pre-market approval) to 510(k) (pre-market notification).   
The Grifols SA company is a Spanish holding company that performs research, development, manufacturing and 
marketing of plasma derivatives, IV therapy, enteral nutrition, diagnostic systems and medical materials.  It is 
currently in Phase II clinical trials using albumin as a plasma replacement fluid for the treatment of Alzheimer’s 
disease.  Grifols has requested that Fenwal design and develop a plasma exchange procedure and disposable set for 
the Auto-C plasmapheresis platform that could use albumin replacement with IVIG for treatment of patients with 
Alzheimer’s for use in their clinical trials. 
The testing described in this document will utilize Autopheresis-C instruments, investigational human-use software, 
along with investigational disposables to perform procedures on Alzheimer’s patients.  Testing is conducted under 
the clinical investigation conducted by Grifols SA. 
Features of the Autopheresis-C Plasma Exchange Protocol investigational human use software include: 
x Operator selection of a replacement fluid target of 160, 190, or 200 mL to correspond with a plasma collection 
volume of 690, 825, and 880 mL of collected plasma, respectively.  An editable option is also available. 
x Return of the programmed volume of replacement fluid after collection of the target plasma volume via a series 
of phases in which patient blood is mixed with replacement fluid and then the mixture is returned to the patient. 
The purpose of this protocol is to investigate the use of the Autopheresis-C Plasma Exchange Protocol to return a 
20% human serum albumin (HSA) solution as the replacement fluid.  The disposable sets for use during this study 
are investigational (Fenwal Product Code FTX-3900); they include a fistula needle set attached at a luer, an attached 
1000 mL plasma collection container, a spike for connection to an anticoagulant solution, and a luer for connection 
to a transfer set supplied by Grifols SA that allows for connection of two bottles of replacement fluid. 
 

Evaluation of the Autopheresis-C Plasma Exchange Procedure within a Clinical Trial 
 
 
CONFIDENTIAL, 
 
 Page 3 of 15 
 
 
Protocol Number 931-PRO-010255 [7.0] 
3. Materials and Equipment 
Materials and equipment that may be used in this study include, but are not limited to: 
x
Plasmacell-C Kit,
 
x
AUTOPHERESIS-C Instrument with investigational plasma exchange protocol software, Code R4R4585 
or 4R4550 
x
Grifols Replacement Fluid Transfer Set, Grifill 3.0 Plastic 2-to-1 Set 
x
Sodium Citrate Solution, USP, 500 mL, Code 4B7889Q or equivalent 
x
Human Serum Albumin 20%, 50 or 100 mL 
x
Tubing sealer 
x
Weight scale, if available 
 
4. Methods 
4.1. Software Installation and Removal 
Installation of the software onto clinical instruments shall be through chipset install as described in TSB-
TSB12560043. Software tracking and removal is also managed in the TSB. 
4.2. Training 
All Autopheresis-C Plasma Exchange Protocol Operators and support team members will be trained on the 
Autopheresis-C Plasma Exchange Protocol per the applicable operating instructions, 07-19-54-188 and REC-
003672.  Operators, prescribers, and support team members will also be trained on this protocol.  All training will be 
documented and recorded per FQA-01-007. 
4.3. General Considerations 
4.3.1. Multiple Companies 
Multiple companies (Fenwal, Inc. and Grifols SA) will contribute to this study.  Each group may have their own 
original data forms, standard operating procedures, etc.  It is neither required nor expected that every form or 
procedure be included or referenced in this protocol.  It is required, however, that all original data be preserved as 
detailed in section 7.2. 
4.3.2. Procedure Data 
The data sheet in Appendix B will be completed as the procedure progresses.  Data will be reported to Fenwal, 
reviewed, and analyzed per the statistical equations indicated in this protocol. 
4.4. Set Up 
4.4.1. Plasma Collection Volumes 
The target Plasma Collection Volume is chosen at the discretion of a physician in accordance with the clinical 
protocol.  It is recorded in Appendix B.  The nomogram that has been tested is indicated below. 
Patient Weight 
lbs (kg) 
Maximum Plasma 
Collection Volume (mL) 
110-149 (50-67) 
690 
150-174 (68-79) 
825 
175-999 (80-454) 
880 
 
4.4.2. Replacement Fluid Infusion Volumes 
The target Replacement Fluid Infusion Volume is chosen at the discretion of a physician in accordance with the 
clinical protocol.  It is recorded in Appendix B.  The nomogram that has been tested is indicated below. 

Evaluation of the Autopheresis-C Plasma Exchange Procedure 
 
 
CONFIDENTIAL, 
 
 Page 4 of 15 
 
 
Protocol Number 931-PRO-010255 [7.0] 
 
Replacement Fluid Infusion Volume (mL) 
Patient Weight 
lbs (kg) 
Maximum Plasma 
Collection Volume (mL) 
Full Dose 
1/2 Dose 
1/3 Dose 
110-149 (50-67) 
690 
160 
80 
55 
150-174 (68-79) 
825 
190 
95 
65 
175-999 (80-999) 
880 
200 
100 
70* 
*This setting has not been tested, but is recommended for use in the clinical trial 
4.5. Patient Assessment 
The physician requesting the plasma exchange protocol may provide guidelines under which a patient may be 
excluded from the study.  The Autopheresis-C plasma exchange protocol is recommended and designed for patients 
weighing at least 110 lbs (50 kg) with a hematocrit of 38% or greater. 
4.6. Sampling and Processing 
4.6.1. Pre-Procedure Samples 
Before the procedure, the patient’s blood is sampled and hematocrit recorded.  Additionally, the weight of the 
replacement fluid containers is measured and recorded.  See Appendix B. 
4.6.2. In-Procedure Samples 
No samples are taken during the procedure, but the following information may be recorded: 
x
Patient Adverse Reactions 
x
Alarm Information (name of alarm and approximate time or state in which it occurred) 
x
Other Notes 
4.6.3. Samples after Patient Disconnect 
After patient disconnect, the following measurements and observations are recorded: 
x
The weights of the following, if a weight scale is available: 
o
The plasma product 
o
The replacement fluid containers 
o
The disposable set, excluding AC spike, needle set and luer, and replacement fluid transfer set and 
luer 
x
The presence of fluid and/or air in the replacement fluid line. 
 
5. Product Performance 
If the Autopheresis-C system does not perform as expected, see Appendix C. 
6. Evaluation of Data and Acceptance Criteria 
6.1. Definitions and Abbreviations 
Term 
Definition 
Hct 
Hematocrit 
HSA 
Human serum albumin 
Kit 
The Plasmacell-C disposable set after the AC spike, plasma bag, replacement fluid luer, and fistula 
needle set (including the luer) have been sealed and removed 
Platelet-Poor Plasma 
(PPP) 
The collected, platelet-poor waste plasma at Day 0 
RF 
Replacement Fluid 
VP Time 
Venipuncture time; the amount of time between the operator acknowledging that venipuncture is 
complete and the instrument instructing the operator to disconnect the patient 
 

Evaluation of the Autopheresis-C Plasma Exchange Procedure 
 
 
CONFIDENTIAL, 
 
 Page 5 of 15 
 
 
Protocol Number 931-PRO-010255 [7.0] 
6.2. Equations 
Kit PRE-WEIGHT
[6] = 165.8 g 
Kit Residual Volume 
 
= [(Kit POST-WEIGHT – Kit PRE-WEIGHT) g ÷ 1.05 g/mL [8]] mL 
Disposable Set and Transfer Set Plasma/RF/AC Line Volumes 
= AC Line Length[7] x AC Tubing Volume per Length[7]  + (Plasma Line Length[7]  + RF Line Length[7]  + RF 
Transfer Set Length) x Blood Tubing Volume per Length[7] 
= 84” x 0.0196 mL/inch + (25” + 27” + 12”) x 0.2043 mL/inch 
= 14.72 mL 
Kit RF Volume 
 
= [(1/4) * (Kit Residual Volume - Disposable Set and Transfer Set Plasma/RF/AC Line Volumes)] mL 
Plasma Volume 
 
= [(PPP POST-WEIGHT – PPP BAG-EMPTY) g ÷ 1.027 g/mL ] mL 
PPP BAG-EMPTY
[6] = 41.87 g
Replacement Fluid Line and Transfer Set Volume 
 
(if filled with fluid) = [39” x 0.2043 mL/inch] = 7.97 mL 
 
(if filled with air) = 0 mL 
 
(if filled with both) = [19.5” x 0.2043 mL/inch] = 3.98 mL 
RF Cap Weight[6] = 3.60 g  
 
Replacement Fluid Volume 
 
= [(RF PRE-WEIGHT – RF POST-WEIGHT – RF Cap Weight) g ÷ 1.06 g/mL [9] - Replacement Fluid Line and Transfer Set 
Volume – Kit RF Volume] mL 
 
 
6.3. Statistical Analysis 
6.3.1. Statistical Equations 
Interval, Mean Confidence 
 
= 
>
@
n
s
t
x
df
 
 
  
  
  
  
)
 ,
2
/
(
y
u
r
D
 
where: x  = Sample Mean (or Average) 
 
 
 
 
 
α = Risk of Type I error (here 0.05, for 95% confidence) 
 
 
 
 
 
n = Sample size 
 
 
 
 
 
df = Degrees of freedom  =  (Sample size – 1) 
 
 
 
 
 
s = Sample Standard Deviation 
 
 
 
 
 
t (α / 2, df) = t-value of  t-Distribution 
 
 
 
 
 
  
(to be determined by study sample sizes) 

Evaluation of the Autopheresis-C Plasma Exchange Procedure 
 
 
CONFIDENTIAL, 
 
 Page 6 of 15 
 
 
Protocol Number 931-PRO-010255 [7.0] 
Interval, Statistical Tolerance 
 
= 
>
@
 
  
  
  
  
)
 ,
 ,
–
1(
s
k
x
n
R
u
r
D
 
where: x  = Sample Mean (or Average) 
 
 
 
 
 
1 – α = Confidence Level 
 
 
 
 
 
  
(here 0.95, for 95% confidence) 
 
 
 
 
 
n = Sample size 
 
 
 
 
 
s = Sample Standard Deviation 
 
 
 
 
 k (1–α ,R, n) = k-factor based on confidence level, reliability, and 
 
 
 
 
 
  
sample size (to be determined for specific confidence 
 
 
 
 
 
  
level and reliability) 
6.3.2. Sample Size 
This study will utilize a minimum sample size of 29 complete Auto-C plasma exchange procedures, including 
post-procedure weight data.  This sample size, with zero failures, will provide 95% confidence that the 
delivered volume of replacement fluid is within ± 10% of programmed volume 90% of the time.  If fewer than 
29 samples are available, the study lacks the statistical power required to demonstrate that the acceptance 
criterion is met. 
6.3.3. Acceptance Criteria 
The acceptance criterion for this portion of Grifols’ clinical trial is that the delivered volume of replacement 
fluid (shown as Replacement Fluid Volume in the Equations section) is within +/-10% of the programmed 
target volume 90% of the time. 
 
7. Post Study Disposition 
7.1. Disposition of Samples 
Upon completion of a procedure, the disposable set and replacement fluid should be discarded.  Collected plasma 
may be retained for sampling and testing.  When testing of the plasma is complete, the plasma should also be 
discarded.  All biological material must be discarded as biohazardous waste. 
7.2. Original Data 
Original data will be recorded during the execution of the protocol on worksheets provided in Appendix B and other 
data forms, as appropriate.  This protocol, all original data, the final report, and all amendments will be archived in 
the appropriate Fenwal, Inc. archives. 
7.3. Hardware and Software 
The instruments will be retained by Grifols after study completion, but the experimental software must be returned 
to Fenwal, Inc.  See TSB-TSB-12560043 for tracking of the return of experimental software. 
 
8. References 
1.
931-PLN-01004, Auto-C Plasma Exchange Product Validation Plan  
2.
TSB-TSB12560043, Install, Test and Configure an Auto-C Instrument with Dory Project Software 
3.
FQA-01-007, Fenwal Training Process 
4.
REC-003672, Autopheresis-C Plasma Exchange Protocol Supplemental Operating Instructions 
5.
07-19-54-188, Autopheresis-C™ Plasmapheresis System Operator’s Manual 
6.
NB00016-134.  “Measurement of Auto-C Plasma Exchange Protocol Kit Tare Weights, Revisited”.  
7.
DWG-0312581824,  AUTO-C Plasma Exchange FTX-3900 Disposable Set 
8.
Trudnowski, RJ and Rico, RC.  “Specific Gravity of Blood and Plasma at 4 and 37oC”.  Clin Chem  20 (1974): 615-616. 
9.
Nugent, RL and Towle, LW.  “The Specific Gravity of Synthetic Solutions of Serum Albumin and Serum Globulin”. J 
Biol Chem  (1933). 

Evaluation of the Autopheresis-C Plasma Exchange Procedure 
 
 
CONFIDENTIAL, 
. 
 Page 7 of 15 
 
 
Protocol Number 931-PRO-010255 [7.0] 
 
9. List of Appendices  
A.
Steps for Recording Auto-C Plasma Exchange Procedure Data 
B.
Auto-C Plasma Exchange Procedure Data Record 
C.
Product Performance Flow Chart 
D.
Product Performance Report 
E.
Revision History 
 
 

Evaluation of the Autopheresis-C Plasma Exchange Procedure 
 
 
CONFIDENTIAL, 
. 
 Page 8 of 15 
 
 
Protocol Number 931-PRO-010255 [7.0] 
A.  Steps for Recording Auto-C Plasma Exchange 
Procedure Data 
Pre-Procedure:
Before the procedure, record the following on the data sheet in Appendix B: 
x
Run ID 
x
Patient Weight 
 
Based on the patient’s weight and physician’s orders, identify and record the following on the data sheet in 
Appendix B: 
x
Plasma Target 
x
Replacement Fluid (RF) Target 
x
Type of RF Used 
 
Record the weight of the replacement fluid containers on the data sheet as “RF Weight - Pre” in Appendix B. 
 
Take a fingerstick hematocrit of the patient and record the hematocrit on the data sheet in Appendix B. 
 
During the Procedure: 
When entering the replacement fluid infusion states, record any changes to the infusion rate under “Flow Rate 
during RF Infusion”.  If no changes are made, the RF Infusion rate is 20 mL/min. 
 
During the procedure, record the following (as applicable) on the data sheet in Appendix B.  If there are no notes for 
the section, write “N/A”. 
x
Patient Adverse Reactions 
x
Alarm Information (name of alarm and approximate time or state in which it occurred) 
x
Other Notes 
 
If any product performance issues are observed, see Appendix C. 
 
After the Procedure:
At the end of the procedure, record the following from the display:  
x
RF Infused 
x
VP Time 
 
Disconnect the patient. 
 
Note whether the replacement fluid line is filled with fluid, air, or both under “Air/Fluid in the RF Line” on the data 
sheet in Appendix B. 
 
 Seal the disposable set in the following locations: 
x
On the apheresis needle set near the luer 
x
On both sides of the replacement fluid transfer set luer 
x
On both pressure transducer connector lines 
x
Near the AC spike 
x
Below the separation device on the plasma line 
x
Above the sampling site on the plasma line 
These locations are shown in the diagram below. 
 

(YDOXDWLRQRIWKH$XWRSKHUHVLV&3ODVPD([FKDQJH3URFHGXUH


&21),'(17,$/

 3DJHRI


3URWRFRO1XPEHU352>@

)LJXUH/RFDWLRQVZKHUHWKHGLVSRVDEOHVHWVKRXOGEHVHDOHGEHIRUHUHPRYLQJWKHVHWIURPWKHLQVWUXPHQWDQGZKHUHWKHVHDOV
VKRXOGEHVHSDUDWHGWRZHLJKWKHNLW

Evaluation of the Autopheresis-C Plasma Exchange Procedure 
 
 
CONFIDENTIAL, 
. 
 Page 10 of 15 
 
 
Protocol Number 931-PRO-010255 [7.0] 
 
Remove the disposable set from the instrument. 
 
Remove the replacement fluid transfer set from the replacement fluid containers and the remainder of the disposable 
set.  Ensure that the luer is removed.  Also remove the fistula needle set including the luer.  Discard appropriately. 
 
If possible, weigh the replacement fluid containers and record their weight under “RF Weight - Post” on the data 
sheet in Appendix B. 
 
Remove the plasma container.  If possible, weigh it and record the weight under “Plasma Bag Weight - Post” on the 
data sheet in Appendix B. 
 
If possible, weigh the remainder of the disposable set and record the weight under “Kit Weight - Post” on the data 
sheet in Appendix B. 
 
If weights are not recorded, write “NR” in the appropriate space on the data sheet in Appendix B. 
 
Discard the disposable set appropriately. 

Evaluation of the Autopheresis-C Plasma Exchange Procedure 
 
 
CONFIDENTIAL, 
 
 Page 11 of 15 
 
 
Protocol Number 931-PRO-010255 [7.0] 
 
 
B.  Auto-C Plasma Exchange Procedure Data Record 
Pre Procedure 
Post Procedure 
Run ID 
RF Infused
mL
  
Patient Weight 
kg
VP Time 
:
Plasma Target 
mL
RF Target 
mL
Air/Fluid in RF Line 
(Circle one) 
Air     Fluid     Both 
Type of RF Used 
[  ] 20% HSA 
[  ] Other: ___________________
RF Weight - Post 
g 
Kit Weight - Post 
g
Patient Hct -OR- 
Hb
____________ % -OR- 
____________ g/dL 
RF Weight - Pre 
g
Plasma Bag Weight - 
Post 
g
During Procedure 
Patient Reaction(s) 
[  ] None 
[  ] Yes (please reference adverse event reporting data): 
_____________________________________________ 
Flow Rate during RF 
Infusion 
(20-60 mL/min) 
Cycle 1: ___________________ mL/min 
Cycle 2:  ___________________ mL/min 
Cycle 3:  ___________________ mL/min 
Cycle 4:  ___________________ mL/min 
Cycle 5:  ___________________ mL/min 
Alarm/Alert/Help
Code Information 
(Please include 
cause if known) 
Other Notes 
Entered by: 
 
 
 
 Signature: 
 
 
 
 
 Date:  
Reviewed by: 
 
 
 
  Signature: 
 
 
 
 
 Date:
 

(YDOXDWLRQRIWKH$XWRSKHUHVLV&3ODVPD([FKDQJH3URFHGXUH


&21),'(17,$/

 3DJHRI


3URWRFRO1XPEHU352>@
& 3URGXFW3HUIRUPDQFH)ORZ&KDUW
,IDSURGXFWSHUIRUPDQFHLVVXHLVREVHUYHGIROORZWKHVWHSVEHORZ


Evaluation of the Autopheresis-C Plasma Exchange Procedure 
 
 
CONFIDENTIAL, Fenwal, Inc. 
 Page 13 of 15 
 
 
Protocol Number 931-PRO-010255 [7.0] 
D.  Product Performance Report 
The product performance report below will be sent by the center to
 at 
  UBS will forward product performance report and relevant adverse 
event data to 

(YDOXDWLRQRIWKH$XWRSKHUHVLV&3ODVPD([FKDQJH3URFHGXUH


&21),'(17,$/

 3DJHRI


3URWRFRO1XPEHU352>@
,PSRUWDQW,IDGYHUVHUHDFWLRQRULQMXU\KDVRFFXUUHGFRQWDFW*ULIROV
:DVWKHGRQDWLRQVXFFHVVIXOO\FRPSOHWHG"<HV
1R
,I1RZDVWKHGRQDWLRQVWRSSHGGXHWRDVRIWJRRGVLQFLGHQW"<HV
1R
,QFLGHQW'DWHBBBBBBBBBBBBBBBBBBBBBBBBBBBB

,QVWUXPHQW6HULDO1XPEHUBBBBBBBBBBBBBBBBBBB
3URGXFW&RGHBBBBBBBBBBBBBBBBBBBBBBBBBBBB

/RW1XPEHUBBBBBBBBBBBBBBBBBBBBBBBBBBBBBB
%DWFK7DJ,QIR7LPHBBBBBBBBBBBB1XPEHUBBBBBBBB9LGHR-HW1XPEHUBBBBBBBBBBBBBBBBBBBBBBBB
3DWLHQW%OHHG1XPEHUBBBBBBBBBBBBBBBBBBBBBBBBBB9ROXPHRI3ODVPD&ROOHFWHGBBBBBBBBBBBBBBBP/
:KHQ:DV7KH,QFLGHQW'HWHFWHG"
%HIRUH8VH
6HW8S
,QVWDOO&KHFN
6ROXWLRQ3ULPH
%ORRG3ULPH
&ROOHFWLRQVSHFLI\F\FOHBBBBBBBBB
'XULQJ9HQLSXQFWXUH
5HLQIXVLRQVSHFLI\F\FOHBBBBBBBBB
5)3ULPLQJ
5)0L[LQJVSHFLI\F\FOHBBBBBBBBB
5),QIXVLRQVSHFLI\F\FOHBBBBBBBBB
3URFHGXUH&RPSOHWLRQ
$IWHU&ROOHFWLRQ
)UHH]LQJ3URFHVVLQJ
,QFLGHQW7\SH0DUNDOODSSOLFDEOH
$ODUP$OHUW+HOS&RGHBBBBBBBBBBBBBBBBB
'HWDFKHG6HSDUDWHG
1RLVH
.LQNHG
%ORRG3ODVPD/HDN
/RZ1R3ODVPD
)ORZ
&XW6OLFH
5HG3ODVPD9LVXDO
,OOHJLEOH/DEHO
,QVWDOODWLRQ&KHFN
'HQWHG
0LVVLQJQRWLQER[
+ROH
2WKHU6SHFLI\BBBBBBBBBBBBBBBBBBBBBBBBBB
3OHDVHFLUFOH1$0(RIWKHVSHFLILFFRPSRQHQWVRQWKHGLDJUDPZKHUHLQFLGHQWRFFXUUHG
.LW5HWXUQ7R)HQZDO
 6DPSOHDYDLODEOHIRUHYDOXDWLRQ"<HV
1R
 6DPSOHUHWXUQER[QHHGHG"<HV
1R
/DEHORQO\QHHGHG
 'R\RXUHTXHVWDOHWWHUUHJDUGLQJWKHLQYHVWLJDWLRQUHVXOWV"
<HV
1R
 3LFWXUHWDNHQRIGHIHFWLYHNLW"<HV
1R
,I\HVVHQGSLFWXUHWR
&HQWHU$XWKRUL]HG6LJQDWXUH'DWH
)HQZDO5HYLHZHG%\'DWH
3OHDVH3ULQW
$FFRXQWBBBBBBBBBBBBBBBBBBBBBBBBBBBBBB
6LWH1DPHBBBBBBBBBBBBBBBBBBBBBBBBBBBBBB
&RQWDFW3HUVRQBBBBBBBBBBBBBBBBBBBBBBBBBB
2SHUDWRU1DPHBBBBBBBBBBBBBBBBBBBBBBBBBB
6WUHHW$GGUHVVBBBBBBBBBBBBBBBBBBBBBBBBBBB
&LW\6WDWH=LSBBBBBBBBBBBBBBBBBBBBBBBBBBBB
3KRQH1XPEHUBBBBBBBBBBBBBBBBBBBBBBBBBBB
(0DLOBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBB
)D[1XPEHUBBBBBBBBBBBBBBBBBBBBBBBBBBBBB
1RWLILFDWLRQ1R)HQZDO3HUVRQQHO2QO\
(PDLOWKLVUHSRUWWR$0%$5VDIHW\#XQLWHGELRVRXUFHFRPDORQJZLWKDQDGYHUVHHYHQWUHSRUWLIDSSOLFDEOH
,QFOXGHDFRS\RIWKLVIRUPZKHQUHWXUQLQJDNLW
3ODVPDFHOO&703URGXFW
3HUIRUPDQFH5HSRUW
$GGLWLRQDO,QFLGHQW'HVFULSWLRQ([SODQDWLRQ
BBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBB
BBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBB
BBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBB
BBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBB
BBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBB
BBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBB

Evaluation of the Autopheresis-C Plasma Exchange Procedure 
 
 
CONFIDENTIAL, Fenwal, Inc. 
 Page 15 of 15 
 
 
Protocol Number 931-PRO-010255 [7.0] 
E.  Revision History 
 
Revision 
Date 
Author 
Description of Change 
1.0 
January 31, 2011 
 
New document created 
2.0 
March 04, 2011 
 
x
Updated kit sealing location on fistula needle set 
and corrected kit  pre-weight accordingly 
x
Updated kit residual and replacement fluid densities 
to 1.05 and  1.06 g/mL, respectively; included 
references 
x
Clarified wording in pre-procedure steps 
x
Updated infusion rates to 20 to 80 mL/min with a 
default of 24 mL/min 
3.0 
August 02, 2011 
 
x
Changed kit tare weight to correspond to kits with 
tubing keepers on the concentrated cell line 
x
Changed the Kit RF Volume formula to correlate 
with the 3:1 mixture of blood and replacement fluid 
x
Corrected statistical equations to 95% confidence 
that the acceptance criteria will be met 90% of the 
time, to align with purpose of study 
x
Updated infusion rates to 20 to 60 mL/min with a 
default of 20 mL/min 
x
Added Cell Stop components to disposable set 
diagram on the product performance report 
4.0 
September 06, 
2011 
 
x
Revised the Training section to indicate that 
prescribers and operators will be trained on this 
protocol, in its entirety 
x
Added sealing location below separation device on 
plasma line (to facilitate sampling of any observed 
issues with plasma quality) 
5.0 
October 19, 2011 
 
x
Revised Software Installation section to include 
software installation and removal 
x
Revised Hardware and Software section to 
reference the TSB for software tracking 
6.0 
March 12, 2012 
S
 
Updated to indicate that weighing of components is 
optional 
7.0 
August 8, 2012 
 
Updated contact information on the product 
performance report 
 





















$33(1',;E




$8525$&/,1,&$/35272&2/
dŚĞƵƌŽƌĂĚĞǀŝĐĞŵĞŶƚŝŽŶĞĚŝŶƚŚŝƐƉƌŽƚŽĐŽů
ĐŽƌƌĞƐƉŽŶĚƐƚŽ&ϱϭϬ;ŬͿĐůĞĂƌĂŶĐĞη
%.

CONFIDENTIAL 
 considers this protocol to be confidential and not subject to disclosure without the express written consent of 
 
 Page 1 of 13 
 
 
Protocol Number 938-PRO-039808 [A]
Protocol Number:  938-PRO-039808 
Title:  Evaluation of the Aurora Plasma Exchange Procedure within the AMBAR Clinical Trial
Proposed Completion Date:  December 31, 2016 
Project:  Aurora Plasma Exchange 
Requesting Individual/Department:
 
Project Management
Additional Distribution (Original to Quality System Archives):   
 
 
 
 
 
Plasma Services 
APPROVALS:
Name 
Department 
Signature 
Date 
 
Author  
Systems Engineering 
See Electronic Signature 
 
Clinical Affairs 
See Electronic Signature 
 
Quality Engineering
See Electronic Signature 
 
Project Management 
See Electronic Signature 
 
 
Clinical Project Manager 
Grifols, S.A 
See Electronic Signature 
Study must not begin until all approval signatures are obtained. 

Evaluation of the Aurora Plasma Exchange Procedure within the AMBAR Clinical Trial 
CONFIDENTIAL 
 considers this protocol to be confidential and not subject to disclosure without the express written consent of 
. 
 Page 2 of 13 
Protocol Number 938-PRO-039808 [A]
1. Purpose 
This protocol defines system evaluation for the Aurora Plasma Exchange Procedure, and applies to completed 
procedures performed as part of the AMBAR clinical trial conducted by Grifols S.A.  The intent of this protocol is 
to outline how data and information will be obtained during the clinical trial to ensure that relevant systems level 
requirements are satisfied.   Additionally, this document will provide the data sheet to be completed for all the 
procedures performed using the Aurora Plasma Exchange System during the clinical trial.  
The following are the primary purposes for this protocol: 
• To document typical return rates during replacement fluid infusion in Alzheimer’s patients, 
• To compare replacement fluid volume delivered to the programmed volume to confirm the accuracy of volume 
delivery.  Specifically, the following requirements from 938-REQ-032960: 
o
SYRS-567: Upon completion of a successful procedure, the system shall have infused to the 
patient at an actual replacement fluid (i.e. 20% albumin solution) infusion volume that is within 
+/- 15% of the Target RF Infusion Volume. 
o
SYRS-1142: If selected protocol is REPLACEMENT_FLUID, the displayed replacement fluid 
(i.e. 20% albumin solution) volume infused to the patient shall be within +/- 15% of the actual 
volume of replacement fluid infused. 
o
SYRS-336: If the selected protocol is a REPLACEMENT_FLUID procedure, the system shall 
display, via the operator visual/input interface, the infused volume of replacement fluid (i.e. 20% 
albumin solution) that is within +/- 15% of the Target RF Infusion Volume upon completion of a 
successful procedure. 
• To document any issues/observations related to Y-Junction Site (aka Injection-Y Site) when performing offline 
Intravenous Immunoglobulin (IVIG) infusion 
• To document specific alerts/alarms/issues observed during execution of the Aurora Plasma Exchange Procedure 
• To provide a method for Grifols, S.A. to communicate this information/data to Fresenius Kabi USA, LLC 
2. Background 
The Aurora Plasmapheresis System (Fresenius Kabi USA, LLC) is an automated plasma collection system based on 
the Autopheresis-C® system (Auto-C).  Aurora uses the same separation technology and many of the same 
components of the Auto-C but also incorporates a touch screen and GUI interface, and updates to replace obsolete 
components.  The Aurora Plasmapheresis System was cleared under 510(k) BK110072, as a design update to the 
pre-existing Auto-C System. The Aurora Plasmapheresis System became the foundation for the development of the 
Aurora Plasma Exchange System.
Grifols, S.A. is a Spanish holding company that performs research, development, manufacturing and marketing of 
plasma derivatives, IV therapy, enteral nutrition, diagnostic systems and medical materials.  Grifols has requested 
that Fresenius Kabi USA, LLC design and develop a plasma exchange procedure and disposable set for the Aurora 
platform to facilitate direct infusion of albumin as a replacement fluid, as well as to provide for infusion of IVIG 
through the venipuncture site when performing non-albumin protocols (accomplished by providing a disposable set 
interface for connection to an external infusion pump) for treatment of patients with Alzheimer’s for use in their 
clinical trial. 
The procedure described in this document will utilize Aurora instruments, investigational human-use software, along 
with investigational disposables to perform procedures on Alzheimer’s patients.  This protocol is to be conducted 
under the clinical trial investigation conducted by Grifols, S.A. 
Features of the investigational Aurora Plasma Exchange System with investigational human use software include: 
• Configurable target replacement fluid infusion volume with presets of  half doses of 80, 95, 100, and full doses 
of 160, 190, or 200 mL to correspond with a plasma collection volume of 690, 825, and 880 mL, respectively. 
An editable option is also available. 
• Infusion of programmed volume of replacement fluid via direct infusion of replacement fluid at programmable 
target infusion rates from 5 to 20 mL/min after collection of the target plasma volume. 

Evaluation of the Aurora Plasma Exchange Procedure within the AMBAR Clinical Trial 
CONFIDENTIAL 
 considers this protocol to be confidential and not subject to disclosure without the express written consent of 
 
 Page 3 of 13 
Protocol Number 938-PRO-039808 [A]
• Ability to infuse IVIG offline from the Aurora instrument using the disposable set interface (Injection Y-Site) for 
connection to an external infusion pump. 
The purpose of this protocol is to investigate the use of the Aurora Plasma Exchange System to return a 20% 
Albutein® (human serum albumin or HSA) solution as the replacement fluid to a patient (if configured for the 
Albumin protocol).  Connection of the Aurora Plasma Exchange Disposable Set to the external infusion pump 
disposable set via the Injection-Y Site is also a subject of investigation (if configured for the No Albumin protocol).  
The disposable sets for use during this study are investigational (Product Code FTX3920); they include a fistula 
needle set attached at a luer, an Injection Y-Site on the patient short line for connection to an external infusion 
pump, an attached 1000 mL plasma collection container, a spike for connection to an anticoagulant solution, and a 
luer for connection to a transfer set (aka Fleboset), supplied by Grifols, S.A., that allows for connection of two 
bottles of 20% Albutein. 
3. Materials and Equipment 
Materials and equipment that may be used in this study include, but are not limited to: 
•
SMARTCONNECT Plasma Exchange Disposable Set, Code FTX3920
•
Aurora Instrument (Code: 6R4601) with investigational plasma exchange procedure software (software 
kit product code: 6S9820)
•
Grifols Replacement Fluid Transfer Set, Fleboset® Double 
•
Sodium Citrate Solution, USP, 500 mL, Code 4B7889Q or equivalent (if configured for 6:100 ratio of 
Anticoagulant-to-Whole Blood)
•
Anticoagulant Citrate Dextrose Solution A (ACD-A), USP, 500mL, Code 4B7898Q or equivalent 
(Grifols, S.A. branded ACD-A USP 500 mL, REF# 721781) (if configured for 8:100 ratio of 
Anticoagulant-to-Whole Blood)
•
20% Albutein® (Human Serum Albumin, or HSA) , 50 or 100 mL
•
RF tubing sealer
•
Weight scale
Materials for Optional IVIG infusion (if configured for the No Albumin Protocol): 
•
Flebogamma® solution
•
External infusion pump & infusion pump disposable set
•
Appropriate adapter to establish connection between infusion pump disposable set to Injection Y-Site of 
FTX3920 SMARTCONNECT Plasma Exchange Disposable Set (e.g. lever-lock luer),
4. Methods 
4.1. Software Installation and Removal 
Installation of the software onto clinical instruments is to be performed as described in TSB12570019. Software 
tracking and removal is also managed in the Technical Service Bulletin (TSB). 
4.2. Training 
All Aurora Plasma Exchange Procedure operators, prescribers and support team members will be trained on the 
Aurora Plasma Exchange Procedure per the applicable operating instructions: REC-011226 Aurora Plasma 
Exchange System Operator’s Manual, REC-011227 Aurora Plasma Exchange System Administrator’s Guide, and 
REC-012040 Aurora Plasma Exchange System Release Notes.  All training, including any additional required per 
this protocol, will be documented and recorded per Fresenius Kabi SOP-FQA01007, Fenwal Training Process, or 
applicable facility or clinical trial training procedures. 

Evaluation of the Aurora Plasma Exchange Procedure within the AMBAR Clinical Trial 
CONFIDENTIAL 
 considers this protocol to be confidential and not subject to disclosure without the express written consent of 
 
 Page 4 of 13 
Protocol Number 938-PRO-039808 [A]
4.3. General Considerations 
4.3.1. Patient Assessment 
The physician requesting the Plasma Exchange Procedure may provide guidelines under which a patient may be 
excluded from the study.  The Aurora Plasma Exchange Procedure is intended for use with Alzheimer’s 
patients having a hematocrit of 38% or greater and a weight of 50 kg (110 lbs) or greater. 
4.3.2. Multiple Companies 
Multiple companies, including Fresenius Kabi USA, LLC and Grifols S.A., will contribute to this study.  Each 
group may have their own original data forms, standard operating procedures, etc.  It is neither required nor 
expected that every form or procedure be included or referenced in this protocol.  It is required, however, that all 
original data be preserved as detailed in section 7.2. 
4.3.3. Procedure Data 
The data sheet in Appendix B will be completed as the procedure progresses.  Data for each procedure is expected to 
be submitted to Fresenius Kabi for review.   Any statistical methods used in data analysis will be documented in the 
final report.   
4.4. Set Up 
4.4.1. Plasma Collection Volumes 
The target Plasma Collection Volume is chosen at the discretion of a physician in accordance with the clinical 
protocol.  The recommended nomogram is indicated below. Note that plasma collection volumes (plasma plus 
anticoagulant) shall comply with local regulatory requirements as applicable. 
Patient Weight 
lbs (kg) 
Maximum Plasma 
Collection Volume 
(Plasma + 
Anticoagulant) (mL) 
110-149 (50-67)
690
150-174 (68-79) 
825 
175 (80)
880
4.4.2. Replacement Fluid Infusion Volumes 
The target Replacement Fluid Infusion Volume is chosen at the discretion of a physician in accordance with the 
clinical protocol.  The recommended nomogram is indicated below. 
Patient Weight 
lbs (kg) 
Replacement Fluid Infusion Volume (mL) 
Full Dose
1/2 Dose
110-149 (50-67) 
160 
80 
150-174 (68-79)
190
95
175 (80) 
200 
100 
4.5. Data Collection 
Collected data shall be recorded in Appendix B, Aurora Plasma Exchange Procedure Data Record per instructions 
provided in Appendix A, Instructions for Recording Aurora Plasma Exchange Procedure Data.
5. Product Performance 
If the Aurora system does not perform as expected, follow the steps outlined in Appendix D, Product Performance 
Flow Chart, and fill out Appendix E, Product Performance Report. 

Evaluation of the Aurora Plasma Exchange Procedure within the AMBAR Clinical Trial 
CONFIDENTIAL 
 considers this protocol to be confidential and not subject to disclosure without the express written consent of 
 
 Page 5 of 13 
Protocol Number 938-PRO-039808 [A]
6. Evaluation of Data and Acceptance Criteria 
6.1. Acceptance Criteria 
The acceptance criterion for this portion of Grifols’ clinical trial is confirmation of the following system-level 
requirements:   
•
SYRS-567: Upon completion of a successful procedure, the system shall have infused to the patient at an 
actual replacement fluid (i.e. 20% albumin solution) infusion volume that is within +/- 15% of the Target 
RF Infusion Volume. 
•
SYRS-1142: If selected protocol is REPLACEMENT_FLUID, the displayed replacement fluid (i.e. 20% 
albumin solution) volume infused to the patient shall be within +/- 15% of the actual volume of 
replacement fluid infused. 
•
SYRS-336: If the selected protocol is a REPLACEMENT_FLUID procedure, the system shall display, via 
the operator visual/input interface, the infused volume of replacement fluid (i.e. 20% albumin solution) that 
is within +/- 15% of the Target RF Infusion Volume upon completion of a successful procedure. 
Any sample size calculation/statistical analyses used to analyze the data will be included in the final report. 
Note that only completed procedures will be included in the data analysis. 
Instructions for calculating the residual albumin volume in the disposable set following a completed procedure is 
outlined in Attachment A, Calculating WRESIDUAL.  The remaining equations for determining total volume of albumin 
infused are included in Section 7.2.1. 
7. Post Study Disposition 
7.1. Disposition of Samples 
Upon completion of a procedure, the disposable set and the 20% Albutein container should be discarded.  Collected 
plasma may be retained for sampling and testing, but eventually when testing of the plasma is complete, the plasma 
should also be discarded.  All biological materials must be discarded as biohazardous waste. 
7.2. Original Data 
Original data will be recorded during the execution of the protocol on worksheets provided in Appendix B, 
Appendix E, and other data forms, as appropriate.  For every procedure, Appendix B must be filled out.  Appendix E 
shall be filled out when the Aurora system does not perform as expected.  This protocol, all original data, the final 
report, and all amendments will be archived in the appropriate Fresenius Kabi archives.  The Aurora Plasma 
Exchange Procedure Data Record (Appendix B) and the Product Performance Report (Appendix E) should be sent 
by the medical facility to United Bio Source (UBS) at AMBARsafety@unitedbiosource.com.  UBS will forward the 
appendices and relevant adverse event data to Fresenius Kabi Quality at Alicia.Gorecki@fresenius-kabi.com.  If 
further procedural data are required for analysis, an Authorized Service Personnel may manually retrieve the 
instrument data at the clinical site (see page 1-3 of the Operator’s Manual for description of an Authorized Service 
Personnel). 
7.2.1. Calculating Volume of Total Infused Albumin to the Patient 
The following sequences of equations outline the method for calculating the volume of infused albumin (VINFUSED) 
in an Albumin Protocol. 
To calculate the volume, various weight measurements of the disposable set and Albutein containers are taken at 
different points in the procedure.  These measurements allows for derivation of the weight of residual albumin inside 
the disposable set after a completed procedure, and the weight of total albumin infused following completion of the 
procedure.  The weights are converted to a volume using the known density of albumin (1.06 g/mL).   
The variables/parameters of interest, necessary for this calculation, are outlined below: 
•
WTOTAL = weight of total albumin used for a procedure 
•
WPRE = weight of Albutein bottles before procedure 
•
WPOST = weight of Albutein bottles after procedure 

Evaluation of the Aurora Plasma Exchange Procedure within the AMBAR Clinical Trial 
CONFIDENTIAL 
 considers this protocol to be confidential and not subject to disclosure without the express written consent of
. 
 Page 6 of 13 
Protocol Number 938-PRO-039808 [A]
•
WINFUSED = weight of albumin infused to the patient 
•
WSET, ALBUMIN RESIDUAL = weight of residual albumin in the disposable set 
•
WCAP = weight of protective cap of the albumin container 
•
VINFUSED = volume of total albumin used for a procedure 
WTOTAL can be calculated by finding the difference between WPRE and WPOST: 
1)
WTOTAL = WPRE - WPOST - WCAP
WTOTAL can also be expressed in terms of WINFUSED and WSET, ALBUMIN RESIDUAL. 
2)
WTOTAL = WINFUSED + WSET, ALBUMIN RESIDUAL
Combining 1) and 2) together, the following equation can be derived: 
3)
WPRE - WPOST – WCAP = WINFUSED + WSET, ALBUMIN RESIDUAL
which can then be rearranged to the equation for calculating WINFUSED 
4)
WINFUSED = WPRE – WPOST – WCAP - WSET, ALBUMIN RESIDUAL
WPRE and WPOST are directly measured by the operators before and after the procedure, and the values recorded as 
Albutein® container weight (Pre-Procedure) and Albutein® container weight (Post-Procedure), respectively, in 
Appendix B.  Steps for estimating WSET, ALBUMIN RESIDUAL is provided in Attachment A, Calculating WSET, ALBUMIN 
RESIDUAL.   
Once WINFUSED(g) is calculated, the calculated weight can be divided by the density of albumin (1.06 g/mL) to 
convert the weight into a volume (i.e. VINFUSED). 
VINFUSED(mL) = (WINFUSED) ÷ (1.06 g/mL) 
7.3. Hardware and Software 
The instruments and the investigational software will be retained by Grifols after study completion under the 
agreement that the software is for the clinical trial/investigation only and not for commercial use.  Disposition of 
clinical inventory, including the clinical software, will be documented by Grifols according to their clinical 
protocol(s). 
8. References 
1.
TSB12570019, Conversion of an Aurora to Aurora Plasma Exchange System (Aurora PES) 
2.
FQA01007, Fenwal Training Process 
3.
REC-011226, Aurora Plasma Exchange System Operator’s Manual 
4.
REC-011227, Aurora Plasma Exchange System Administrator’s Guide 
5.
931-PRO-010255, Evaluation of the Autopheresis-C Plasma Exchange Procedure within a Clinical Trial 
6.
Trudnowski, RJ and Rico, RC.  “Specific Gravity of Blood and Plasma at 4 and 37oC”.  Clin Chem 20 (1974): 
615-616. 
7.
Nugent, RL and Towle, LW.  “The Specific Gravity of Synthetic Solutions of Serum Albumin and Serum 
Globulin”. J Biol Chem  (1933). 
9. List of Appendices  
A.
Instructions for Recording Aurora Plasma Exchange Procedure Data in Appendix B 
B.
Aurora Plasma Exchange Procedure Data Record 
C.
Instructions for Post-Procedure Disposable Set Weighing 
D.
Product Performance Flow Chart 
E.
Product Performance Report 
10. List of Attachments 
A.
Calculating WSET, ALBUMIN RESIDUAL

Evaluation of the Aurora Plasma Exchange Procedure within the AMBAR Clinical Trial 
CONFIDENTIAL 
 considers this protocol to be confidential and not subject to disclosure without the express written consent of 
 
 Page 7 of 13 
Protocol Number 938-PRO-039808 [A]
Appendix 
A.Instructions for Recording Aurora Plasma Exchange 
Procedure Data in Appendix B 
For every procedure, Appendix B, Aurora Plasma Exchange Procedure Data Record, must be filled out.  Follow the 
instructions provided below to complete the appendix.  Completed Appendix B must be sent to 
AMBARsafety@unitedbiosource.com.  UBS will forward the appendices and relevant adverse event data to 
Fresenius Kabi at Alicia.Gorecki@fresenius-kabi.com.  If further procedural data are required for analysis, an 
Authorized Service Personnel may manually retrieve the instrument data at the clinical facility. 
10.1.1. Pre-Procedure Data 
•
Procedure ID: identifier for every procedure.  All data sheets must be labeled and identified with Procedure 
ID, and configured per instructions in Section 4.5, Entering Patient and Procedure Information in the 
Operator’s Manual. 
•
Albutein® container size and weight: the protective cap on the bottle shall NOT be removed before weighing 
the containers.  Measure the weight of the full container before spiking to the Fleboset. 
•
Patient’s weight and hematocrit (Hct) 
•
Selected protocol: IVIG infusion is to be performed under the No Albumin Protocol. 
10.1.2. Intra-Procedure Data 
No samples are taken during the procedure, but the following information is to be recorded: 
•
Patient Adverse Reactions 
•
Alarm/Alert Information (number and name of alarm/alert and approximate time or procedural phase in 
which it occurred) 
•
Flow Rate(s) during RF Infusion: if the RF infusion rate is modified at any point during RF infusion, the 
new modified rate shall be recorded also.  The progress of the infusion (i.e. the volume of replacement fluid 
infused) at the point of modification shall also be recorded. 
•
Other Observations and Notes.  Any issues/observations related to the injection Y-site for IVIG infusion 
shall also be recorded in this section.  Notable observations may include, but not be limited to, integrity of 
the component and the presence of air bubbles. 
10.1.3. Post-Procedure Data 
Before sealing the disposable set, check and record the presence of fluid in the Replacement Fluid Line.  Follow 
instructions in Appendix C for sealing points in the disposable set.  The disposable set must be sealed at these 
locations to ensure accurate data analysis.  After patient disconnect, the following measurements and 
observations are to be recorded.  The section Recording Procedure Information of the Aurora Plasma 
Exchange System Operator’s Manual provides a description of many of the elements of Appendix B: 
•
Presence of fluid in Replacement Fluid Line: note whether the line is filled with fluid, half-full, or empty.  
See Section 2.4, Plasma Exchange Disposable Set Components, of the Operator’s Manual for illustration 
of the disposable set. 
•
Replacement Fluid Infused/Target Replacement Fluid Volume 
•
Collected Plasma Volume/Target Plasma Collection Volume 
•
Weight scale measurements of the following: 
o
The collected plasma  
o
20% Albutein® containers (excluding Fleboset) 
•
Needle-in, Needle-out Time (NiNo Time, aka VP Time) 
•
Disposable set weight (after sealed in locations identified in Appendix C) 
•
If IVIG infusion was performed, indicate whether any issues were observed by circling “Yes” or “No”.  If 
“Yes”, provide a description of the issue under the “Other Notes” section.

Evaluation of the Aurora Plasma Exchange Procedure within the AMBAR Clinical Trial 
CONFIDENTIAL 
Fresenius 
 considers this protocol to be confidential and not subject to disclosure without the express written consent of 
 
 Page 8 of 13 
Protocol Number 938-PRO-039808 [A]
B.Aurora Plasma Exchange Procedure Data Record 
Procedure (Run) ID 
RF Infused/Target RF Infusion 
Volume
mL /            mL 
 NiNo (VP) Time (min : sec) 
:
Post-procedure Disposable Set Weight 
(see Appendix C) 
g 
Collected Plasma/ Target Plasma 
Collection Volume 
mL /          mL 
Patient Weight (circle lbs/kg) 
lbs  /  kg 
Selected Protocol 
[  ] Albumin 
[  ] No Albumin
Albutein® container weight (Post-
Procedure) 
g 
Patient Hct -OR- Hb 
____________ % -
OR- 
____________ g/dL 
Plasma Bag Weight – post-procedure 
g 
Albutein® container weight (Pre-
Procedure) 
g 
Air/Fluid in RF Line (circle one) 
Air 
Fluid 
Both 
Number of air purges during RF 
infusion phase 
0 
1 
>1 
If infusing IVIG, were there issues 
observed with injection Y-site? If Yes, 
document in “Other Notes” 
Yes 
No 
Patient Reaction(s) 
[  ] None 
[  ] Yes (please reference adverse event reporting data): 
_____________________________________________ 
Flow Rate during RF Infusion 
(5-20 mL/min, Albumin Protocol Only) 
Initial rate: ___________________ mL/min 
If the RF infusion rate is modified at any point during RF infusion, record the 
modified rate and the progress of the RF infusion at the time of modification below. 
Modified rate: ____________ mL/min, Infusion progress: _______mL/_______mL 
Modified rate: ____________ mL/min, Infusion progress: _______mL/_______mL 
Modified rate: ____________ mL/min, Infusion progress: _______mL/_______mL 
Alarm/Alert Information 
(Please include cause/procedural phase if 
known) 
  
Other Notes 
  
 
 
 
 
 
Entered by: 
 
 
 
 Signature: 
 
 
 
 
 Date: 
 
 
Reviewed by: 
 
 
 
  Signature: 
 
 
 
 
 Date: 
 
 

Evaluation of the Aurora Plasma Exchange Procedure within the AMBAR Clinical Trial 
CONFIDENTIAL 
Fresenius 
 considers this protocol to be confidential and not subject to disclosure without the express written consent of 
 
 Page 9 of 13 
Protocol Number 938-PRO-039808 [A]
C.Instructions for Post-Procedure Disposable Set Weighing 
Step 1.
Sealing the Disposable Set 
1.1) Prior to sealing the disposable set at the locations designated in 1.2), also ensure that the Robert’s Clamp on the 
Fleboset Double is closed. 
1.2) Using the RF sealer, Seal the disposable set in the following locations per Figure 1: 
•
On the apheresis needle set near the luer 
•
On both sides of the replacement fluid transfer set luer 
•
On both pressure transducer connector lines 
•
Near the AC spike 
•
Below the separation device on the plasma line 
•
Above the sampling site on the plasma line 
Note: Only seal the disposable set at the specified locations.  DO NOT disconnect any components until 
indicated in Step 2.
Step 2.
Disconnect the Plasma Bag, the Plasma Line, AC Line, and the Needle Assembly (beneath the 
Donor/Patient Short Line) from the rest of the disposable set 
At the locations designated in Figure 1 (see Locations to Remove before Weighing), disconnect the Plasma Line and 
the Plasma Bag from the disposable set. 
Step 3.
Remove Fleboset spike from the albumin bottles 
Disconnect the Fleboset from the albumin bottles by removing both of the spikes from the silicone septum. 
Step 4.
Weigh the remaining disposable set INCLUDING the Fleboset, then record the weight 
Do not disconnect the Fleboset from the disposable set.  Weigh the disposable set and record the weight in Appendix 
B.  If weights are not recordable, write “NR” in the appropriate location in the data sheet in Appendix B with reason 
for not recording the weight. 
Step 5.
Discard the disposable set appropriately 

(YDOXDWLRQRIWKH$XURUD3ODVPD([FKDQJH3URFHGXUHZLWKLQWKH$0%$5&OLQLFDO7ULDO
&21),'(17,$/
)UHVHQLXV
FRQVLGHUVWKLVSURWRFROWREHFRQILGHQWLDODQGQRWVXEMHFWWRGLVFORVXUHZLWKRXWWKHH[SUHVVZULWWHQFRQVHQWRI

 3DJHRI
3URWRFRO1XPEHU352>$@
)LJXUH/RFDWLRQVZKHUHWKHGLVSRVDEOHVHW
VKRXOGEHVHDOHGEHIRUHUHPRYLQJWKHVHW
IURPWKHLQVWUXPHQWDQGZKHUHWKHVHDOV
VKRXOGEHVHSDUDWHGWRZHLJKWKHNLW

(YDOXDWLRQRIWKH$XURUD3ODVPD([FKDQJH3URFHGXUHZLWKLQWKH$0%$5&OLQLFDO7ULDO
&21),'(17,$/
)UHVHQLXV
FRQVLGHUVWKLVSURWRFROWREHFRQILGHQWLDODQGQRWVXEMHFWWRGLVFORVXUHZLWKRXWWKHH[SUHVVZULWWHQFRQVHQWRI

 3DJHRI
3URWRFRO1XPEHU352>$@
' 3URGXFW3HUIRUPDQFH)ORZ&KDUW
,I DSURGXFWSHUIRUPDQFHLVVXHLVREVHUYHGIROORZWKHVWHSVEHORZ
,VWKHUH
DQLPPHGLDWH
ULVNWRWKH
SDWLHQW"
<HV
,VWKHSDWLHQW
FRQQHFWHG"
&DQWKH
SURFHGXUHEH
FRPSOHWHG"
,VWKHUHDQ
DODUPDOHUW"
<HV
1R
<HV
<HV
5HVXPH
SURFHGXUH
1R
1R
/ƐƚŚĞĚŝƐƉ͘ƐĞƚ
ŝŶƐƚĂůůĞĚ͍
<HV
)ROORZRSHUDWLQJ
LQVWUXFWLRQVIRU
'LVFRQQHFW3DWLHQW
1R
&RQWDFW*ULIROV
IRULPPHGLDWH
DVVLVWDQFH
1R
,VWKHUHD
SURGXFW
SHUIRUPDQFH
LVVXH"
<HV
1R
3UHVV6723
5HFRUGDODUPDOHUW
LQIRUPDWLRQLQ
$SSHQGL[ %
&RQVXOWRSHUDWLQJ
LQVWUXFWLRQVIRU$ODUP
$OHUW0HVVDJHV
&RQWDFW
*ULIROVIRU
LPPHGLDWH
DVVLVWDQFH
<HV
5HPRYH'LVS
6HW
,QVWDOODQHZ
GLVSVHW
&KHFN
'LVS6HW
ĂŶ
ƚŚĞŝƐƐƵĞďĞ
ƌĞƐŽůǀĞĚǁŝƚŚŽƵƚ
ƌĞŵŽǀŝŶŐƚŚĞ
ĚŝƐƉ͘ƐĞƚ͍
1R
)LOORXWIRUPLQ
$SSHQGL[(
5HSRUWWR
*ULIROV
:KDW
LVWKHLVVXH
UHODWHG
WR"
,QVWUXPHQW
'LVSRVDEOH6HW
5HSODFHPHQW)OXLG
7UDQVIHU6HW
7KHUDS\
)LOORXWIRUP LQ
$SSHQGL[(
:DVWKHUHD
SDWLHQWDGYHUVH
UHDFWLRQ"
<HV
1RIXUWKHU
DFWLRQUHTXLUHG
1R
,VVXH
REVHUYHG

(YDOXDWLRQRIWKH$XURUD3ODVPD([FKDQJH3URFHGXUHZLWKLQWKH$0%$5&OLQLFDO7ULDO
&21),'(17,$/
)UHVHQLXV
FRQVLGHUVWKLVSURWRFROWREHFRQILGHQWLDODQGQRWVXEMHFWWRGLVFORVXUHZLWKRXWWKHH[SUHVVZULWWHQFRQVHQWRI

 3DJHRI
3URWRFRO1XPEHU352>$@
(3URGXFW3HUIRUPDQFH5HSRUW
,PSRUWDQW,IDGYHUVHUHDFWLRQRULQMXU\KDVRFFXUUHGFRQWDFW*ULIROV
:DVWKHSURFHGXUHVXFFHVVIXOO\FRPSOHWHG"<HV
1R
,I1RZDVWKHSURFHGXUHVWRSSHGGXHWRDGLVSRVDEOHVHWLQFLGHQW"<HV
1R

,QFLGHQW'DWHBBBBBBBBBBBBBBBBBBBBBBBBBBBB

,QVWUXPHQW6HULDO1XPEHUBBBBBBBBBBBBBBBBBBB
3URGXFW&RGHBBBBBBBBBBBBBBBBBBBBBBBBBBBB

/RW1XPEHUBBBBBBBBBBBBBBBBBBBBBBBBBBBBBB
%DWFK7DJ,QIR7LPHBBBBBBBBBBBB1XPEHUBBBBBBBB
9LGHR-HW1XPEHUBBBBBBBBBBBBBBBBBBBBBBBB
3DWLHQW%OHHG1XPEHUBBBBBBBBBBBBBBBBBBBBBBBBBB
9ROXPHRI3ODVPD&ROOHFWHGBBBBBBBBBBBBBBBP/
:KHQ:DV7KH,QFLGHQW'HWHFWHG"
%HIRUH8VH
6HW8S
,QVWDOO&KHFN
6ROXWLRQ3ULPH
%ORRG3ULPH
&ROOHFWLRQVSHFLI\F\FOHBBBBBBBBB
'XULQJ9HQLSXQFWXUH
5HLQIXVLRQVSHFLI\F\FOHBBBBBBBBB
5)3ULPLQJ
5),QIXVLRQBBBBBBBBB
3URFHGXUH&RPSOHWLRQ
'XULQJ,9,*,QIXVLRQ
3RVW3URFHGXUH3URFHVVLQJ
,QFLGHQW7\SH0DUNDOODSSOLFDEOH
$ODUP$OHUWBBBBBBBBBBBBBBBBB
'HWDFKHG6HSDUDWHG
1RLVH
.LQNHG
%ORRG3ODVPD/HDN
/RZ1R3ODVPD)ORZ
&XW6OLFH
5HG3ODVPD9LVXDO
,OOHJLEOH/DEHO
,QVWDOODWLRQ&KHFN
'HQWHG
0LVVLQJQRWLQER[
+ROH
2WKHU6SHFLI\BBBBBBBBBBBBBBBBBBBBBBBBBB
3OHDVHFLUFOH1$0(RIWKHVSHFLILFFRPSRQHQWVRQWKHGLDJUDPZKHUHLQFLGHQWRFFXUUHG
'LVSRVDEOH6HW5HWXUQ7R)UHVHQLXV.DEL

6DPSOHDYDLODEOHIRUHYDOXDWLRQ"<HV
1R


6DPSOHUHWXUQER[QHHGHG"<HV
1R
/DEHORQO\QHHGHG


3LFWXUHWDNHQRIGHIHFWLYHNLW"<HV
1R
,I\HVVHQGSLFWXUHWR$0%$5VDIHW\#XQLWHGELRVRXUFHFRP
3OHDVH3ULQW
$FFRXQWBBBBBBBBBBBBBBBBBBBBBBBBBBBBBB
6LWH1DPHBBBBBBBBBBBBBBBBBBBBBBBBBBBBBB
&RQWDFW3HUVRQBBBBBBBBBBBBBBBBBBBBBBBBBB
2SHUDWRU1DPHBBBBBBBBBBBBBBBBBBBBBBBBBB
6WUHHW$GGUHVVBBBBBBBBBBBBBBBBBBBBBBBBBBB
&LW\6WDWH=LSBBBBBBBBBBBBBBBBBBBBBBBBBBBB
3KRQH1XPEHUBBBBBBBBBBBBBBBBBBBBBBBBBBB
(0DLOBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBB
)D[1XPEHUBBBBBBBBBBBBBBBBBBBBBBBBBBBBB
)DFLOLW\$XWKRUL]HG6LJQDWXUH'DWH
)UHVHQLXV.DEL5HYLHZHG%\'DWH
(PDLOWKLVUHSRUWWR$0%$5VDIHW\#XQLWHGELRVRXUFHFRPDORQJZLWKDQDGYHUVHHYHQWUHSRUWLIDSSOLFDEOH
,QFOXGHDFRS\RIWKLVIRUPZKHQUHWXUQLQJDGLVSRVDEOHVHW
3ODVPD([FKDQJH
3HUIRUPDQFH5HSRUW
$GGLWLRQDO,QFLGHQW'HVFULSWLRQ([SODQDWLRQ
BBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBB
BBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBB
BBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBB
BBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBB
BBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBB
BBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBB

Evaluation of the Aurora Plasma Exchange Procedure within the AMBAR Clinical Trial 
CONFIDENTIAL 
 considers this protocol to be confidential and not subject to disclosure without the express written consent of 
 
 Page 13 of 13 
Protocol Number 938-PRO-039808 [A]
F.Revision History 
Revision 
Date 
Author 
Description of Change 
A 
See Pilgrim 
SmartSolve 
 
 
Initial Release 





















APPENDIX  4 




REPORTING OF SERIOUS ADVERSE EVENTS

6(5,286$'9(56((9(17)250
6WXG\,*
$0%$5
3DWLHQW,'BBBBBBBBBBBB
,QLWLDO)ROORZXSBBB
3DJHRI
9HUVLRQ'HF
3$7,(17,1)250$7,21

&RXQWU\

'DWHRI%LUWK
''000<<<<
BBBBBBBBBBBBBBBBBB

*HQGHU
0DOH
)HPDOH

:HLJKW

OE
NJ

5DFH
:KLWHRU&DXFDVLDQ
%ODFNRU$IULFDQ$PHULFDQ
$VLDQ
$PHULFDQ,QGLDQRU$ODVNDQ1DWLYH
1DWLYH+DZDLLDQ2WKHU3DFLILF,VODQGHU
2WKHUBBBBBBBBBBBBBBBBBBBBBBBBB

(WKQLFLW\
+LVSDQLF/DWLQR
1RW+LVSDQLF/DWLQR
,,(9(17 ,1)250$7,21

(YHQW7HUP'LDJQRVLV

5HDVRQIRU6HULRXVQHVVFKHFNDOOWKDWDSSO\
5HVXOWHGLQ'($7+LI\HVFRPSOHWHVHFWLRQ
/,)(7+5($7(1,1*
 5HTXLUHGSURORQJHG+263,7$/,=$7,21RQ
BBBBBBBBBBBBBBBBBB''000<<<<
3HUVLVWHQWRUVLJQLILFDQW',6$%,/,7<,1&$3$&,7<
&21*(1,7$/ DQRPDO\ELUWKGHIHFW
27+(5,PSRUWDQWPHGLFDOHYHQW


'HVFULEH SDWLHQWVWDWXVGHWDLOVRIHYHQW DQGFRPSOLFDWLRQV DWWDFKDGGLWLRQDOVKHHWLIH[WUD
VSDFHLVQHHGHG

'HDWK'HWDLOV
'DWHRIGHDWK
BBBBBBBBBBBBBBBBBB''000<<<<
$XWRSV\<HV1R
,VGHDWKFHUWLILFDWHDWWDFKHG"<HV1R

(YHQW2QVHW6WDUW'DWH ''000<<<<
BBBBBBBBBBBBBBBBBB6WDUW7LPHBBBBBBBBKUV
 (YHQW6WRS'DWH''000<<<<2QJRLQJ
BBBBBBBBBBBBBBBBBB6WRS7LPHBBBBBBBBKUV
+RVSLWDOGLVFKDUJHGDWHLIDSSOLFDEOHBBBBBBBBBBBBBBBBBB

5HODWLRQVKLSWR
6WXG\'UXJ
815(/$7('
5(/$7('
{8QOLNHO\
{3RVVLEO\
{3UREDEO\
{'HILQLWHO\

5HODWLRQVKLSWR
0HGLFDO&RQGLWLRQ
815(/$7('
5(/$7('
{8QOLNHO\
{3RVVLEO\
{3UREDEO\
{'HILQLWHO\

5HODWLRQVKLSWR2WKHU
'UXJVRU3URFHGXUHV
815(/$7('
5(/$7('
{8QOLNHO\
{3RVVLEO\
{3UREDEO\
{'HILQLWHO\

(YHQW2XWFRPH
5(&29(5('5(62/9('
 5(&29(5,1*5(62/9,1*
5(&29(5('5(62/9(':,7+
6(48(/$(
 1275(&29(5('1275(62/9('
)$7$/

6HYHULW\
0,/'
02'(5$7(
6(9(5(
,,,678'<0(',&$7,21

7UHDWPHQWDUP
 7UHDWPHQW$7UHDWPHQW% 7UHDWPHQW& 6KDPJURXS
)XOOGRVH$OEXWHLQ)OHERJDPPD',)+DOIGRVH$OEXWHLQ)OHERJDPPD',)+DOIGRVH$OEXWHLQRQO\1RWKHUDS\

3URGXFW ODVWDGPLQLVWHUHGSULRUHYHQW
BBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBB
 6WXG\SHULRG
6FUHHQLQJ)3(««,9/93(««)9
 3URGXFWVWDUWHGRQ
''000<<<<
BBBBBBBBBBBBBBBBBB
 /DVWGDWHRI6WXG\
7UHDWPHQWSULRUHYHQW
''000<<<<
BBBBBBBBBBBBBBBBBB

'RVH

)UHTXHQF\

5RXWHRI
DGPLQLVWUDWLRQ

/RWQXPEHU

$FWLRQWDNHQZLWKVWXG\GUXJGXHWRWKHHYHQW
1RFKDQJH1RQH
 'RVHUHGXFHG
 ,QWHUUXSWHG
'LVFRQWLQXHG
2WKHUVSHFLI\BBBBBBBBBBBBB

'LGHYHQWDEDWH
DIWHUVWRSSLQJRU
UHGXFLQJVWXG\
WUHDWPHQW"
<HV
 1R
 1RW$SSOLFDEOH

'LGHYHQWUHDSSHDU
DIWHUUHLQWURGXFWLRQ
RIVWXG\WUHDWPHQW"
<HV
 1R
 1RW$SSOLFDEOH

([SLUDWLRQ'DWH

6(5,286$'9(56((9(17)250
6WXG\,*
$0%$5
3DWLHQW,'BBBBBBBBBBBB
,QLWLDO)ROORZXSBBB
3DJHRI
9HUVLRQ'HF
,927+(50(',&$/,1)250$7,21

3DWLHQW¶VUHOHYDQW0HGLFDO+LVWRU\

5HOHYDQW/DE&RQILUPDWRU\ WHVWV,PDJLQJUHSRUWV
3OHDVHLQFOXGHXQLWVDQGUHIHUHQFHUDQJHVLPDJLQJUHSRUWV
 &KHFNLIUHSRUWVDUHDWWDFKHG
 7UHDWPHQW0HGLFDWLRQV'UXJVXVHGWRWUHDWWKHDGYHUVHHYHQW
7UDGHDQG*HQHULFQDPH
'RVH
5RXWHRI
DGPLQLVWUDWLRQ
6WDUW'DWH
''000<<<<
6WRS'DWH
''000<<<<
,QGLFDWLRQ

2WKHUQRQGUXJWUHDWPHQWV IRUWKHDGYHUVHHYHQWHJVXUJHU\HWF
 &RQFRPLWDQWGUXJV2QO\WKRVHGUXJVWKHVXEMHFWUHFHLYHGDWRQVHWRUXSWRPRQWKSULRUWRWKHHYHQWH[FOXGHWKRVHWRWUHDWHYHQW
7UDGHDQG*HQHULFQDPH
'RVH
5RXWHRI
DGPLQLVWUDWLRQ
6WDUW'DWH
''000<<<<
6WRS'DWH
''000<<<<
,QGLFDWLRQ
95(3257(5,19(67,*$725,1)250$7,21

5HSRUWHU¶VQDPH

5HSRUWHU¶V3KRQH

5HSRUWHU¶VHPDLO

3ULQFLSDO,QYHVWLJDWRU QDPH

3ULQFLSDO,QYHVWLJDWRU 3KRQH

3ULQFLSDO,QYHVWLJDWRU HPDLO

+RVSLWDO1DPHDQG$GGUHVV

6LJQDWXUH
 'DWHRIWKHQRWLILFDWLRQ''000<<<<
BBBBBBBBBBBBBBBBBB
3OHDVHVHQGE\HPDLOZLWKLQKWR
39'HSDUWPHQW


Serious Adverse Event (SAE) Report 
Completion Guidelines 
IG1002 – AMBAR study
                                Dec 2015 
Page 1 of 2 
General Guidelines: 
• 
The Subject No. (Which includes the site and subject number) must be completed on both pages of the 
form.   
• 
The SAE report must be signed and dated by the Investigator.  However, if for some reason the 
investigator is not available to sign the report, DO NOT hold up sending in the report.  The report must be 
completed and sent to Grifols within 24 hours of being informed of the event. As soon as possible, the 
Investigator must send in a signed copy of the original that was previously sent to Grifols and annotate 
next to the checked “Initial” or “Follow-up” box “signature” to indicate that the only thing changed was an 
added signature. 
• 
Send the completed Serious Adverse Event Report via E-mail to 
.  
Report Status (Initial or Follow-up):  
Check on the form header whether the report is an initial or a follow-up: 
- Initial Report –If any information is not available at the time of the Initial Report, leave the field blank.   
- Follow-up Report – Must be submitted when new information becomes available or previously reported 
information has changed.  
You can use a copy of the initial report and make the applicable corrections/updates or use a blank form. In 
the second case, DO NOT rewrite all the information from the initial report; provide only new information. 
A follow-up Report must always have identifying information (Subject No.) completed on each page, event 
name (7), event onset date (11), Investigator’s signature and date (43 & 44).  
SAE Form boxes: 
1. Country of Origin: Record the country where the event occurred. 
2. Date of Birth: Record the subject’s Date of Birth. 
3. Gender: Check Male or Female.
4. Weight: Record weight in kilograms or pounds and check the appropriate box for the units.  
5. Race: Record the subject’s race.  
6. Ethnicity: Record the subject’s ethnicity. Please note that as per FDA guidelines Hispanic/Latino is 
described as “a person of Cuban, Mexican, Puerto Rican, South or Central American, or other 
Spanish culture or origin, regardless of race.”
7. Event Term/Diagnosis: Record the clinical diagnosis (verbatim of the event). Do not include 
concurrent diagnoses or symptoms associated with this event.  If a diagnosis is unknown, record the 
main symptom(s) of the event. If the event is an exacerbation of a chronic condition present prior to 
study, include the wording “Worsening of …” to the event name. 
8. Reason for Seriousness: Check ALL serious criteria that apply for this event. There must be at least 
one criteria checked.  Note:  “Resulted in Death” should only be checked if death was the outcome of 
the event reported. 
9. Describe details of event:  Describe the event details including a description of what occurred and a 
summary of all relevant clinical information (medical status prior to the event, signs, symptoms, 
diagnoses, clinical course, labs or diagnostic testing, treatment, and outcome). If relevant, include 
synopses of any office visit notes or the hospital discharge summary. You may record only the basic 
information and attach copies of hospital discharge summaries with any confidential information 
blacked out. Use an additional page if more space is needed. 
10. Death Details (Only for the event which resulted in death): Enter the date of death, check if autopsy 
and/or death certificated are attached, or leave blank if the subject did not die from THIS event. 
11. Event Onset/Start Date and time: Record the date and time the first symptoms of the event 
presented or when the event satisfied one of the serious event criteria, whichever date was earlier. 
12. Event Stop Date and time: Record the date and time the event resolved. If event is continuing, 
check the “Ongoing” box.  
Event Stop Date is required for all events except cases where subject was lost to follow-up, 
permanently disabling/incapacitating events, or in cases of death not related to the event. If the event 
led to the subject’s death, then Outcome of this event should be marked “Fatal” and date of death 
should be entered as the Event Stop Date. If the subject died of another cause while experiencing 
this adverse event, the Event Stop Date should be left blank, “Ongoing” checked, and Event Outcome 
of this event should be marked as “Not Recovered/Not Resolved”.  
If the patient was hospitalized as result of the event, please also complete discharge date in this box.
13. Relationship to Study Drug: Check the event’s relationship to study drug.  This MUST be 
completed. Note that “Unlikely” is classified as potentially related to study drug. 

Serious Adverse Event (SAE) Report 
Completion Guidelines 
IG1002 – AMBAR study
                                Dec 2015 
Page 2 of 2 
14. Relationship to Medical Condition: Check the event’s relationship to patient’s medical condition.  
15. Relationship to Other Drugs or Procedures: Check the event’s relationship to other drugs or study 
procedures.
16. Event Outcome: Check the appropriate outcome of this event. If the subject’s death was related to 
the event, then Outcome should be marked “Fatal.” If the subject died from another cause while 
experiencing this event, DO NOT mark “Fatal” as an outcome, but check “Not Recovered/Not 
Resolved”.
17. Severity: Check the appropriate severity for this event. 
18. Treatment arm: please indicate randomization arm for the subject.  
19. Product* (*last administered prior event): please indicate the study product that the patient last 
received prior presenting the serious adverse event.
20. Study period: please indicate in which study phase the patient presented the serious adverse event, 
it can either be the screening phase, while undergoing weekly Full Plasma Exchange (please specify 
visit number), intermediate visit, while undergoing monthly Low Volume Plasma Exchange (please 
specify visit number) or Follow-up visit.
21. Product* started on: Record the date the patient first received the study product indicated in box 
#19.
22. Last date of Study Treatment (prior event): Record the date the study product indicated in box #19 
was last administered before the patient presented the serious adverse event.
23. Dose: Record infused dose or volume of the study product indicated on box #19.
24. Frequency: Record the frequency of dosing for the study product indicated on box #19.
25. Route of administration: Record the route of administration for the study product indicated on box 
#19.
26. Lot number: Record the lot number for the study product indicated on box #19.
27. Action taken with study drug due to the event (check all that apply): Check the appropriate 
action(s) taken with study product indicated on box #19 due to THIS serious adverse event.  Check 
“No Change” if action was taken due to some other event, and NOT to THIS event. 
28. Did event abate after stopping or reducing study treatment? Check the appropriate response.
29. Did event reappear after reintroduction of study treatment? Check the appropriate response.
30. Expiration date: Record the expiration date for the study product indicated on box #19.
31. Medical History: Record only relevant medical history and include allergies, smoking and alcohol 
use, or drug abuse (if applicable). If preferred, attach a copy of the Medical History eCRF and record 
“see attached”.
32. Relevant Lab/Confirmatory tests/Imaging reports: Record relevant laboratory data including date 
collected, test name, test results, units, and reference ranges.  If preferred, attach copies of any 
reports (all confidential information blacked out) and record “see attached.”  If the event is a lab 
abnormality, include lab data prior to the event (baseline).  Include all laboratory data used in 
diagnosing the event and lab data at the time of resolution. Include a synopsis of any relevant 
autopsy or pathology reports, if applicable.
33. Treatment Medications: Record all medications used to treat the event or if attaching Concomitant 
Medication electronic case report forms, circle the treatment medications.
34. Other non-drug treatments for the adverse event (e.g. surgery, etc.): Record any procedures and 
surgeries used to treat the event.
35. Concomitant drug(s): Record only relevant medications taken within 1 month prior to the onset of 
the event.  If preferred, attach a copy of the Concomitant Medication eCRF and record “see 
attached”.
36. Reporter’s name: Print the name and title of the person who is reporting the event to UBC. 
37. Reporter’s Phone #: Record the Reporter’s phone number. 
38. Reporter’s e-mail: Record the Reporter’s e-mail address. 
39. Principal Investigator name:  Record the Principal Investigator’s name. 
40. Principal Investigator Phone #:  Record the Investigator’s phone number. 
41. Principal Investigator e-mail:  Record the Investigator’s e-mail. 
42. Hospital Name and Address:  Record the hospital name and address where the study is performed. 
43. Signature: The Investigator MUST sign and date this form prior to sending it.  If the investigator 
cannot sign and date prior to the form meeting the 24 hour submission deadline, a copy must be 
signed as soon as possible annotating block #1 Report status with “signature.” 
44. Date of the notification:  Record the Date of Investigator’s Signature. 





















APPENDIX  5 




DECLARATION OF HELSINKI

	

	
	
 
!
	"	#$%&
'&
	($)	#$'
	*+*,

	,-$.,
.$#$
&!	/*
,$#$!000
&'	
*123,#$!00!45.
26$7
&&
	"	#$!0045.26$7
&
	,-$.+#$!00

	898#$!0'

:"
$$47
;
1$.
.
$$.$$
;;*
<$
$*$
6
:
"
1$=
$
.$
*

=
$.
;*
:
!:2=

.

1$
	
	$:"
$*
=
;;$
$
;;*
<$
$:
	
	
':"
1$.;.


	$=

=

	

	


	



		
 	
! "
@

>"


.	=	6$?
)2.
$/
$$
>
	$
$
A=

;*$$:?
:)
	.

	$.*


=B*
*
.$*
=
;;$$
:"


	$A=*$$$$
.6.
	:
&:$*$

	$
;;*
<$:
:"
	.$$
;;*
<$

$;C$.;;;
*$
$;4
$7:/;

;;;$	
*
$
.

.	C$;D$$	$$	E	:
%:$$
<$
$

$.
<$$


*
:
:

	.$$
*==*

*$;$$;
*
.;
$
<$:
:)
	.
	$=
;;$$
$

.

*	*	*
.B;$	$6	.
..$
<$:"
	.
$.
$
<$=	=


	$


$
.;=

$
<$;
*

	
;*;
$:
0:F
	$$

$**	
.$
;;*
<$
=$=
$:5
$*
*	E
$	.
$.
$
<$.

1$:
:$$

$$



;:
!:$$
;;*
<$$$		
!@

;=


$$6$$*
E6$:-$


	;E
;.
$	E6
	$


$.:
':
$$

;
$$$$
:
:F
	$=
$$$
=
$$
;;

$
	
G

<6	
;;*$
$;.

	$
*
;
$
$
	=;	C$


.

=
;$
<$:
&:$.<$=


.$*$
:
#
$ 	
	
$	%
:)$$$$$
;;;
:
$$
;;*
<$		$$.

$.
<$;=*


$
<$:
%:$$
;;*
<$$	$.
.$
;*;;

$
$=
.6

;
*C$	
$;*:

:"

$	$	
$
:
:F
	$	;;$
	;;*
<$

	$6


;E	$
.$	*:


.=*

6=


$$;..6;$
	$=

$
.		
	:
& 	
 
	
	 
'@

:,*;$	;	
;
$
.*=*.$*
:
;*;
$;$6$	$
$:
!0:$$
=
;*	<6.
$

;


.
*
$
$
$B;*:)
*
6
.
=*$$;
.
$
:
!	%
' 	
	


!:$$
;;*
<$$.*	
$$$6$$
*
=*.
$6$

;$..E	
G:"
=...$

$:
!!:"
*.$.$
$
	;;*
<$
$	$<6$
$:
"
$
$.

$$;;

$
=
$
1$
;:"

$
$.**.*
D$H$.$;.<$.
**;.*@$*<$=


$E$.$
$
	:
)$$
$$*.
B;:


(
!':"
$
$.$$
*$;
$$$

$$.
	
*:"
$.$*.

$

	
H$	E6:
)$
=*.
$	$
=
$

$
.=$
@


=$	.
$
.$
<$.

1$:
"
$
;
*
**:"
$

;*.
$$	.
	;;:5
$	=

$;	
$:.
.
	

$
6
$$*	.

	I6*$$:
)
	
(	%	)
!:/;	$$
;$	.$
<$

$6	.
.:
	
(		
!&:F$	;$.*;*.$<$
$$
;	:
*
	$.	
$	;$.*;*.$	
$
	

.	*:
!:)$$
;;*
<$$.*;*.
$$
<$E	..


$..*	$H$.D.

$

$6.
	

$.	B	;	
;$.

	:"
<$..
*
.$

	=
=$$	=
:,$

*;
$6$..;
<$=

;
.:
.*

<$

.


	$
	E6;


<$I.	B*;.$.	=*:).
$$
G=*
B=$.	$
=:
$$
<$
*;
.*.

*$.
	:
&@

!%:
*.$.$$
	


	$$	$.
<$

=


	$	$:)$


.$*
		E6;=

$	.

:
!:$
<$=
$.*;*.$


	$.$.
*	
;:
"
;$$
	


.
6.



.
*
	
<$
$
$.=

$.;*.$
$
	
:
!:
$
<$=
$.*;*.
$*;$$$



	$

$.
*	

;:"
<$I
$:
'0:-$
;;*<$=

	$		$.*;*
$.G$$		.

	$
$
;*;*.$$	$
$$
.
$
*:)$
$$$

	$.
$.
*	
;:).$
;
;.
$
$	
		$=

.$;

$6$.;;*<$=

$

*;.$
;

$
$
	
;	$

$$:
2
$
.

<$*	
;:
':"

	$.	.
=
$
$.
$

$
:"
..$	

I$=
=.
	;;	C$
B

	$
:
'!:$$
*6
$

$
$
	$
.$.$$*@:"
	
G$=
$=$$
@

.$
$
:)$

$
		.
$;.$

$$:
*


'':"
6C$;.=;
*
.
;;47G$
.=*
$$$ 

;;G
.$;
$$J

.$*$6$	
*$

.	;C$;

;
.$
;$	
D$$	.	.;

=
$;	;C$;


;$;=<$.
;
.$;*
;;:
/G$;.
:
+
	
':);$.$$$

$	
*;
;.B$$.$=

;66$
:"
.
$$*
.$$:

	
	
 	
	
		

 
'&:/;	$
	;;*
<$*$	
$$.$.
6<$:
':-$



;
$
*=
*
$.
.$
:
-$

;	$	;
.
$


<$$$.
$$$$	.

:

$$*.
$*:5*;
$$;=;

=
%@

$	;:,$..*D$H$.
$
$:-.$
$$$=


$.
1$
$$.$:
*		
			
	
(	

'%:)
.;=
;;
G
=;
;C$;

	$.*
G;$=
.$.
*	

;	;;.

	$A<*
C
.;*.B
*

;*C*:"

;
E	
<$.$
*
;.	D$$	:)$=.$
=
$	;:
,
-
./01


	#
	2


2

	 
)

	

	

	


	



	2

 
	
	

 

 
3

)
	4
)


	


	

	
 	
5	 )
0#
./062
7
 
' 	#

	




832	2
K$$)$:B-*
;:
K$$LM$B"$
;:
KNA$M$B"M;M:
@










$33(1',;


(*&3*8,'(/,1(6


EN

EN
'UDIW
COMMISSION DIRECTIVE ../…/EC
of […]
laying down principles and detailed guidelines for good clinical practice as regards 
investigational medicinal products for human use, as well as the requirements for 
authorisation of manufacturing or importation of such products
7+(&200,66,212)7+((8523($1&20081,7,(6
+DYLQJUHJDUGWRWKH7UHDW\HVWDEOLVKLQJWKH(XURSHDQ&RPPXQLW\
+DYLQJ UHJDUG WR 'LUHFWLYH (& RI WKH (XURSHDQ 3DUOLDPHQW DQG RI WKH &RXQFLO RI
$SULORQWKHDSSUR[LPDWLRQRIWKHODZVUHJXODWLRQVDQGDGPLQLVWUDWLYHSURYLVLRQVRI
WKH0HPEHU6WDWHVUHODWLQJWRWKHLPSOHPHQWDWLRQRIJRRGFOLQLFDOSUDFWLFHLQWKHFRQGXFWRI
FOLQLFDO WULDOV RQ PHGLFLQDO SURGXFWV IRU KXPDQ XVH DQG LQ SDUWLFXODU $UWLFOH 
$UWLFOHDQG$UWLFOHWKHUHRI
:KHUHDV
 $UWLFOHRI'LUHFWLYH(&UHTXLUHVWKDWSULQFLSOHVRIJRRGFOLQLFDOSUDFWLFHDQG
GHWDLOHGJXLGHOLQHVLQOLQHZLWKWKRVHSULQFLSOHVVKDOOEHDGRSWHG$UWLFOHRI'LUHFWLYH
(&UHTXLUHVWKDWPLQLPXPUHTXLUHPHQWVIRUDXWKRULVDWLRQRIPDQXIDFWXUHDQGLPSRUW
RILQYHVWLJDWLRQDOPHGLFLQDOSURGXFWVVKDOOEHDGRSWHG$UWLFOHRIGLUHFWLYH(&
UHTXLUHVWKDWGHWDLOHGJXLGHOLQHVRQWKHGRFXPHQWDWLRQUHODWLQJWRWKHFOLQLFDOWULDOWRYHULI\WKH
FRPSOLDQFHRIWKHFOLQLFDOWULDOLQTXHVWLRQZLWK'LUHFWLYH(&VKDOOEHDGRSWHG
 7KHSULQFLSOHVDQGJXLGHOLQHVIRUJRRGFOLQLFDOSUDFWLFHVKRXOGHQVXUHWKDWWKHFRQGXFWRI
FOLQLFDO WULDOV RQ LQYHVWLJDWLRQDO PHGLFLQDO SURGXFWV DV GHILQHG LQ $UWLFOH G RI 'LUHFWLYH
(&LVIRXQGHGLQWKHSURWHFWLRQRIKXPDQULJKWVDQGWKHGLJQLW\RIWKHKXPDQEHLQJ

 0DQXIDFWXULQJ UHTXLUHPHQWV WR EH DSSOLHG WR LQYHVWLJDWLRQDO PHGLFLQDO SURGXFWV DUH
SURYLGHG IRU E\ &RPPLVVLRQ 'LUHFWLYH (& RI  2FWREHU  OD\LQJ GRZQ WKH
SULQFLSOHVDQGJXLGHOLQHVRIJRRGPDQXIDFWXULQJSUDFWLFHLQUHVSHFWRIPHGLFLQDOSURGXFWVIRU
KXPDQ XVH DQG LQYHVWLJDWLRQDO PHGLFLQDO SURGXFWV IRU KXPDQ XVH 7LWOH ,9 RI 'LUHFWLYH
(& RI WKH (XURSHDQ 3DUOLDPHQW DQG RI WKH &RXQFLO RI  1RYHPEHU  RQ WKH
&RPPXQLW\ FRGH UHODWLQJ WR PHGLFLQDO SURGXFWV IRU KXPDQ XVH FRQWDLQV WKH SURYLVLRQV
DSSOLHG IRU WKH DXWKRULVDWLRQ IRU WKH PDQXIDFWXUH RI PHGLFLQDO SURGXFWV DV SDUW RI WKH
UHTXLUHPHQWV QHHGHG IRU WKH DSSOLFDWLRQ IRU D PDUNHWLQJ DXWKRULVDWLRQ $UWLFOH  RI WKLV

2-/S
2-/S
2-/S


EN

EN
'LUHFWLYH HVWDEOLVKHV WKDW WKHVH UHTXLUHPHQWV DUH QRW DSSOLFDEOH IRU PHGLFLQDO SURGXFWV
LQWHQGHGIRUUHVHDUFKDQGGHYHORSPHQWWULDOV,WLVWKHUHIRUHQHFHVVDU\WROD\GRZQPLQLPDO
UHTXLUHPHQWV UHJDUGLQJ DSSOLFDWLRQV IRU DQG PDQDJHPHQW RI DXWKRULVDWLRQV WR PDQXIDFWXUH
DQGRULPSRUWLQYHVWLJDWLRQDOPHGLFLQDOSURGXFWVDVZHOODVIRUWKHJUDQWLQJDQGWKHFRQWHQW
RIWKHDXWKRULVDWLRQVWRJXDUDQWHHWKHTXDOLW\RIWKHLQYHVWLJDWLRQDOPHGLFLQDOSURGXFWXVHGLQ
WKHFOLQLFDOWULDO
 :LWKUHJDUGWRWKHSURWHFWLRQRIWULDOVXEMHFWVDQGWRHQVXUHWKDWXQQHFHVVDU\FOLQLFDOWULDOV
ZLOO QRW EH FRQGXFWHG LW LV LPSRUWDQWWR GHILQH SULQFLSOHV DQG GHWDLOHG JXLGHOLQHVRI JRRG
FOLQLFDOSUDFWLFHDOORZLQJWKDWWKHUHVXOWVRIWKHWULDOVDUHGRFXPHQWHGIRUXVHLQDODWHUSKDVH
 7RHQVXUHWKDWDOOH[SHUWVDQGLQGLYLGXDOVLQYROYHGLQWKHGHVLJQLQJLQLWLDWLQJFRQGXFWLQJ
DQG UHFRUGLQJ RI FOLQLFDO WULDOV ZLOO DSSO\ WKH VDPH VWDQGDUGV RI JRRG FOLQLFDO SUDFWLFH
SULQFLSOHVDQGGHWDLOHGJXLGHOLQHVRIJRRGFOLQLFDOSUDFWLFHKDYHWREHGHILQHG
 3URYLVLRQV IRU WKH IXQFWLRQLQJ RI WKH (WKLFV &RPPLWWHHV VKRXOG EH HVWDEOLVKHG LQ HDFK
0HPEHU6WDWHEDVHGRQFRPPRQGHWDLOHGJXLGHOLQHVLQRUGHUWRHQVXUHWKHSURWHFWLRQRIWKH
WULDO VXEMHFW ZKLOH DW WKH VDPH WLPH DOORZLQJ D KDUPRQLVHG DSSOLFDWLRQ LQ WKH GLIIHUHQW
0HPEHU6WDWHVRIWKHSURFHGXUHVWREHXVHGE\(WKLFV&RPPLWWHHV
 7RVHFXUHWKHFRPSOLDQFHRIFOLQLFDOWULDOVZLWKWKHSURYLVLRQVRQJRRGFOLQLFDOSUDFWLFH
LQVSHFWRUVVKDOOHQVXUHWKHSUDFWLFDOHIIHFWLYHQHVVRIVXFKSURYLVLRQV,WLVHVVHQWLDOWKHUHIRUH
WRSURYLGHGHWDLOHGJXLGHOLQHVRQWKHPLQLPXPVWDQGDUGVIRUWKHLUTXDOLILFDWLRQLQSDUWLFXODU
DVUHJDUGVWKHLUHGXFDWLRQDQGWUDLQLQJ)RUWKHVDPHUHDVRQGHWDLOHGJXLGHOLQHVRQLQVSHFWLRQ
SURFHGXUHVLQSDUWLFXODURQWKHFRRSHUDWLRQRIWKHYDULRXVDJHQFLHVDQGWKHIROORZXSWRWKH
LQVSHFWLRQVVKRXOGEHODLGGRZQ
 7KH ,QWHUQDWLRQDO &RQIHUHQFH RQ +DUPRQLVDWLRQ ,&+ UHDFKHG D FRQVHQVXV LQ  WR
SURYLGHDKDUPRQLVHGDSSURDFK IRU*RRG&OLQLFDO3UDFWLFH7KHFRQVHQVXVSDSHUVKRXOG EH
WDNHQLQWRDFFRXQWDVDJUHHGXSRQE\WKH&RPPLWWHHIRU0HGLFLQDO3URGXFWVIRU+XPDQ8VH
&+03RIWKH(XURSHDQ0HGLFLQHV$JHQF\(0($DQGSXEOLVKHGE\WKH(0($
 6SRQVRUV LQYHVWLJDWRUV DQG RWKHU SDUWLFLSDQWV VKDOO WDNH LQWR DFFRXQW WKH VFLHQWLILF
JXLGHOLQHVUHODWLQJWRWKHTXDOLW\VDIHW\DQGHIILFDF\RIPHGLFLQDOSURGXFWVIRUKXPDQXVHDV
DJUHHG XSRQ E\ WKH &+03 DQG SXEOLVKHG E\ WKH (0($ DQG WKH RWKHU SKDUPDFHXWLFDO
&RPPXQLW\JXLGHOLQHVSXEOLVKHG E\WKH&RPPLVVLRQ LQWKHGLIIHUHQWYROXPHVRIThe rules 
governing medicinal products in the European Community.
 ,Q FRQGXFWLQJ FOLQLFDO WULDOV RQ LQYHVWLJDWLRQDO PHGLFLQDO SURGXFWV IRU KXPDQ XVH WKH
VDIHW\ DQG WKH SURWHFWLRQ RI WKH ULJKWV RI WULDO VXEMHFWV VKRXOG EH HQVXUHG $UWLFOH  RI
'LUHFWLYH(&SURYLGHVIRUWKH0HPEHU6WDWHVWRDGRSWGHWDLOHGUXOHVWRSURWHFWIURP
DEXVHLQGLYLGXDOVZKRDUHLQFDSDEOHRIJLYLQJWKHLULQIRUPHGFRQVHQWWKLVVKRXOGDOVRLQFOXGH
LQGLYLGXDOV WHPSRUDULO\ LQFDSDEOH RI JLYLQJ WKHLU LQIRUPHG FRQVHQW LH LQ HPHUJHQF\
VLWXDWLRQV
1RQFRPPHUFLDOFOLQLFDOWULDOVFRQGXFWHGE\UHVHDUFKHUVZLWKRXWWKHSDUWLFLSDWLRQRIWKH
SKDUPDFHXWLFDO LQGXVWU\ PD\ EH RI JUHDW EHQHILW WR WKH SDWLHQWV FRQFHUQHG 'LUHFWLYH
(&UHFRJQLVHVWKHVSHFLILFLW\RIWKHVHQRQFRPPHUFLDOFOLQLFDOWULDOV,QSDUWLFXODU
ZKHQWULDOVDUHFRQGXFWHGZLWKDXWKRULVHGPHGLFLQDOSURGXFWVDQGRQSDWLHQWVZLWKWKHVDPH
FKDUDFWHULVWLFVDVWKRVHFRYHUHGE\WKHDXWKRULVHGLQGLFDWLRQUHTXLUHPHQWVDOUHDG\IXOILOOHGE\
WKHVHDXWKRULVHGPHGLFLQDOSURGXFWVDVIDUDVPDQXIDFWXULQJRULPSRUWDWLRQDUHFRQFHUQHG


EN

EN
VKRXOGEHWDNHQLQWRFRQVLGHUDWLRQ+RZHYHULWFRXOGDOVREHQHFHVVDU\GXHWRWKHVSHFLILF
FRQGLWLRQV XQGHU ZKLFK QRQFRPPHUFLDO WULDOV DUH FRQGXFWHG WKDW 0HPEHU 6WDWHV IRUHVHH
VSHFLILF PRGDOLWLHV WR EH DSSOLHG WR WKHVH WULDOV QRW RQO\ ZKHQ FRQGXFWHG ZLWK DXWKRULVHG
PHGLFLQDOSURGXFWVDQGRQSDWLHQWVZLWKWKHVDPHFKDUDFWHULVWLFVLQRUGHUWRFRPSO\ZLWKWKH
SULQFLSOHV LPSRVHG E\ WKLV 'LUHFWLYH LQ SDUWLFXODU DV IDU DV WKH PDQXIDFWXULQJ RU LPSRUW
UHTXLUHPHQWVIRUDXWKRULVDWLRQDQGWKHGRFXPHQWDWLRQWREHVXEPLWWHGDQGDUFKLYHGIRUWKH
WULDOPDVWHUILOHDUHFRQFHUQHG7KHFRQGLWLRQVXQGHUZKLFKWKHQRQFRPPHUFLDOUHVHDUFKLV
FRQGXFWHG E\ SXEOLF UHVHDUFKHUVDQG WKH SODFHV ZKHUH WKLV UHVHDUFK WDNHV SODFH PDNH WKH
DSSOLFDWLRQRIFHUWDLQRIWKHSULQFLSOHVRIJRRGFOLQLFDOSUDFWLFHXQQHFHVVDU\RUJXDUDQWHHGE\
RWKHU PHDQV 0HPEHU 6WDWHV ZLOO HQVXUH LQ WKHVH FDVHV ZKHQ SURYLGLQJ IRU VSHFLILF
PRGDOLWLHVWKDWWKHREMHFWLYHVRIWKHSURWHFWLRQRIWKHULJKWVRIWKHSDWLHQWVZKLFKSDUWLFLSDWH
WR WKH WULDO DV ZHOO DV LQ JHQHUDO WKH FRUUHFW DSSOLFDWLRQ RI WKH JRRG FOLQLFDO SUDFWLFH
SULQFLSOHVDUHDFKLHYHG
7KH PHDVXUHVSURYLGHG IRULQWKLV'LUHFWLYHDUHLQDFFRUGDQFHZLWKWKHRSLQLRQRIWKH
6WDQGLQJ &RPPLWWHH RQ 0HGLFLQDO 3URGXFWV IRU +XPDQ 8VH VHW XS E\ $UWLFOH  RI
'LUHFWLYH(&
+$6$'237('7+,6',5(&7,9(
Chapter 1
Scope
Article 1
 7KLV 'LUHFWLYH OD\V GRZQ WKH IROORZLQJ SURYLVLRQV WR EH DSSOLHG WR LQYHVWLJDWLRQDO
PHGLFLQDOSURGXFWVIRUKXPDQXVH
D
WKH SULQFLSOHV RI JRRG FOLQLFDO SUDFWLFH DQG GHWDLOHG JXLGHOLQHV LQ OLQH ZLWK WKRVH
SULQFLSOHV DV UHIHUUHG WR LQ $UWLFOH  RI 'LUHFWLYH (& IRU WKH GHVLJQ
FRQGXFWDQGUHSRUWLQJRIFOLQLFDOWULDOVRQKXPDQVXEMHFWVLQYROYLQJVXFKSURGXFWV
E
WKH UHTXLUHPHQWV IRU WKH DXWKRULVDWLRQ RI WKH PDQXIDFWXUH RU LPSRUWDWLRQ RI VXFK
SURGXFWVDVIRUHVHHQLQ$UWLFOHRI'LUHFWLYH(&
F
WKH GHWDLOHG JXLGHOLQHV RQ WKH GRFXPHQWDWLRQ UHODWLQJ WR FOLQLFDO WULDOV DUFKLYLQJ
TXDOLILFDWLRQV RI LQVSHFWRUV DQG LQVSHFWLRQ SURFHGXUHV LQ DFFRUGDQFH ZLWK $UWLFOH
RI'LUHFWLYH(&
 :KHQDSSO\LQJWKHVHSULQFLSOHVGHWDLOHGJXLGHOLQHVDQGUHTXLUHPHQWV0HPEHU6WDWHVVKDOO
WDNHLQWRDFFRXQWWKHWHFKQLFDOLPSOHPHQWLQJPRGDOLWLHVSURYLGHGIRULQWKHGHWDLOHGJXLGDQFH
SXEOLVKHG E\ WKH &RPPLVVLRQ LQThe Rules governing medicinal products in the European 
Union
:KHQDSSO\LQJWKHVHSULQFLSOHVGHWDLOHGJXLGHOLQHVDQGUHTXLUHPHQWVRQQRQFRPPHUFLDO
FOLQLFDO WULDOV FRQGXFWHG E\ UHVHDUFKHUV ZLWKRXW WKH SDUWLFLSDWLRQ RI WKH SKDUPDFHXWLFDO


EN

EN
LQGXVWU\0HPEHU6WDWHVPD\LQWURGXFHVSHFLILFPRGDOLWLHVLQRUGHUWRWDNHLQWRDFFRXQWWKH
VSHFLILFLW\RIWKHVHWULDOVDVIDUDV&KDSWHUDQG&KDSWHURIWKLV'LUHFWLYHDUHFRQFHUQHG
0HPEHU6WDWHVPD\DOVRWDNHLQWRDFFRXQWWKHVSHFLDOSRVLWLRQRIWKHWULDOVZKRVHSODQQLQJGR
QRW UHTXLUH SDUWLFXODU PDQXIDFWXULQJ RU SDFNDJLQJ SURFHVVHV FDUULHG RXW ZLWK PHGLFLQDO
SURGXFWV ZLWK PDUNHWLQJ DXWKRULVDWLRQV ZLWKLQ WKH PHDQLQJ RI 'LUHFWLYH (&
PDQXIDFWXUHGRULPSRUWHGLQDFFRUGDQFHZLWKWKHVDPH'LUHFWLYHDQGFRQGXFWHGRQSDWLHQWV
ZLWKWKHVDPHFKDUDFWHULVWLFVDVWKRVHFRYHUHGE\WKHLQGLFDWLRQVSHFLILHGLQWKLVPDUNHWLQJ
DXWKRULVDWLRQ/DEHOOLQJRILQYHVWLJDWLRQDOPHGLFLQDOSURGXFWVLQWHQGHGIRUWULDOVRIWKLVQDWXUH
PD\ EH VXEMHFW WR VLPSOLILHG SURYLVLRQV ODLG GRZQ LQ WKH JRRG PDQXIDFWXULQJ SUDFWLFH
JXLGHOLQHV RQ LQYHVWLJDWLRQDO PHGLFLQDO SURGXFWV 0HPEHU 6WDWHV VKDOO LQIRUP WKH
&RPPLVVLRQDVZHOODVWKHRWKHU0HPEHU6WDWHVRIDQ\VSHFLILFPRGDOLWLHVLPSOHPHQWHGLQ
DFFRUGDQFHZLWKWKLVSDUDJUDSK7KHVHPRGDOLWLHVZLOOEHSXEOLVKHGE\WKH&RPPLVVLRQ
Chapter 2 
Good clinical practice, for the design, conduct, record and
reporting of clinical trials 
GOOD CLINICAL PRACTICE
Article 2
D 7KHULJKWVVDIHW\DQGLQWHUHVWVRIWKHWULDOVXEMHFWVVKDOOSUHYDLORYHUWKRVHRIVFLHQFHDQG
VRFLHW\
E(DFK LQGLYLGXDO LQYROYHG LQFRQGXFWLQJDWULDOVKDOOEHTXDOLILHG E\HGXFDWLRQWUDLQLQJ
DQGH[SHULHQFHWRSHUIRUP>KLVKHU@UHVSHFWLYHWDVNV
F&OLQLFDOWULDOVVKDOOEHVFLHQWLILFDOO\ VRXQGDQGHWKLFDO ZHOOGHILQHG LQDOODVSHFWVRIWKH
WULDOV

G0HPEHU6WDWHVVKDOOHQVXUHWKDWQHFHVVDU\SURFHGXUHVWRVHFXUHWKDWWKHTXDOLW\RIHYHU\
DVSHFWRIWKHWULDOVDUHFRPSOLHGZLWK

Article 3
7KH DYDLODEOH QRQFOLQLFDO DQG FOLQLFDO LQIRUPDWLRQ RQ DQ LQYHVWLJDWLRQDO PHGLFLQDO SURGXFW
VKDOOEHDGHTXDWHWRVXSSRUWWKHSURSRVHGFOLQLFDOWULDO


EN

EN
&OLQLFDOWULDOVVKDOOEHFRQGXFWHGLQDFFRUGDQFHZLWKWKHHWKLFDOSULQFLSOHVODLGGRZQLQWKH
(WKLFDO3ULQFLSOHVIRU0HGLFDO5HVHDUFK,QYROYLQJ+XPDQ6XEMHFWVWKDWDUHUHIOHFWHGLQ:RUOG
0HGLFDO$VVRFLDWLRQ'HFODUDWLRQRI+HOVLQNL
Article 4
7KHFOLQLFDOWULDOVSURWRFROUHIHUUHGWRLQ$UWLFOHRI'LUHFWLYH(&VKDOOSURYLGHIRU
WKHGHILQLWLRQRI LQFOXVLRQDQGH[FOXVLRQRIVXEMHFWVSDUWLFLSDWLQJ LQDWULDO PRQLWRULQJDQG
SXEOLFDWLRQSROLF\
7KHLQYHVWLJDWRUDQGVSRQVRUVKDOOFRQVLGHUDOOUHOHYDQWJXLGDQFHZLWKUHVSHFWWRFRPPHQFLQJ
DQGFRQGXFWLQJRIDFOLQLFDOWULDO
Article 5
$OOFOLQLFDOWULDOLQIRUPDWLRQVKDOOEHUHFRUGHGKDQGOHGDQGVWRUHGLQVXFKDZD\WKDWLWFDQ
EHDFFXUDWHO\UHSRUWHGLQWHUSUHWHGDQGYHULILHGZKLOHSURWHFWLQJWKHFRQILGHQWLDOLW\RIUHFRUGV
RIWKHWULDOVVXEMHFWV

THE ETHICS COMMITTEE
Article 6

(DFK (WKLFV &RPPLWWHH VKDOO DGRSW WKH UHOHYDQW UXOHV RI SURFHGXUH QHFHVVDU\ WR
LPSOHPHQWWKHUHTXLUHPHQWVVHW RXW LQ 'LUHFWLYH (&DQG LQ SDUWLFXODU LQ
$UWLFOHVDQGWKHUHRI

7KH (WKLFV &RPPLWWHHV VKDOO LQ HYHU\ FDVH UHWDLQ WKH HVVHQWLDO GRFXPHQWV DV
GHILQHGLQ$UWLFOHRI'LUHFWLYH(&UHODWLQJWRDFOLQLFDOWULDOIRUDWOHDVW
\HDUV DIWHU LWV FRPSOHWLRQ 7KH\ VKDOO UHWDLQ WKH GRFXPHQWV IRU D ORQJHU SHULRG
ZKHUHUHTXLUHGE\RWKHUDSSOLFDEOHUHJXODWRU\UHTXLUHPHQWV

&RPPXQLFDWLRQRILQIRUPDWLRQEHWZHHQWKH(WKLFV&RPPLWWHHVDQGWKHFRPSHWHQW
DXWKRULWLHVRIWKH0HPEHU6WDWHVVKDOOEHHQVXUHGWKURXJKDSSURSULDWHDQGHIILFLHQW
V\VWHPV

THE SPONSORS 
Article 7

$VSRQVRUPD\GHOHJDWHDQ\RUDOORI KLVWULDOUHODWHGIXQFWLRQVWRDQ LQGLYLGXDOD
FRPSDQ\DQLQVWLWXWLRQRUDQRUJDQLVDWLRQ


EN

EN

+RZHYHU LQ VXFK FDVHV WKH VSRQVRU VKDOO UHPDLQ UHVSRQVLEOH IRU HQVXULQJ WKDW WKH
FRQGXFW RI WKH WULDOV DQG WKH ILQDO GDWD JHQHUDWHG E\ WKRVH WULDOV FRPSO\ ZLWK WKH
UHTXLUHPHQWVRI'LUHFWLYH(&DVZHOODVRIWKLV'LUHFWLYH

7KHLQYHVWLJDWRUDQGWKHVSRQVRUPD\EHWKHVDPHSHUVRQ

INVESTIGATOR'S BROCHURE
Article 8

7KHLQIRUPDWLRQLQWKHLQYHVWLJDWRU
VEURFKXUHUHIHUUHGWRLQ$UWLFOHJRI'LUHFWLYH
(& VKDOO EH SUHVHQWHG LQ D FRQFLVH VLPSOH REMHFWLYH EDODQFHG DQG QRQ
SURPRWLRQDOIRUPWKDWHQDEOHVDFOLQLFLDQRUSRWHQWLDOLQYHVWLJDWRUWRXQGHUVWDQGLW
DQGPDNHDQXQELDVHGULVNEHQHILWDVVHVVPHQWRIWKHDSSURSULDWHQHVVRIWKHSURSRVHG
FOLQLFDOWULDO7KLVVXPPDULVHGVW\OHLVDOVRUHTXLUHGIRUDQ\XSGDWHRIWKLVEURFKXUH

,IWKHLQYHVWLJDWLRQDOPHGLFLQDOSURGXFWKDVDPDUNHWLQJDXWKRULVDWLRQWKH6XPPDU\
RI3URGXFW&KDUDFWHULVWLFVFDQEHXVHGLQVWHDGRIWKHLQYHVWLJDWRU¶VEURFKXUH

7KHLQYHVWLJDWRU¶VEURFKXUHVKDOOEHYDOLGDWHGDQGXSGDWHGRQDUHJXODUEDVLVE\WKH
VSRQVRUDWOHDVWDQQXDOO\

Chapter 3
Manufacturing or import authorisation
Article 9

7KH DXWKRULVDWLRQ WR PDQXIDFWXUH RU LPSRUW LQYHVWLJDWLRQDO PHGLFLQDO SURGXFWV
UHIHUUHGWRLQ$UWLFOHRI'LUHFWLYH(&VKDOOEHUHTXLUHGIRUERWKWRWDO
DQGSDUWLDOPDQXIDFWXUHDQGIRUWKHYDULRXVSURFHVVHVRIGLYLGLQJXSSDFNDJLQJRU
SUHVHQWDWLRQ
7KHDXWKRULVDWLRQVKDOOEHUHTXLUHGQRWZLWKVWDQGLQJWKDWWKHSURGXFWVPDQXIDFWXUHG
DUH LQWHQGHG IRU H[SRUW 7KH DXWKRULVDWLRQ VKDOO DOVR EH UHTXLUHG IRU LPSRUWV IURP
WKLUGFRXQWULHVLQWRD0HPEHU6WDWH

+RZHYHU VXFK DXWKRULVDWLRQ VKDOO QRW EH UHTXLUHG IRU SUHSDUDWLRQ GLYLGLQJ XS
FKDQJHVLQSDFNDJLQJRUSUHVHQWDWLRQZKHUHWKHVHSURFHVVHVDUHFDUULHGRXWVROHO\IRU
UHWDLO VXSSO\ E\ SKDUPDFLVWV LQ GLVSHQVLQJ SKDUPDFLHV RU E\ SHUVRQV OHJDOO\
DXWKRULVHGLQWKH0HPEHU6WDWHVWRFDUU\RXWVXFKSURFHVVHV


EN

EN
Article 10
 ,Q RUGHU WR REWDLQ WKH DXWKRULVDWLRQ WKH DSSOLFDQW PXVW PHHW DW OHDVW WKH IROORZLQJ
UHTXLUHPHQWV
D
VSHFLI\ WKH PHGLFLQDO SURGXFWV DQG SKDUPDFHXWLFDO IRUPV WR EH PDQXIDFWXUHG RU
LPSRUWHG
E
VSHFLI\WKHUHOHYDQWPDQXIDFWXUHRULPSRUWRSHUDWLRQV
F
VSHFLI\ ZKHUH UHOHYDQW DV LQ WKH FDVH RI YLUDO RU QRQ FRQYHQWLRQDO DJHQWV¶
LQDFWLYDWLRQWKHPDQXIDFWXULQJSURFHVV
G
VSHFLI\WKHSODFHZKHUHWKHSURGXFWVDUHWREHPDQXIDFWXUHGRUKDYHDWKLVGLVSRVDO
IRU WKH PDQXIDFWXUH RU LPSRUW RI WKH DERYH VXLWDEOH DQG VXIILFLHQW SUHPLVHV
WHFKQLFDOHTXLSPHQWDQGFRQWUROIDFLOLWLHVFRPSO\LQJZLWKWKHOHJDOUHTXLUHPHQWVRI
&RPPLVVLRQ'LUHFWLYH(&DVUHJDUGVWKHPDQXIDFWXUHFRQWURODQGVWRUDJH
RIWKHSURGXFWV
H
KDYH SHUPDQHQWO\ DQG FRQWLQXRXVO\ DW KLV GLVSRVDO WKH VHUYLFHV RI DW OHDVW RQH
TXDOLILHGSHUVRQDVUHIHUUHGWRLQ$UWLFOHRI'LUHFWLYH(&
7KHDSSOLFDQW PXVWSURYLGHZLWKKLVDSSOLFDWLRQGRFXPHQWDU\HYLGHQFHWKDWKHFRPSOLHV
ZLWKWKHILUVWSDUDJUDSK
Article 11

7KH FRPSHWHQW DXWKRULW\ VKDOO LVVXH WKH DXWKRULVDWLRQ RQO\ DIWHU YHULI\LQJ WKH
DFFXUDF\RIWKHSDUWLFXODUVSURYLGHGE\WKHDSSOLFDQWLQDFFRUGDQFHZLWK$UWLFOH
E\WKHPHDQVRIDQLQTXLU\FDUULHGRXWE\LWVDJHQWV

0HPEHU6WDWHVVKDOOWDNHDOODSSURSULDWHPHDVXUHVWRHQVXUHWKDWWKHSURFHGXUHIRU
JUDQWLQJDQDXWKRULVDWLRQ LVFRPSOHWHGZLWKLQGD\VRIWKHVXEPLVVLRQRIDYDOLG
DSSOLFDWLRQIURPWKHGD\RQZKLFKWKHFRPSHWHQWDXWKRULW\UHFHLYHVWKHDSSOLFDWLRQ

7KHFRPSHWHQWDXWKRULW\RIWKH0HPEHU6WDWHPD\UHTXLUHIURPWKHDSSOLFDQWIXUWKHU
LQIRUPDWLRQ FRQFHUQLQJ WKH SDUWLFXODUV VXSSOLHG SXUVXDQW WR $UWLFOH  DQG
FRQFHUQLQJ WKH TXDOLILHG SHUVRQ UHIHUUHG WR LQ $UWLFOH  ZKHUH WKH FRPSHWHQW
DXWKRULW\FRQFHUQHGH[HUFLVHVWKLVULJKWWKHDSSOLFDWLRQRIWKHWLPHOLPLWVUHIHUUHGWR
LQ WKLV $UWLFOH VKDOO EH VXVSHQGHG XQWLO WKH DGGLWLRQDO GDWD UHTXLUHG KDYH EHHQ
VXSSOLHG
Article 12
,Q RUGHU WR HQVXUH WKDW WKH UHTXLUHPHQWV UHIHUUHG WR LQ $UWLFOH  DUH FRPSOLHG ZLWK
DXWKRULVDWLRQ PD\ EH PDGH FRQGLWLRQDO RQ WKH FDUU\LQJ RXWRI FHUWDLQ REOLJDWLRQV LPSRVHG
HLWKHUZKHQDXWKRULVDWLRQLVJUDQWHGRUDWDODWHUGDWH
7KH DXWKRULVDWLRQ VKDOO DSSO\ RQO\ WR WKH SUHPLVHV VSHFLILHG LQ WKH DSSOLFDWLRQ DQG WR WKH
PHGLFLQDOSURGXFWVDQGSKDUPDFHXWLFDOIRUPVVSHFLILHGLQWKDWVDPHDSSOLFDWLRQ


EN

EN
Article 13
7KHKROGHURIWKHDXWKRULVDWLRQVKDOODWOHDVWEHREOLJHG
D
WRKDYHDWKLVGLVSRVDOWKHVHUYLFHVRIVWDIIWKDWFRPSO\ZLWKWKHOHJDOUHTXLUHPHQWV
H[LVWLQJLQWKH0HPEHU6WDWHFRQFHUQHGERWKDVUHJDUGVPDQXIDFWXUHDQGFRQWUROV
E
WR GLVSRVH RI WKH LQYHVWLJDWLRQDODXWKRULVHG PHGLFLQDO SURGXFWVRQO\ LQ DFFRUGDQFH
ZLWKWKHOHJLVODWLRQRIWKH0HPEHU6WDWHVFRQFHUQHG
F
WRJLYHSULRUQRWLFHWRWKHFRPSHWHQWDXWKRULW\RIDQ\FKDQJHVWKHKROGHUPD\ZLVKWR
PDNH WR DQ\ RI WKH SDUWLFXODUV VXSSOLHG SXUVXDQW $UWLFOH  LQ SDUWLFXODU WKH
FRPSHWHQWDXWKRULW\VKDOOEHLQIRUPHGLPPHGLDWHO\LIWKHTXDOLILHGSHUVRQUHIHUUHGWR
LQ$UWLFOHRI'LUHFWLYH(&LVUHSODFHGXQH[SHFWHGO\
G
WRDOORZDJHQWVRIWKHFRPSHWHQWDXWKRULW\RIWKH0HPEHU6WDWHFRQFHUQHGDFFHVVWR
KLVSUHPLVHVDWDQ\WLPH
H
WRHQDEOHWKHTXDOLILHGSHUVRQUHIHUUHGWRLQ$UWLFOHRI'LUHFWLYH(&WR
FDUU\RXWKLVGXWLHVIRUH[DPSOHE\SODFLQJDWKLVGLVSRVDODOOWKHQHFHVVDU\IDFLOLWLHV
I
WR FRPSO\ ZLWK WKH SULQFLSOHV DQG JXLGHOLQHV IRU JRRG PDQXIDFWXULQJ SUDFWLFH IRU
PHGLFLQDOSURGXFWVDVODLGGRZQE\&RPPXQLW\ODZ'HWDLOHGJXLGHOLQHVLQOLQHZLWK
WKRVHSULQFLSOHVZLOOEHSXEOLVKHGE\WKH&RPPLVVLRQDQGUHYLVHGQHFHVVDU\WRWDNH
DFFRXQWRIWHFKQLFDODQGVFLHQWLILFSURJUHVV
Article 14
,IWKHKROGHURIWKHPDQXIDFWXULQJDXWKRULVDWLRQUHTXHVWVDFKDQJH LQDQ\RIWKHSDUWLFXODUV
UHIHUUHGWRLQSRLQWVDDQGHRIWKH ILUVWSDUDJUDSKRI $UWLFOHWKHWLPHWDNHQIRUWKH
SURFHGXUHUHODWLQJWRWKLVUHTXHVWVKDOOQRWH[FHHGGD\V,QH[FHSWLRQDOFDVHVWKLVSHULRGRI
WLPHPD\EHH[WHQGHGWRGD\V
Article 15
7KHFRPSHWHQWDXWKRULW\VKDOOVXVSHQGRUUHYRNHWKHDXWKRULVDWLRQDVDZKROHRULQSDUWLIWKH
KROGHURIWKHDXWKRULVDWLRQIDLOVDWDQ\WLPHWRFRPSO\ZLWKWKHUHOHYDQWUHTXLUHPHQWV



EN

EN
Chapter 4 
Documentation constituting the Trial Master File and archiving
Article 16
7KHGRFXPHQWDWLRQUHIHUUHGWR$UWLFOHRI'LUHFWLYH(&DVWKH7ULDO0DVWHU)LOH
VKDOOFRQVLVWRIHVVHQWLDOGRFXPHQWVZKLFKHQDEOHERWKWKHFRQGXFWRIDFOLQLFDOWULDODQGWKH
TXDOLW\ RI WKH GDWD SURGXFHG WR EH HYDOXDWHG 7KRVH GRFXPHQWV KDYH WR VKRZ ZKHWKHU WKH
LQYHVWLJDWRUDQGWKHVSRQVRUKDYHFRPSOLHGZLWKWKHSULQFLSOHVDQGJXLGHOLQHVRIJRRGFOLQLFDO
SUDFWLFHDQGZLWKWKHDSSOLFDEOHUHJXODWRU\UHTXLUHPHQWVDQGLQSDUWLFXODUZLWK$QQH[,WR
'LUHFWLYH(&
7KH 7ULDO 0DVWHU )LOH VKDOO SURYLGH WKH EDVLV IRU WKH DXGLW E\ WKH VSRQVRU¶V LQGHSHQGHQW
DXGLWRUDQGIRUWKHLQVSHFWLRQE\WKHFRPSHWHQWDXWKRULW\
7KH FRQWHQW RI WKH HVVHQWLDO GRFXPHQWV UHIHUUHG WR DERYHVKDOO EH LQ DFFRUGDQFH ZLWK WKH
VSHFLILFLWLHVRIHDFKSKDVHRIWKHFOLQLFDOWULDO
Article 17
7KHVSRQVRUDQGWKHLQYHVWLJDWRUVKDOOLQHYHU\FDVHUHWDLQWKHHVVHQWLDOGRFXPHQWVUHODWLQJWR
DFOLQLFDOWULDOIRUDWOHDVW\HDUVDIWHULWVFRPSOHWLRQ
7KH\ VKDOO UHWDLQ WKH GRFXPHQWV IRU D ORQJHU SHULRG ZKHUH UHTXLUHG E\ RWKHU DSSOLFDEOH
UHJXODWRU\UHTXLUHPHQWVRUE\DQDJUHHPHQWEHWZHHQWKHVSRQVRUDQGWKHLQYHVWLJDWRU
(VVHQWLDOGRFXPHQWVVKDOOEHDUFKLYHGLQDZD\WKDWHQVXUHVWKDWWKH\DUHUHDGLO\DYDLODEOH
XSRQUHTXHVWWRWKHFRPSHWHQWDXWKRULWLHV
7KHWULDOVVXEMHFW¶VPHGLFDOILOHVVKRXOGEHUHWDLQHGLQDFFRUGDQFHZLWKQDWLRQDOOHJLVODWLRQ
DQGLQDFFRUGDQFHZLWKWKHPD[LPXPSHULRGRIWLPHSHUPLWWHGE\WKHKRVSLWDOLQVWLWXWLRQRU
SULYDWHSUDFWLFH
Article 18
$Q\WUDQVIHURIRZQHUVKLSRIWKHGDWDRURIGRFXPHQWVVKDOOEHGRFXPHQWHG7KHQHZRZQHU
VKDOODVVXPHUHVSRQVLELOLW\IRUGDWDUHWHQWLRQDQGDUFKLYLQJ
Article 19
7KHVSRQVRUVKDOODSSRLQWLQGLYLGXDOVZLWKLQLWVRUJDQLVDWLRQZKRDUHUHVSRQVLEOHIRUDUFKLYHV
$FFHVVWRDUFKLYHVVKDOOEHUHVWULFWHGWRWKHQDPHGLQGLYLGXDOVUHVSRQVLEOHIRUWKHDUFKLYH


EN

EN
Article 20
7KH PHGLD XVHG WR VWRUH HVVHQWLDO GRFXPHQWV VKDOO EH VXFK WKDW WKRVH GRFXPHQWV UHPDLQ
FRPSOHWHDQGOHJLEOHWKURXJKRXWWKHUHTXLUHGSHULRGRIUHWHQWLRQDQGFDQEHPDGHDYDLODEOHWR
WKHFRPSHWHQWDXWKRULWLHVXSRQUHTXHVW
$Q\DOWHUDWLRQWRUHFRUGVVKDOOEHWUDFHDEOH

Chapter 5
Qualifications of inspectors
Article 21

7KHLQVSHFWRUVDSSRLQWHGE\WKH0HPEHU6WDWHVLQFRQIRUPLW\ZLWK$UWLFOHRI
'LUHFWLYH(&VKDOOEHPDGHDZDUHRIDQGPDLQWDLQFRQILGHQWLDOLW\ZKHQHYHU
WKH\ JDLQ DFFHVV WR FRQILGHQWLDO LQIRUPDWLRQ DV D UHVXOW RI JRRG FOLQLFDO SUDFWLFH
LQVSHFWLRQV DFFRUGLQJ WR DSSOLFDEOH &RPPXQLW\ UHTXLUHPHQWV QDWLRQDO ODZV RU
LQWHUQDWLRQDODJUHHPHQWV

0HPEHU6WDWHVVKDOOHQVXUHWKDWLQVSHFWRUVKDYH FRPSOHWHGHGXFDWLRQDWXQLYHUVLW\
OHYHO RU KDYH HTXLYDOHQW H[SHULHQFH LQ PHGLFLQH SKDUPDF\ SKDUPDFRORJ\
WR[LFRORJ\RURWKHUUHOHYDQWILHOGV

0HPEHU 6WDWHV VKDOO HQVXUH WKDW LQVSHFWRUV UHFHLYH DSSURSULDWH WUDLQLQJ WKDW WKHLU
WUDLQLQJQHHGVDUHDVVHVVHGUHJXODUO\DQGWKDWDSSURSULDWHDFWLRQLVWDNHQWRPDLQWDLQ
DQGLPSURYHWKHLUVNLOOV
0HPEHU6WDWHVVKDOOJXDUDQWHHWKDWWKHLQVSHFWRUVKDYHNQRZOHGJHRIWKHSULQFLSOHV
DQG SURFHVVHV WKDW DSSO\ WR WKH GHYHORSPHQW RI PHGLFLQDO SURGXFWV DQG FOLQLFDO
UHVHDUFK ,QVSHFWRUV VKDOO DOVR KDYH NQRZOHGJH RI DSSOLFDEOH &RPPXQLW\ DQG
QDWLRQDOOHJLVODWLRQDQGJXLGHOLQHVDSSOLFDEOHWRWKHFRQGXFWRIFOLQLFDOWULDOVDQGWKH
JUDQWLQJRIPDUNHWLQJDXWKRULVDWLRQV
7KH LQVSHFWRUV VKDOO EH IDPLOLDU ZLWK WKH SURFHGXUHV DQG V\VWHPV IRU UHFRUGLQJ
FOLQLFDOGDWDDQGZLWKWKHRUJDQLVDWLRQDQGUHJXODWLRQRIWKHKHDOWKFDUHV\VWHPLQWKH
UHOHYDQW0HPEHU6WDWHVDQGZKHUHDSSURSULDWHLQWKLUGFRXQWULHV

0HPEHU6WDWHVVKDOO PDLQWDLQXSWRGDWHUHFRUGVRIWKHTXDOLILFDWLRQVWUDLQLQJDQG
H[SHULHQFHRIHDFKLQVSHFWRU

(DFK LQVSHFWRU VKDOO EH SURYLGHG ZLWK D GRFXPHQW VHWWLQJ RXW VWDQGDUG RSHUDWLQJ
SURFHGXUHV DQG JLYLQJ GHWDLOV RI WKH GXWLHV UHVSRQVLELOLWLHV DQG RQJRLQJ WUDLQLQJ
UHTXLUHPHQWV7KRVHSURFHGXUHVVKDOOEHPDLQWDLQHGXSWRGDWH

,QVSHFWRUVVKDOOEHSURYLGHGZLWKVXLWDEOHPHDQVRILGHQWLILFDWLRQ


EN

EN

(DFK LQVSHFWRU VKDOO VLJQ D VWDWHPHQW GHFODULQJ DQ\ ILQDQFLDORU RWKHU OLQNVWRWKH
SDUWLHV WR EH LQVSHFWHG 7KDW VWDWHPHQW VKDOO EH WDNHQ LQWR FRQVLGHUDWLRQ ZKHQ
LQVSHFWRUVDUHWREHDVVLJQHGWRDVSHFLILFLQVSHFWLRQ
Article 22
,QRUGHUWRHQVXUHWKHSUHVHQFHRIVNLOOVQHFHVVDU\IRUVSHFLILFLQVSHFWLRQV0HPEHU6WDWHPD\
DSSRLQW WHDPV RI LQVSHFWRUV DQG H[SHUWV ZLWK DSSURSULDWH TXDOLILFDWLRQV DQG H[SHULHQFH WR
IXOILOFROOHFWLYHO\WKHUHTXLUHPHQWVQHFHVVDU\IRUFRQGXFWLQJWKHLQVSHFWLRQ

Chapter 6
Inspection procedures 
Article 23

*RRGFOLQLFDOSUDFWLFHLQVSHFWLRQVPD\WDNHSODFHEHIRUHGXULQJRUDIWHUWKHFRQGXFW
RI FOLQLFDO WULDOV DQGRU DV SDUW RI WKH YHULILFDWLRQ RI DSSOLFDWLRQV IRU PDUNHWLQJ
DXWKRULVDWLRQVRUDVIROORZXSWRWKHVH

,QDFFRUGDQFHZLWK$UWLFOHDQGRI'LUHFWLYH(&LQVSHFWLRQVPD\
EHUHTXHVWHGDQGFRRUGLQDWHGE\WKH(XURSHDQ0HGLFLQHV$JHQF\(0($ZLWKLQ
WKHVFRSHRI 5HJXODWLRQ (& 1RRIWKH(XURSHDQ3DUOLDPHQWDQGRIWKH
&RXQFLORI0DUFKOD\LQJGRZQ&RPPXQLW\SURFHGXUHVIRUWKHDXWKRULVDWLRQ
DQGVXSHUYLVLRQRIPHGLFLQDOSURGXFWVIRUKXPDQDQGYHWHULQDU\XVHDQGHVWDEOLVKLQJ
D(XURSHDQ0HGLFLQHV$JHQF\HVSHFLDOO\LQFRQQHFWLRQZLWKFOLQLFDOWULDOVUHODWLQJ
WRDSSOLFDWLRQVWKURXJKWKHSURFHGXUHHVWDEOLVKHGE\WKLV5HJXODWLRQ

,QVSHFWLRQV VKDOO EH FRQGXFWHG LQ DFFRUGDQFH ZLWK WKH LQVSHFWLRQV JXLGDQFH
GRFXPHQWVGHYHORSHGWRVXSSRUWWKHPXWXDOUHFRJQLWLRQRILQVSHFWLRQILQGLQJVZLWKLQ
WKH&RPPXQLW\

,PSURYHPHQW DQG KDUPRQLVDWLRQ RI LQVSHFWLRQ JXLGDQFH VKDOO EH DFKLHYHG E\ WKH
0HPEHU6WDWHVLQFROODERUDWLRQZLWKWKH&RPPLVVLRQDQGWKH(0($WKURXJKMRLQW
LQVSHFWLRQVDJUHHGSURFHVVHVDQGSURFHGXUHVDQGVKDULQJRIH[SHULHQFHDQGWUDLQLQJ
Article 24
0HPEHU6WDWHVVKDOOPDNHSXEOLFO\DYDLODEOHZLWKLQWKHLUWHUULWRULHVWKHGRFXPHQWVUHODWLQJWR
WKHDGRSWLRQRIJRRGFOLQLFDOSUDFWLFHSULQFLSOHV

2-/S


EN

EN
7KH\VKDOOHVWDEOLVKWKHOHJDODQGDGPLQLVWUDWLYHIUDPHZRUNZLWKLQZKLFKWKHLUJRRGFOLQLFDO
SUDFWLFHLQVSHFWLRQVRSHUDWHZLWKGHILQLWLRQRIWKHSRZHUVRILQVSHFWRUVIRUHQWU\LQWRFOLQLFDO
WULDOVLWHVDQGDFFHVVWRGDWD7KH\VKDOOHQVXUHWKDWLQVSHFWRUVRIWKHFRPSHWHQWDXWKRULW\RI
WKHRWKHU0HPEHU6WDWHVKDYHDOVRDFFHVVWRWKHFOLQLFDOWULDOVLWHVDQGGDWDDWDQ\WLPH
Article 25
0HPEHU 6WDWHV VKDOO SURYLGH IRU VXIILFLHQW UHVRXUFHV DQG LQ SDUWLFXODU VKDOO DSSRLQW DQ
DGHTXDWH QXPEHU RI LQVSHFWRUV WR HQVXUH HIIHFWLYH YHULILFDWLRQ RI FRPSOLDQFH ZLWK JRRG
FOLQLFDOSUDFWLFH
Article 26
0HPEHU6WDWHVVKDOOHVWDEOLVKWKHUHOHYDQWSURFHGXUHVIRUYHULILFDWLRQRIJRRGFOLQLFDOSUDFWLFH
FRPSOLDQFH
7KH SURFHGXUHV VKDOO LQFOXGH WKH PRGDOLWLHV ZKLFK ZLOO EH XVHG WR H[DPLQH ERWK WKH VWXG\
PDQDJHPHQWSURFHGXUHVDQGWKHFRQGLWLRQVXQGHUZKLFKFOLQLFDOWULDOVDUHSODQQHGSHUIRUPHG
PRQLWRUHGDQGUHFRUGHGDQGIROORZXSPHDVXUHV
Article 27
0HPEHU6WDWHVVKDOOHVWDEOLVKWKHUHOHYDQWSURFHGXUHVIRU

DSSRLQWLQJH[SHUWVIRUDFFRPSDQ\LQJLQVSHFWRUVLQFDVHRIQHHG

UHTXHVWLQJ LQVSHFWLRQVDVVLVWDQFH IURP RWKHU 0HPEHU 6WDWHV LQ OLQH ZLWK $UWLFOH
RI'LUHFWLYH(&DQGIRUFRRSHUDWLQJLQLQVSHFWLRQVVLWHVLQDQRWKHU
0HPEHU6WDWH

DUUDQJLQJLQVSHFWLRQVLQWKLUGFRXQWULHV
Article 28
0HPEHU6WDWHVVKDOOPDLQWDLQUHFRUGVRIQDWLRQDODQGLIDSSOLFDEOHLQWHUQDWLRQDOLQVSHFWLRQV
LQFOXGLQJWKHJRRGFOLQLFDOSUDFWLFHFRPSOLDQFHVWDWXVDQGRIWKHLUIROORZXS
Article 29

,QRUGHUWRKDUPRQLVHWKHFRQGXFWLRQRILQVSHFWLRQVE\WKHFRPSHWHQWDXWKRULWLHVRI
WKHGLIIHUHQW0HPEHU6WDWHVJXLGDQFHGRFXPHQWVFRQWDLQLQJWKHFRPPRQSURYLVLRQV
RQWKHFRQGXFWLRQRIWKHVHLQVSHFWLRQVVKDOOEHSXEOLVKHGE\WKH&RPPLVVLRQDIWHU
FRQVXOWDWLRQZLWKWKH0HPEHU6WDWHV

0HPEHU6WDWHVVKDOOHQVXUHWKDWQDWLRQDO LQVSHFWLRQVSURFHGXUHVDUHLQFRPSOLDQFH
ZLWKWKHJXLGDQFHGRFXPHQWVUHIHUUHGLQSDUDJUDSK


EN

EN

7KH JXLGDQFH GRFXPHQWV UHIHUUHG WR LQ SDUDJUDSK  PD\ EH XSGDWHG UHJXODUO\
DFFRUGLQJWRVFLHQWLILFDQGWHFKQLFDOGHYHORSPHQW
Article 30

0HPEHU 6WDWHV VKDOO OD\ GRZQ DOO QHFHVVDU\ UXOHV WR HQVXUH FRQILGHQWLDOLW\ E\
LQVSHFWRUV DQG RWKHU H[SHUWV :LWK UHJDUG WR SHUVRQDO GDWD WKH UHTXLUHPHQWV RI
'LUHFWLYH((&RIWKH(XURSHDQ3DUOLDPHQWDQGRIWKH&RXQFLORI2FWREHU
RQWKHSURWHFWLRQRILQGLYLGXDOVZLWKUHJDUGWRWKHSURFHVVLQJRISHUVRQDOGDWD
DQGRQWKHIUHHPRYHPHQWRIVXFKGDWDVKDOOEHUHVSHFWHG

,QVSHFWLRQ UHSRUWV VKDOO EH PDGH DYDLODEOH E\ WKH 0HPEHU 6WDWHV RQO\ WR WKH
UHFLSLHQWVUHIHUUHGWRLQ$UWLFOHRI'LUHFWLYH(&LQDFFRUGDQFHZLWK
QDWLRQDOUHJXODWLRQVRIWKH0HPEHU6WDWHVDQGVXEMHFWWRDQ\DUUDQJHPHQWVFRQFOXGHG
EHWZHHQWKH&RPPXQLW\DQGWKLUGFRXQWULHV

Chapter 7
Final provisions
Article 31
0HPEHU 6WDWHV VKDOO EULQJ LQWR IRUFH WKH ODZV UHJXODWLRQV DQG DGPLQLVWUDWLYH SURYLVLRQV
QHFHVVDU\WRFRPSO\ZLWKWKLV'LUHFWLYHE\>PRQWKVDIWHUHQWU\LQWRIRUFH@DWWKHODWHVW7KH\
VKDOOFRPPXQLFDWHWRWKH&RPPLVVLRQWKHWH[WRIWKHSURYLVLRQVDQGFRUUHODWLRQWDEOHEHWZHHQ
WKRVHSURYLVLRQVDQGWKHSURYLVLRQVRIWKLV'LUHFWLYH
:KHQ0HPEHU6WDWHVDGRSWWKHVHSURYLVLRQVWKH\VKDOOFRQWDLQDUHIHUHQFHWRWKLV'LUHFWLYH
RU EH DFFRPSDQLHG E\ VXFK D UHIHUHQFH RQ WKH RFFDVLRQ RI WKHLU RIILFLDO SXEOLFDWLRQ7KH
0HPEHU6WDWHVVKDOOGHWHUPLQHKRZVXFKUHIHUHQFHLVWREHPDGH
Article 32
7KLV'LUHFWLYHVKDOOHQWHULQWRIRUFHRQWKHWZHQWLHWKGD\IROORZLQJWKDWRILWVSXEOLFDWLRQLQ
WKHOfficial Journal of the European Union
Article 33
7KLV'LUHFWLYHLVDGGUHVVHGWRWKH0HPEHU6WDWHV

2-/S


EN

EN
'RQHDW%UXVVHOV>«@
For the Commission
[…]
Member of the Commission










$33(1',;


%(+$9,25$/$1'&2*1,7,9(,03$,50(176&$/(6$1'7(676





















APPENDIX  8 




STUDY SUMMARY TABLE AND STUDY FLOW CHART

ŽŶĨŝĚĞŶƚŝĂů
3URWRFRO,*








3DJHRI
9HUVLRQ)HEUXDU\
9LVLW
6FUHHQLQJ
5DQGRP
L]DWLRQ
)3(
)3(
)3(
)3(
)3(
)3(
,9
/93
(
/93
(
/93
(
/93
(
/93
(
/93
(
/93
(
/93
(
/93
(
/93
(
/93
(
/93
(
)LQDO
7LPH:HHNV























:LQGRZ5DQJH
GD\V




















0RQWKV
















6WXG\6FKHGXOH
,QIRUPHG&RQVHQW
;





















,QFOXVLRQ([FOX
VLRQFULWHULD
;





















'HPRJUDSKLFGDWD
;





















0HGLFDO+LVWRU\
;

;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
3K\VLFDO
H[DPLQDWLRQ
;

;
;
;
;
;
;

;
;
;
;
;
;
;
;
;
;
;
;

(&*
;





















*HQHWLF0DUNHUV
;





















9LWDOVLJQV
;
%'
$
%'
$
%'
$
%'
$
%'
$
%'
$

%'
$
%'
$
%'
$
%'
$
%'
$
%'
$
%'
$
%'
$
%'
$
%'
$
%'
$
%'
$
$GYHUVH(YHQWV
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
&RQFRPLWDQW
0HGLFDWLRQ
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
&HQWUDOFDWKHWHU
LPSODQWDWLRQ
;




















&HQWUDOFDWKHWHU
H[WUDFWLRQ







;













3ODVPDSKHUHVLV
)3(
)3(
)3(
)3(
)3(
)3(
/93(
/93(
/93(
/93(
/93(
/93(
/93(
/93(
/93(
/93(
/93(
/93(
$OEXPLQ


PONJ


PONJ


PONJ


PONJ


PONJ


PONJ














VWDQGQG$UP
$OEXPLQ










P
/


P/


P/



P/


P/


P/


P
/


P/

P
/
VWDQGQG$UP
,J,9








J
J



J
J



J
J




UG$UP
$OEXPLQ







P/

P/

P/

P/

P/

P/

P/

P/

P/

P/

P/

P/

ŽŶĨŝĚĞŶƚŝĂů
3URWRFRO,*








3DJHRI
9HUVLRQ)HEUXDU\
9LVLW
6FUHHQLQJ
5DQGRP
L]DWLRQ
)3(
)3(
)3(
)3(
)3(
)3(
,9
/93
(
/93
(
/93
(
/93
(
/93
(
/93
(
/93
(
/93
(
/93
(
/93
(
/93
(
/93
(
)LQDO
7LPH:HHNV























:LQGRZ5DQJH
GD\V




















0RQWKV
















6WXG\6FKHGXOH
1HXURSV\FKR
ORJLDO7HVWV$
;
2
2
2
2
2
2
;
2
2
2
;
2
2
;
2
2
;
2
2
;
/XPEDU3XQFWXUH
;






;












;
$'%LRPDUNHUV%
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
/DERUDWRU\7HVWV&
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
;
1HXURLPDJLQJ
05,
;






;



;


;





;
)'*3(7
;






;






;





;
)3()XOO3ODVPD([FKDQJH
/93(/RZ9ROXPH3ODVPD
([FKDQJH
;0DQGDWRU\IRUDOOJURXSV7UHDWPHQW
*URXSDQG6KDP*URXS
%%HIRUH
''XULQJ
$$IWHU
2$%6	2$6MXVWLILW¶VQHFHVVDU\
,9,QWHUPHGLDWH9LVLW
$6HHVHSDUDWHEUHDNRXWRI1HXURSV\FKRORJLDO7HVWV
%6HHVHSDUDWHEUHDNRXWRI$'%LRPDUNHUV
&6HHVHSDUDWHEUHDNRXWRI/DERUDWRU\7HVWV









ŽŶĨŝĚĞŶƚŝĂů
3URWRFRO,*








3DJHRI
9HUVLRQ)HEUXDU\
9LVLW
6FUHHQLQJ
5DQGRPL
]DWLRQ
)3(

)3(

)3(

)3(

)3(

)3(

,9
/93
(
/93
(
/93
(
/93
(
/93
(
/93
(
/93
(
/93
(
/93
(
/93
(
/93
(
/93
(
)LQDO
7LPH:HHNV























:LQGRZ5DQJH
GD\V




















0RQWKV
















1HXURSV\FKRORJLDO7HVWV
$'$6&RJ
;






;



;


;


;


;
006(
;






;



;


;


;


;
136EDWWHU\
;






;



;


;


;


;
$'&6$'/
;






;



;


;


;


;
13,
;






;



;


;


;


;
&'56E
;






;



;


;


;


;
$'&6&*,&
;






;



;


;


;


;
&6''
;






;



;


;


;


;
&6656
;






;



;


;


;


;
4R/$'
;










;


;


;


;
58'/LWH
;










;


;


;


;
2$6
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
$%6
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
)3()XOO3ODVPD([FKDQJH
/93(/RZ9ROXPH3ODVPD([FKDQJH
;0DQGDWRU\IRUDOOJURXSV7UHDWPHQW
*URXSDQG6KDP*URXS
%%HIRUH
''XULQJ
$$IWHU
2-XVWLILW¶VQHFHVVDU\
,9,QWHUPHGLDWH9LVLW





ŽŶĨŝĚĞŶƚŝĂů
3URWRFRO,*








3DJHRI
9HUVLRQ)HEUXDU\
9LVLW
6FUHHQLQJ
5DQGRPL
]DWLRQ
)3(

)3(

)3(

)3(

)3(

)3(

,9
/93
(
/93
(
/93
(
/93
(
/93
(
/93
(
/93
(
/93
(
/93
(
/93
(
/93
(
/93
(
)LQDO
7LPH:HHNV























:LQGRZ5DQJH
GD\V




















0RQWKV
















$'%LRPDUNHUV
&6)$ȕ
;






;












;
&6)$ȕ
;






;












;
&6)77DX
;






;












;
&6)37DX
;






;












;
&6)ȕVHFUHWDVH
;






;












;
&6)ȖVHFUHWDVH
;






;












;
&6)FKROHVWHURO
;






;












;
&6)/'/
;






;












;
&6)+'/
;






;












;
&6)9/'/
;






;












;
&6)&53
;






;












;
&6)5KHXPDWRLG
IDFWRU
;






;












;
&6),/E
;






;












;
&6),/
;






;












;
&6))HUULWLQ
;






;












;
&6)71)Į
;






;












;
&6)&HOOFRXQWV
;






;












;
&6)*OXFRVD
;






;












;
&6)3URWHLQV
;






;












;
&6)$OEXPLQ
;






;












;

ŽŶĨŝĚĞŶƚŝĂů
3URWRFRO,*








3DJHRI
9HUVLRQ)HEUXDU\
9LVLW
6FUHHQLQJ
5DQGRPL
]DWLRQ
)3(

)3(

)3(

)3(

)3(

)3(

,9
/93
(
/93
(
/93
(
/93
(
/93
(
/93
(
/93
(
/93
(
/93
(
/93
(
/93
(
/93
(
)LQDO
7LPH:HHNV























:LQGRZ5DQJH
GD\V




















0RQWKV
















$'%LRPDUNHUV
3ODVPD$ȕ
;
%$
%$
%$
%$
%$
%$
;
%$
%$
%$
%$
%$
%$
%$
%$
%$
%$
%$
%$
;
3ODVPD$ȕ
;
%$
%$
%$
%$
%$
%$
;
%$
%$
%$
%$
%$
%$
%$
%$
%$
%$
%$
%$
;
3ODVPDȕ
VHFUHWDVH
;
%$
%$
%$
%$
%$
%$
;
%$
%$
%$
%$
%$
%$
%$
%$
%$
%$
%$
%$
;
3ODVPDȖVHFUHWDVH
;
%$
%$
%$
%$
%$
%$
;
%$
%$
%$
%$
%$
%$
%$
%$
%$
%$
%$
%$
;
3ODVPDFKROHVWHURO
;
%$
%$
%$
%$
%$
%$
;
%$
%$
%$
%$
%$
%$
%$
%$
%$
%$
%$
%$
;
3ODVPD/'/
;
%$
%$
%$
%$
%$
%$
;
%$
%$
%$
%$
%$
%$
%$
%$
%$
%$
%$
%$
;
3ODVPD+'/
;
%$
%$
%$
%$
%$
%$
;
%$
%$
%$
%$
%$
%$
%$
%$
%$
%$
%$
%$
;
3ODVPD9/'/
;
%$
%$
%$
%$
%$
%$
;
%$
%$
%$
%$
%$
%$
%$
%$
%$
%$
%$
%$
;
3ODVPD&53
;
%$
%$
%$
%$
%$
%$
;
%$
%$
%$
%$
%$
%$
%$
%$
%$
%$
%$
%$
;
3ODVPD
5KHXPDWRLGIDFWRU
;
%$
%$
%$
%$
%$
%$
;
%$
%$
%$
%$
%$
%$
%$
%$
%$
%$
%$
%$
;
3ODVPD,/E
;
%$
%$
%$
%$
%$
%$
;
%$
%$
%$
%$
%$
%$
%$
%$
%$
%$
%$
%$
;
3ODVPD,/
;
%$
%$
%$
%$
%$
%$
;
%$
%$
%$
%$
%$
%$
%$
%$
%$
%$
%$
%$
;
3ODVPD)HUULWLQ
;
%$
%$
%$
%$
%$
%$
;
%$
%$
%$
%$
%$
%$
%$
%$
%$
%$
%$
%$
;
3ODVPD71)Į
;
%$
%$
%$
%$
%$
%$
;
%$
%$
%$
%$
%$
%$
%$
%$
%$
%$
%$
%$
;
3ODVPD6DPSOH
&ROOHFWLRQ
;
%$
%$
%$
%$
%$
%$
;
%$
%$
%$
%$
%$
%$
%$
%$
%$
%$
%$
%$
;
)3()XOO3ODVPD([FKDQJH
/93(/RZ9ROXPH3ODVPD([FKDQJH
;0DQGDWRU\IRUDOOJURXSV7UHDWPHQW
*URXSDQG6KDP*URXS
%%HIRUH
''XULQJ
$$IWHU
2-XVWLILW¶VQHFHVVDU\
,9,QWHUPHGLDWH9LVLW

ŽŶĨŝĚĞŶƚŝĂů
3URWRFRO,*








3DJHRI
9HUVLRQ)HEUXDU\
9LVLW
6FUHHQLQJ
5DQGRPL
]DWLRQ
)3(

)3(

)3(

)3(

)3(

)3(

,9
/93
(
/93
(
/93
(
/93
(
/93
(
/93
(
/93
(
/93
(
/93
(
/93
(
/93
(
/93
(
)LQDO
7LPH:HHNV























:LQGRZ5DQJH
GD\V




















0RQWKV
















/DERUDWRU\7HVWV
%ORRGFHOOFRXQWV
;
%$
%$
%$
%$
%$
%$
%
%
%
%
%
%
%
%
%
%
%
%
;
3ODWHOHWFRXQWV
;
%$
%$
%$
%$
%$
%$
%
%
%
%
%
%
%
%
%
%
%
%
;
3URWKURPELQWLPH
4XLFN
;
%$
%$
%$
%$
%$
%$

%;

$2
%;

$2
%;

$2
%;

$2
%;

$2
%;

$2
%;

$2
%;

$2
%;

$2
%;

$2
%;

$2
%;

$2
;
D377
;
%$
%$
%$
%$
%$
%$
%;

$2
%;

$2
%;

$2
%;

$2
%;

$2
%;

$2
%;

$2
%;

$2
%;

$2
%;

$2
%;

$2
%;

$2
;
)LEULQRJHQ
;
%$
%$
%$
%$
%$
%$
%
%
%
%
%
%
%
%
%
%
%
%
;
3URWHLQRJUDP
;
%$
%$
%$
%$
%$
%$
;
%
%
%
%
%
%
%
%
%
%
%
%
;
3ODVPD,J*
;
%$
%$
%$
%$
%$
%$
;
%;

$2
%;

$2
%;

$2
%;

$2
%;

$2
%;

$2
%;

$2
%;

$2
%;

$2
%;

$2
%;

$2
%;

$2
;
&DOFLXP
;
%$
%$
%$
%$
%$
%$

%;

$2
%;

$2
%;

$2
%;

$2
%;

$2
%;

$2
%;

$2
%;

$2
%;

$2
%;

$2
%;

$2
%;

$2
;
$67
;
$
$
$
$
$
$













;
$/7
;
$
$
$
$
$
$













;
%LOLUXELQ
;



















;
/'+
;
$
$
$
$
$
$













;
&UHDWLQLQH
;
$
$
$
$
$
$













;
7URSRQLQ
;
$
$
$
$
$
$













;
$QWL+,9
;



















;
+&9DQWLERGLHV
;



















;
+%V9$J
;



















;
)3()XOO3ODVPD
([FKDQJH
/93(/RZ9ROXPH3ODVPD
([FKDQJH
;0DQGDWRU\IRUDOOJURXSV7UHDWPHQW*URXS
DQG6KDP*URXS
%
%HIR
UH
''XULQJ
$$IWHU
2-XVWLILW¶VQHFHVVDU\
,9,QWHUPHGLDWH9LVLW
7URSRQLQZLOOEHDVVHVVHGLQDFHQWUDOODERUDWRU\

)3(ZHHN $
3URWRW\SH$XWR&)HQZDO  /93(PRQWK
)
$
$
$
)
$
$ $
)
$
$ $
)9
$J
)J
&RQILGHQWLDO
$J
$
$
$
$ $
$
$ $ $
$ $ $
)9
$ J
)J
)3( )3( )3( )3( )3( )3( ,9
%
)
$
$
$
)
$
$ $
)
$ $ $
)9















6KDP
6LPXODWHG
WUHDWPHQW
)9
6
%
,9
6
6
0RQWKV
)3()XOO3ODVPD([FKDQJH
$'%LRPDUNHUV

)'*3(7
/93(/RZ9ROXPH3ODVPD([FKDQJH


1HXURSV\FKRORJLFDO7HVWV
))OHERJDPPD',))L[HGGRVH

05,
$$OEXWHLQ:HLJKWGHSHQGHQWGRVH

/XPEDU3XQFWXUH
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6





















APPENDIX  9 




SHAM MANUAL GUIDELINE


9HUVLRQWK'HF
6KDP0DQXDO



&RQILGHQWLDO
RI
,*&OLQLFDO7ULDO6KDP3URFHGXUH,QVWUXFWLRQV
9HU\LPSRUWDQWWKLVPDQXDOPXVWEHDFFRPSDQLHGE\D'9'ZLWKWKH
YLGHRV VKRZLQJ WKH SURFHGXUHV GHVFULEHG LQ LW 3OHDVH UHIHU WR WKRVH
YLGHRVWRYLVXDOO\IROORZWKHGHWDLOVDFFRUGLQJWRWKHLQGLFDWLRQVJLYHQLQ
WKHVHLQVWUXFWLRQV
,I\RXDUHWRXVHDSHULSKHUDOFDWKHWHUIRU)XOO3ODVPD([FKDQJH)3(
\RXZLOOUHFHLYHD'9'ZLWKVKRUWYLGHRVIRUWKHVKDPSURFHGXUHV
 6KDPSURFHGXUHV)3($OEXWHLQSHULSKHUDODFFHVV
 6KDP SURFHGXUHV /RZ 9ROXPH 3ODVPD ([FKDQJH /93( 
$OEXWHLQ
 6KDPSURFHGXUHV/93()OHERJDPPD',)
,I\RXDUHWRXVHDFHQWUDOFDWKHWHUIRU)3(\RXZLOOUHFHLYHD'9'ZLWK
VKRUWYLGHRV
 6LPXODWHGMXJXODUFHQWUDOFDWKHWHULPSODQWDWLRQ
 6KDPSURFHGXUHV)3($OEXWHLQFHQWUDODFFHVV
 6KDP SURFHGXUHV /RZ 9ROXPH 3ODVPD ([FKDQJH /93( 
$OEXWHLQ
 6KDPSURFHGXUHV/93()OHERJDPPD',)



9HUVLRQWK'HF
6KDP0DQXDO



&RQILGHQWLDO
RI
,QWURGXFWLRQ
$ VKDP SURFHGXUH ZLOO EH XVHG LQ WKH FRQWURO JURXS RI WKH PXOWLFHQWHU UDQGRPL]HG
FRQWUROOHG VWXG\ ,* WR HYDOXDWH WKH HIILFDF\ DQG VDIHW\ RI VKRUWWHUP SODVPD
H[FKDQJH IROORZHG E\ ORQJWHUP SODVPDSKHUHVLV ZLWK LQIXVLRQ RI KXPDQ DOEXPLQ
FRPELQHG ZLWK LQWUDYHQRXV LPPXQRJOREXOLQ ,9,* LQ SDWLHQWV ZLWK PLOGPRGHUDWH
$O]KHLPHU¶VGLVHDVH7KHVKDPSURFHGXUHZLOOEHDSSOLHGWRERWKIXOOSODVPDH[FKDQJH
DQGORZYROXPHSODVPDH[FKDQJHSHULRGV
•
)XOOSODVPDH[FKDQJH)3(SHULRGRQHPRQWKDQGKDOIZHHNVZLWKRQHIXOO
SODVPDH[FKDQJHSHUZHHN
•
/RZYROXPHSODVPDH[FKDQJH/93(SHULRGRQHORZYROXPHSODVPDH[FKDQJH
SHUPRQWKIRUPRQWKV
7KHVWXG\JURXSVZLOOEHGLYLGHGLQWRDUPVWUHDWPHQWDUPVDQGFRQWUROVKDPDUP
7KHWUHDWPHQWDUPVFRQVLVWRIDUPVWKDWFRPELQHSODVPDSKHUHVLVWRJHWKHUZLWKDOEXPLQ
DQG ,9,* DGPLQLVWUDWLRQ LQ  GLIIHUHQW GRVHV 7KH WKLUG WUHDWPHQW DUP ZLOO UHFHLYH
SODVPDSKHUHVLV ZLWK DOEXPLQ RQO\ LQIXVLRQV VHH SURWRFRO VHFWLRQ  IRU GRVLQJ DQG
VFKHGXOLQJGHWDLOV
7KHSXUSRVHRIWKHVKDPSURFHGXUHLVWRPLPLFWKRVHWZRW\SHVRISODVPDSKHUHVHV)3(
DQG/93(EXWZLWKQHLWKHUIOXLGH[FKDQJHQRUDOEXPLQRU,9,*DGPLQLVWUDWLRQ
7KHIROORZLQJLQVWUXFWLRQVGHVFULEHKRZWRSURFHHGZLWKWKHVKDPSURFHGXUHLQWKHWZR
GLIIHUHQWH[FKDQJHSHULRGV$VDJHQHUDOUHPLQGHUWKHFRQWUROVKDPJURXSZLOOXQGHUJR
VLPXODWHG SODVPD H[FKDQJHV XQGHU VLPLODU FRQGLWLRQV DV WKH SDWLHQWV LQ WKH WUHDWPHQW
JURXSV ,W LV LPSRUWDQW WR PDNH WKH VKDP SURFHGXUH ORRN DV µUHDO¶ DV SRVVLEOH IRU WKH
EHQHILWRIWKHSDWLHQWV
3DWLHQWVXQGHUJRLQJDFWXDODQGVKDPSURFHGXUHVPXVWQRWFRLQFLGHLQWKHVDPHWUHDWPHQW
IDFLOLW\ DW WKH VDPH WLPH 7KDW LV LI WKHUH LV PRUH WKDQ RQH SDWLHQW VFKHGXOHG IRU DQ
H[FKDQJHVHVVLRQRQO\WUHDWPHQWSDWLHQWVRURQO\FRQWUROVKDPSDWLHQWVPXVWFRLQFLGH
7KLV FDQ EH DFKLHYHG IRU LQVWDQFH E\ VFKHGXOLQJ WUHDWPHQW DQG FRQWURO SDWLHQWV LQ


9HUVLRQWK'HF
6KDP0DQXDO



&RQILGHQWLDO
RI
GLIIHUHQWGD\V$WWKHVDPHWLPHIDPLO\PHPEHUVDQGFDUHJLYHUVZLOOQRWEHDOORZHGWR
HQWHUDQGDFFRPSDQ\WKHSDWLHQWGXULQJWKHSURFHGXUHIRUERWKWKHWUHDWPHQWDQGFRQWURO
VKDPJURXSV([FHSWLRQDOO\DJLWDWHGSDWLHQWVFRXOGEHDFFRPSDQLHGE\WKHFDUHJLYHU
GXULQJWKHSURFHGXUHWRHDVHSDWLHQW¶VDQ[LHW\,QWKLVFDVHLWLVPDQGDWRU\WKHVXEMHFWWRE
VFKHGXOHGIRUWKHWUHDWPHQWDGLIIHUHQWGD\WKDQWKHUHVWRIWKHSDWLHQWV
 &HQWUDO&DWKHWHU,PSODQWDWLRQ
,I\RXDUHWRSHUIRUP)3(WKURXJKDSHULSKHUDOFDWKHWHUSOHDVHJRGLUHFWO\WRVHFWLRQ
)XOO3ODVPD([FKDQJH3URFHGXUH
,I\RXDUHWRSHUIRUP)3(WKURXJKDFHQWUDOFDWKHWHUSOHDVHIROORZWKLVVHFWLRQ
%HIRUH WKH ILUVW VKDP )3( UHSODFHPHQW VHVVLRQ D VLPXODWHG LPSODQWDWLRQ RI D FHQWUDO
FDWKHWHU ZLOO EH SHUIRUPHG 3OHDVH DOVR ZDWFK WKH YLGHR HQWLWOHG ³6LPXODWHG MXJXODU
FHQWUDOFDWKHWHULPSODQWDWLRQ´

6SHFLILFPDWHULDOV

&DWKHWHUFKDUDFWHULVWLFV
$ GRXEOH OXPHQ FHQWUDO FDWKHWHU W\SH
(YHQPRUH IURP $QJLRG\QDPLFV ZLWK
)U)U PPDQGVXUJLFDO
ZLQJVMRLQHGWRWKHFDWKHWHUZLOOEHXVHG
)LJXUH  7KH FDWKHWHU ZLOO EH FXW IRU
WKH VKDP SURFHGXUH VHH ,PSODQWDWLRQ
EHORZ
$WFOLQLFDOVLWHVZKHUHDGLIIHUHQWW\SHRI
GRXEOH OXPHQ FDWKHWHU LV XVHG IRU WKH
DFWXDO SURFHGXUH WKH VDPH W\SH RI
FDWKHWHUFDQEHXVHGIRUWKHVKDPSURFHGXUHLIWKHVXUJLFDOZLQJVDUHDOVRMRLQHGWRWKH
FDWKHWHU
)LJXUH&DWKHWHUZLWKVXUJLFDOZLQJVMRLQHG


9HUVLRQWK'HF
6KDP0DQXDO



&RQILGHQWLDO
RI

5RXQGK\GURFROORLGSDWFKFKDUDFWHULVWLFV
$XURVWRP\EDJK\GURFROORLGSDWFK$VVXUD
SLHFH SHGLDWULF XURVWRP\ FOHDU EDJ 
PP SURGXFW UHIHUHQFH  IURP WKH
FRPSDQ\ &RORSODVW /WG ZLOO EH XVHG WR
DWWDFKLWWRWKHFDWKHWHU)LJXUH7KHSDWFK
ZLOODFWDVDNLQGRI³VHFRQGVNLQ´DQGWKH
FXWFDWKHWHUZLOOEHVWLWFKHGWRWKHSDWFKQRW
WRWKHVNLQ7KHSDWFKLVQRUPDOO\ERXQGWR
WKHXURVWRP\EDJVRLWZLOOQHHGWREHFXWLQ
RUGHUWRIUHHWKHURXQGK\GURFROORLGSDWFK

$GKHVLYHJDX]HGUHVVLQJFKDUDFWHULVWLFV
([WHUQDO DGKHVLYH JDX]HV W\SH 0HSRUH IURP WKH FRPSDQ\ 0|OQO\FNH +HDOWK &DUH D
ZDWHUEDVHGSRO\DFU\ODWHDGKHVLYHVL]H[FP[LQZLOOEHXVHG

6XUJLFDOVLONFKDUDFWHULVWLFV
6XUJLFDOVLONZLWKFXUYHGVXWXUHQHHGOHVL]HZLOOEHXVHG

,PSODQWDWLRQSURFHGXUH
3DWLHQWVZLOOEHVHQWWRWKHVXUJLFDODUHDIROORZLQJWKHVWDQGDUGSURFHGXUHDWHDFKVLWH
LQFOXGLQJWKHSUHPHGLFDWLRQXVHGDWHDFKVLWHIRUWKHUHDOSURFHGXUH

&HQWUDOFDWKHWHUDVVHPEO\WRK\GURFROORLGSDWFK
)LUVWFXWWKHK\GURFROORLGSDWFKIURPWKHXURVWRP\EDJDQGWKHQGLVFDUGWKHEDJ)LJXUH

1H[WDEHYHOFXWZLOOEHPDGHWRWKHFDWKHWHUWRDYRLGLWVLQVHUWLRQLQWRWKHSDWLHQW¶V
VNLQULJKWEHIRUHWKHSRO\HVWHUFXII)LJXUH
)LJXUH8URVWRP\EDJZLWKK\GURFROORLGSDWFK


9HUVLRQWK'HF
6KDP0DQXDO



&RQILGHQWLDO
RI
)LJXUH5HYHUVHVLGHRIVLPXODWHGFHQWUDOFDWKHWHU
)LJXUH)URQWVLGHRIVLPXODWHGFHQWUDOFDWKHWHU
7KH FXW FDWKHWHU ZLOO EH LQWURGXFHG DFURVV WKH FHQWUDO KROH RI WKH URXQG K\GURFROORLG
SDWFKDOORZLQJWKHGLVWDOSDUWRIWKHFDWKHWHUWRUHPDLQVOLJKWO\XQGHUWKHSDWFKEHWZHHQ
WKHSDWFKDQGWKHVNLQ7KHQWKHFDWKHWHUZLOOEHVHFXUHGWRWKHK\GURFROORLGSDWFKZLWK
VXUJLFDOVLONVWLWFKHVRQERWKVLGHVRIK\GURFROORLGSDWFKWZRVWLWFKHVDWWKHERWWRP
EDVHZKHUHWKHDUWHULDODQGYHQRXVFRQQHFWLRQMRLQVLQHDFKRIWKHVXUJLFDOZLQJVIL[LQJ
WKH FDWKHWHU RQWR WKH IURQW VLGH RI WKH K\GURFROORLG SDWFK )LJXUH  DQG WZR PRUH
VWLWFKHVWRVHFXUHWKHGLVWDOSDUWRIWKHFDWKHWHUWRWKHFHQWUDOKROHRIWKHSDWFKIURPWKH
UHYHUVHVLGHRIK\GURFROORLGSDWFK)LJXUH
)LJXUH&XWWKHK\GURFROORLGSDWFKIURPWKHXURVWRP\EDJ
)LJXUH0DNHDEHYHOMXVWEHIRUHFDWKHWHU
VFXII


9HUVLRQWK'HF
6KDP0DQXDO



&RQILGHQWLDO
RI
)LJXUH6LPXODWHGFHQWUDOFDWKHWHUGUHVVLQJ

6LPXODWHGFDWKHWHULPSODQWDWLRQ
7KHDQDWRPLFDOMXJXODUUHJLRQZKHUHWKHVLPXODWHGFDWKHWHUVKRXOGEHLPSODQWHGZLOOEH
VKDYHGDQGFOHDQHGZLWKDVWDQGDUGDQWLVHSWLFSURFHGXUHFOHDQZLWKVDOLQHVROXWLRQDQG
DOFRKRO
:KHQWKHLPSODQWDWLRQUHJLRQLVFRPSOHWHO\GULHGWKHK\GURFROORLGSDWFKDVVHPEOHGWR
WKHFDWKHWHUZLOOEHDGKHUHGRQSDWLHQW¶VVNLQ
7RIXUWKHUVHFXUHWKHK\GURFROORLGSDWFKDSODVWLFVNLQGUHVVLQJVSUD\ZLOOEHDSSOLHGRQ
WKHLPSODQWDWLRQDUHD$IWHUWKDWDQDGKHVLYHJDX]HGUHVVLQJZLOOFRYHUWKHLPSODQWDWLRQ
DUHDLQWKHVDPHPDQQHUDVWKHDFWXDOFHQWUDOFDWKHWHUWRDYRLGYLVXDOFRQWDFWDQGSK\VLFDO
DFFHVVWRWKHFDWKHWHUDFFRUGLQJVWDQGDUGSURFHGXUHVRIHDFKFHQWHU)LJXUH7KHQ
FDWKHWHU/XHUORFNVZLOOEHSODFHGDQGWKHYLVLEOHSRUWLRQRIWKHGRXEOHFDWKHWHUZLOOEH
FRYHUHGZLWKDGKHVLYHJDX]H)LQDOO\JDX]HZLOOFRYHUWKHDSSDUHQWFDWKHWHU¶VLQVHUWLRQ
SRLQWLQWKHXSSHUSDUWRILPSODQWDWLRQDUHD
7KH SDWLHQW ZLOO EH LQVWUXFWHG QRW WR
UHPRYH WKH FDWKHWHU RU VFUDWFK WKH
VXUURXQGLQJ DUHD DQG KRZ WR SURFHHG
LQFDVHDQDGYHUVHHYHQWUHODWHGWRWKH
FDWKHWHURFFXUV

5HPRYDORIVLPXODWHGFDWKHWHU¶VLQVHUWLRQSRLQW
,QWKHDFWXDOSURFHGXUHRIFDWKHWHULPSODQWDWLRQWZRVWLWFKHVDUHSODFHGLQWKHFDWKHWHU
LQVHUWLRQSRLQWWRFORVHWKHZRXQGDQGWKHDUHDLVFRYHUHGZLWKJDX]H$IWHUZHHNV
WKHVHVWLWFKHVDUHWREHUHPRYHGDQGWKHDUHDZLOOEHYLVLEOH


9HUVLRQWK'HF
6KDP0DQXDO



&RQILGHQWLDO
RI
,QERWKWKHWUHDWHGJURXSDQGWKHFRQWUROVKDPJURXSVRPHSUHFDXWLRQVZLOOEHWDNHQWR
DVVXUH WKDW WKH UDWHU PDLQWDLQV KLVKHU EOLQG GXULQJ WKH VXEVHTXHQW QHXURSV\FKRORJLFDO
WHVWV
7KHUHIRUHIROORZLQJWKHDFWXDOSURFHGXUHVZHHNVDIWHUWKHFDWKHWHULPSODQWDWLRQLQ
WUHDWHGJURXSVWKHVWLWFKHVZLOOEHUHPRYHGEXWRQHH[WUDVWHSZLOOEHQHHGHG,RGLQH
VROXWLRQZLOOEHDSSO\DURXQGWKHLQVHUWLRQSRLQWDQGZUDSSHGZLWKJDX]HRUSODVWHUIRU
WKHOHQJWKRIZHHNV,WFDQEHUHPRYHGEHIRUHWKHQH[W)3(
7RPLPLFWKLVVLWXDWLRQLQWKHFRQWUROVKDPSDWLHQWVDWWKHVDPHWLPHZLWKRXWDFWXDOO\
DGGLQJ DQ\ VWLWFKHV LWDOVR LV UHFRPPHQGHG WR DSSO\ VRPH LRGLQHVROXWLRQ DURXQG WKH
DSSDUHQWFDWKHWHU¶VLQVHUWLRQSRLQWDQGZUDSLWZLWKJDX]HIRUZHHNVXQWLOWKHQH[W)3(
0HDQLQJDIWHUZHHNVPRUHWKHFHQWUDOFDWKHWHULQVHUWLRQZRXQGLVFRPSOHWHO\KHDOHG
DQGWKHDUHDLVXQFRYHUHGLQERWKJURXSV
 )XOOSODVPDH[FKDQJHSURFHGXUH
,I\RXDUHWRSHUIRUP)3(WKURXJKDSHULSKHUDOFDWKHWHUSOHDVHZDWFKWKHYLGHRHQWLWOHG
³6KDPSURFHGXUHV)3($OEXWHLQSHULSKHUDODFFHVV´,I\RXDUHWRSHUIRUP)3(
WKURXJK D FHQWUDO FDWKHWHU SOHDVH ZDWFK WKH YLGHR HQWLWOHG ³6KDP SURFHGXUHV )3( 
$OEXWHLQFHQWUDODFFHVV´
%HIRUH WKH SDWLHQW HQWHUV WKH WUHDWPHQW URRP VRPH SURFHGXUHV PXVW EH SUHSDUHG
EHIRUHKDQG
)LUVWWKHVDOLQHVROXWLRQZLWKLQWUDYHQRXVLURQ
)HRUEHWDGLQHXVHGDVDVKDPVROXWLRQZLOO
EHSUHSDUHG7RSUHSDUHLWRULQWUDYHQRXV
)HYLDOVGHSHQGLQJRQWKHFRPPHUFLDOEUDQG
ZLOO EH DGGHG WR WKH VDOLQH VROXWLRQ XQWLO D
GDUN DOPRVWEODFNFRORU VROXWLRQLV REWDLQHG
)LJXUH2WKHUZLVH EHWDGLQHVROXWLRQFDQ
EHXVHGWR JHWWKHEODFNFRORUVROXWLRQ7KLV )LJXUH 3UHSDUDWLRQ RIWKHVDOLQHVROXWLRQZLWK LQWUDYHQRXV
)HRUEHWDGLQH


9HUVLRQWK'HF
6KDP0DQXDO



&RQILGHQWLDO
RI
ZLOO JLYH D UHDOLVWLF SODVPDEORRG FRORU RQFH WKH VKDP VROXWLRQ LV SURFHVVHG E\ WKH
SODVPDSKHUHVLVGHYLFH
6HFRQG WKH SODVPDSKHUHVLV GHYLFH ZLOO EH
VHWXS DQG WKH SODVPDSKHUHVLV NLW ZLOO EH
LQVWDOOHG (DFK VLWH ZLOO SHUIRUP WKH VKDP
SURFHGXUH XVLQJ LWV VWDQGDUG )3( GHYLFH
7KHUHIRUHWKHVWDQGDUGSURFHGXUHRIHDFKVLWH
ZLOOJXLGHWKHVHWXSRIWKH)3(GHYLFH
7KLUGWKHVDOLQHVROXWLRQZLWKLQWUDYHQRXV)H
RU EHWDGLQH ZLOO EH FRQQHFWHG WR WKH
SODVPDSKHUHVLV NLW ,Q FDVH WKH WUHDWPHQW LV
GRQHLQDEHGWKHEDJZLOOEHSODFHGKLGGHQ
XQGHUWKHSDWLHQWEHGSLOORZ)LJXUH
7KHEHGZLOOEHLQFOLQHGDW ,QFDVHWKHWUHDWPHQWLVGRQHLQDFKDLUWKHEDJZLOOEH
SODFHGKLGGHQKDQJLQJEHKLQGWKHGHYLFHDQGZLOOEHFRYHUHGZLWKD FORWKWRDYRLGDQ\
YLVXDOFRQWDFW
$WWKLVSRLQWWKHSDWLHQWZLOOHQWHUWKHURRPIDPLO\PHPEHUVDQGFDUHJLYHUVPXVWUHPDLQ
RXWVLGHRIWKHURRP'XULQJWKHVKDPSURFHGXUHEORRGVDPSOHVH[WUDFWLRQZLOOEHUHDO
DQGZLOOEHSHUIRUPHGDFFRUGLQJWRWKH /DE 0DQXDO$QDFWXDOSHULSKHUDOYHQRXVOLQH
LPSODQWDWLRQ ZLOO EH UHTXLUHG VLQFH EORRG VDPSOHV DOVR ZLOO EH QHHGHG SUH DQG SRVW
SODVPDSKHUHVLV 9LWDO VLJQV KHDUW UDWH
EORRGSUHVVXUHERG\WHPSHUDWXUHZLOOEH
PHDVXUHG  PLQXWHV EHIRUH GXULQJ
DQG

PLQXWHV
DIWHU
WKH
SODVPDSKHUHVLVSURFHGXUH
,Q FDVH WKH VKDP SURFHGXUH IRU )3( LV
SHUIRUPHG E\ XVLQJ D FHQWUDO FDWKHWHU LW
)LJXUH3ODFHWKHVDOLQHVROXWLRQZLWKLQWUDYHQRXV)HRU
EHWDGLQHKLGGHQXQGHUWKHSLOORZ
)LJXUH6KDP)3(XQGHUVWHULOHFRQGLWLRQV


9HUVLRQWK'HF
6KDP0DQXDO



&RQILGHQWLDO
RI
)LJXUH6KDPFRQQHFWLRQWRSHULSKHUDOYHQRXVOLQH
UHTXLUHVWKHXVHRIDVLPXODWHGFHQWUDOFDWKHWHUDVGHVFULEHGLQVHFWLRQXQGHUVWHULOH
FRQGLWLRQV)LJXUH7KHUHIRUHWKHQXUVHZLOOEHGUHVVHGZLWKDSSURSULDWHFORWKLQJ
DQG ZLOO ZRUN WR PDLQWDLQ D VWHULOH HQYLURQPHQW IRU H[DPSOH FOHDQLQJ WKH VLPXODWHG
FHQWUDOFDWKHWHU

6KDPFRQQHFWLRQWRSHULSKHUDOYHQRXVOLQH
,I\RXDUHWRSHUIRUP)3(WKURXJKDSHULSKHUDOFDWKHWHUSOHDVHIROORZWKLVVHFWLRQ,I\RX
DUHWRSHUIRUP)3(WKURXJKDFHQWUDOFDWKHWHUSOHDVHIROORZVHFWLRQ6KDPFRQQHFWLRQ
WRVLPXODWHGFHQWUDOFDWKHWHU
&RQWUROVKDPSDWLHQWVZLOODSSHDUWREHFRQQHFWHGWRWKH)3(GHYLFH7RVLPXODWHWKH
FRQQHFWLRQ WKH SODVPDSKHUHVLV NLW WXELQJ IURP WKH GHYLFH ZLOO EH SODFHG QH[W WR WKH
SHULSKHUDOYHQRXVOLQH7KHSODVPDSKHUHVLVNLWWXELQJZLOOEHVHFXUHGRQWRWKHSDWLHQW¶V
VNLQZLWKVXUJLFDOWDSHDQGWKHQFRYHUHGZLWKDVWHULOHFORWKWRDYRLGDQ\YLVXDOFRQWDFW
IURPWKHSDWLHQW)LJXUH
3DWLHQWVZLOOEHWROGWKDWVXFKPHDVXUHVDUHQHHGHGWRDYRLGOLQHFRQWDPLQDWLRQ'XULQJ
WKHVLPXODWHGFRQQHFWLRQWKHSDWLHQWVZLOOEHLQVWUXFWHGWRWXUQWKHLUKHDGLQWKHRSSRVLWH
GLUHFWLRQDQGLWZLOOEHFRYHUHGZLWKDVWHULOHFORWK


9HUVLRQWK'HF
6KDP0DQXDO



&RQILGHQWLDO
RI

6KDPFRQQHFWLRQWRVLPXODWHGFHQWUDOFDWKHWHU
,I\RXDUHWRSHUIRUP)3(WKURXJKDFHQWUDOFDWKHWHUSOHDVHIROORZWKLVVHFWLRQ,I\RXDUH
WRSHUIRUP)3(WKURXJKDSHULSKHUDOFDWKHWHUSOHDVHIROORZVHFWLRQ6KDPFRQQHFWLRQ
WRVLPXODWHGSHULSKHUDOYHQRXVOLQH
&RQWUROVKDPSDWLHQWVZLOODSSHDUWREHFRQQHFWHGWRWKH)3(GHYLFH7RVLPXODWHWKH
FRQQHFWLRQ WKH SODVPDSKHUHVLV NLW WXELQJ IURP WKH GHYLFH ZLOO EH SODFHG QH[W WR WKH
YLVLEOHSRUWLRQRIVLPXODWHGFHQWUDOFDWKHWHUDQGZLOOEHVHFXUHGXVLQJVXUJLFDOWDSHWRWKH
VLPXODWHGFHQWUDOFDWKHWHUDQGFRYHUHGZLWKDJDX]H
7KHVKDPFRQQHFWLRQWKHQZLOOEHFRYHUHGE\DVWHULOHFORWKWRDYRLGDQ\YLVXDOFRQWDFW
IURPWKHSDWLHQW3DWLHQWVZLOOEHWROGWKDWVXFKPHDVXUHVDUHQHHGHGWRDYRLGFDWKHWHU
FRQWDPLQDWLRQ 'XULQJ WKH VLPXODWHG FRQQHFWLRQ WKH SDWLHQWV ZLOO EH LQVWUXFWHG WR WXUQ
WKHLUKHDGLQWKHRSSRVLWHGLUHFWLRQDQGLWZLOOEHFRYHUHGZLWKDVWHULOHFORWK

6KDPIXOOSODVPDH[FKDQJHSURFHGXUH
(DFKVLWHZLOOSHUIRUPWKHVKDPSURFHGXUHXVLQJLWVVWDQGDUG)3(GHYLFH,QDOOFDVHV
WZRERWWOHVRI$OEXWHLQZLOOEHSODFHGDWWKHWRSRIWKH)3(GHYLFHVDPHDVLQWKH
WUHDWPHQW JURXSV EXW QR DOEXPLQ LQIXVLRQ ZLOO EH FDUULHG RXW ,Q SDUDOOHO WKH VDOLQH
VROXWLRQZLWKLQWUDYHQRXVLURQRUEHWDGLQHZLOOEHFLUFXODWLQJLQDFORVHGFLUFXLWPDQQHU
WKURXJKWKHSODVPDSKHUHVLVNLWOLQH7KH)3(GHYLFHZLOOEHUXQQLQJIRUDSSUR[LPDWHO\
PLQXWHVZKLFKZLOOEHHQRXJKWLPHWRVLPXODWHWKHUHDOSURFHGXUHPLQXWHV
$IWHU VWRSSLQJ WKH )3( GHYLFH WKH GLVFRQQHFWLRQ IURP WKH SODVPDSKHUHVLV NLW ZLOO EH
VLPXODWHG$JDLQWKHVLPXODWLRQRIFDWKHWHUFOHDQLQJZLOOEHSHUIRUPHGDQGQHZFOHDQ
DGKHVLYH JDX]HV ZLOO EH SODFHG 7KH VWDII WKDW GLVFRQQHFWV WKHSDWLHQW IURP WKH GHYLFH
GRHVDQHYDOXDWLRQRIWKHFDWKHWHU¶VIDVWHQLQJ,IDQ\RIWKHVLGHVLVXQIDVWHQHGDSODVWLF
VNLQ GUHVVLQJ VSUD\ ZLOO EH DSSOLHG WR VHDO WKH VLGHV $IWHU WKDW DQ DGKHVLYH JDX]H
GUHVVLQJZLOOFRYHUWKHLPSODQWDWLRQDUHDLQWKHVDPHPDQQHUDVGHVFULEHGLQ
'XULQJ WKH VLPXODWHG GLVFRQQHFWLRQ WKH SDWLHQWV ZLOO EH LQVWUXFWHG DJDLQ WR WXUQ WKHLU
KHDGLQWKHRSSRVLWHGLUHFWLRQDQGLWZLOOEHFRYHUHGZLWKDVWHULOHFORWK


9HUVLRQWK'HF
6KDP0DQXDO



&RQILGHQWLDO
RI
3RVWSODVPDSKHUHVLVEORRGVDPSOHVZLOOEHREWDLQHGDQGWKHSHULSKHUDOYHQRXVOLQHZLOO
EHUHPRYHG9LWDOVLJQVZLOOEHPHDVXUHGRQFHDJDLQDQGWKHSDWLHQWZLOOEHOHWWRUHVW
DQGUHFRYHUIURPWKHSODVPDSKHUHVLVSURFHGXUHIRUDSSUR[LPDWHO\PLQXWHV
6RPHDGKHVLYHJDX]HGUHVVLQJVZLOOEHJLYHQWRWKHFDUHJLYHU7KH\ZLOOEHLQVWUXFWHG
WKDWLQFDVHWKHGUHVVLQJLVXQIDVWHQHGWKH\PXVWFRYHUWKHROGGUHVVLQJZLWKQHZDGKHVLYH
JDX]H7KHFDWKHWHUPXVWQRWEHPDQLSXODWHGHLWKHUWDNHQRIIXQGHUDQ\FLUFXPVWDQFHV
 /RZYROXPHSODVPDH[FKDQJH

/RZYROXPHSODVPDH[FKDQJHZLWK$OEXWHLQ
3OHDVHZDWFKWKHYLGHRHQWLWOHG³6KDPSURFHGXUHV/93($OEXWHLQ´
$SURWRW\SHGHYLFHEDVHGRQWKH$XWRSKHUHVLV&IURP)HQZDOZLOOEHXVHGIRUWKH/93(
LQDOOVLWHV
%HIRUH WKH SDWLHQW HQWHUV WKH WUHDWPHQW URRP VRPH SURFHGXUHV PXVW EH SUHSDUHG
EHIRUHKDQG
)LUVW WKH )HQZDO GHYLFH ZLOO EH VHWXS DQG FDOLEUDWHG WKH SODVPDSKHUHVLV NLW ZLOO EH
LQVWDOOHG DQG DQWLFRDJXODQW DQG DOEXPLQ ERWWOHV WZR ERWWOHV FRQQHFWHG WKURXJK D
)OHERVHWNLWIURP*ULIROVZLOOEHKDQJHGRQWRSRIWKHGHYLFH7KH)HQZDOGHYLFHZLOO
EH SURJUDPPHG E\ WKH QXUVH WR REWDLQ  P/ RI SODVPD DQG LQIXVH  P/ RI
UHSODFHPHQWIOXLG
6HFRQGKXPDQEORRGEDJVH[SLUHGRUZLWKQRQVWDQGDUGYROXPHZLOOEHXVHGDVVKDP
VROXWLRQ IRU WKLV SURFHGXUH ,Q VRPH FDVHV WKH EORRG EDJ IRU WKH VLPXODWLRQ ZLOO EH
SUHSDUHGE\GLVFDUGLQJWKHGRQDWLRQNLWFRXSOHGWRWKHEORRGEDJ$VSLNHZLOOEHLQVHUWHG
LQWR WKH EORRG EDJ 7KHQ WKH EORRG EDJ ZLOO EH FRQQHFWHG WR WKH SODVPDSKHUHVLV NLW
)LJXUH,QFDVHWKHWUHDWPHQWLVGRQHLQDEHGWKHEORRGEDJZLOOEHSODFHGKLGGHQ
XQGHUWKHVKHHW)LJXUHFRYHUHGZLWKWKHSDWLHQWEHGSLOORZDQGWKHEHGLQFOLQHGDW



9HUVLRQWK'HF
6KDP0DQXDO



&RQILGHQWLDO
RI
,Q FDVH WKH WUHDWPHQW LV GRQH LQ D FKDLU WKH EORRG EDJ ZLOO EH SODFHG KLGGHQ KDQJLQJ
EHKLQGWKHGHYLFHDQGFRYHUHGE\DJDX]H
$WWKLVSRLQWWKHSDWLHQWZLOOHQWHUWKHWUHDWPHQWURRPIDPLO\PHPEHUVDQGFDUHJLYHUV
PXVWUHPDLQRXWVLGHRIWKHURRP'XULQJWKHVKDPSURFHGXUHEORRGVDPSOHVH[WUDFWLRQ
ZLOOEHUHDODFFRUGLQJWRWKH/DE0DQXDO$QDFWXDOSHULSKHUDOYHQRXVOLQHLPSODQWDWLRQ
ZLOOEHUHTXLUHGVLQFHEORRGVDPSOHVZLOOEHDOVRQHHGHGSUHDQGSRVWSODVPDSKHUHVLV
9LWDOVLJQVKHDUWUDWHEORRGSUHVVXUHERG\WHPSHUDWXUHZLOOEHPHDVXUHGPLQXWHV
EHIRUHGXULQJDQGPLQXWHVDIWHUWKHSODVPDSKHUHVLVSURFHGXUH

6KDPFRQQHFWLRQWRSHULSKHUDOYHQRXVOLQH
&RQWUROVKDPSDWLHQWVZLOODSSHDUWREHFRQQHFWHGWRWKH)HQZDOGHYLFH7RVLPXODWHWKH
FRQQHFWLRQ WKH SODVPDSKHUHVLV NLW WXELQJ IURP WKH GHYLFH ZLOO EH SODFHG QH[W WR WKH
SHULSKHUDOYHQRXVOLQH7KHSODVPDSKHUHVLVNLWWXELQJZLOOEHVHFXUHGRQWRWKHSDWLHQW¶V
VNLQZLWKVXUJLFDOWDSHDQGWKHQFRYHUHGZLWKDVWHULOHFORWKWRDYRLGDQ\YLVXDOFRQWDFW
IURPWKHSDWLHQW)LJXUH3DWLHQWVZLOOEHWROGWKDWVXFKPHDVXUHVDUHQHHGHGWRDYRLG
OLQHFRQWDPLQDWLRQ'XULQJWKHVLPXODWHGFRQQHFWLRQWKHSDWLHQWVZLOOEHLQVWUXFWHGWRWXUQ
WKHLUKHDGLQWKHRSSRVLWHGLUHFWLRQDQGLWZLOOEHFRYHUHGZLWKDVWHULOHFORWK
)LJXUH%ORRGEDJKLGGHQXQGHUWKHSDWLHQWSLOORZ
)LJXUH%ORRGEDJFRQQHFWLRQWRWKHSODVPDSKHUHVLVNLW


9HUVLRQWK'HF
6KDP0DQXDO



&RQILGHQWLDO
RI

6KDPORZYROXPHSODVPDH[FKDQJHSURFHGXUHZLWKDOEXPLQ
7KH)HQZDO$XWRSKHUHVLV&SURWRW\SHZLOOSURYLGHDQDSSDUHQWO\DQGUHDOLVWLFZRUNLQJ
VWDWXVLQZKLFKKXPDQEORRGZLOOEHFLUFXODWLQJLQDFORVHGFLUFXLWPDQQHU(DFKVHVVLRQ
ZLOOODVWRQHF\FOHWKDWLVDSSUR[LPDWHO\PLQXWHVLQGXUDWLRQZKLFKZLOOEHHQRXJK
WLPHWRVLPXODWHWKHUHDOSURFHGXUHPLQXWHV
,QWKHFDVHRIWKHVKDP/93(ERWWOHVRI$OEXWHLQZLOOEHSODFHGDWWKHWRSRIWKH
)HQZDOGHYLFH$VGHILQHGE\WKHSURWRFRODWWKHHQGRIWKHDFWXDO/93(DOEXPLQZLOO
EH LQIXVHG LQ WKH WUHDWPHQW JURXSV )RU WKLV UHDVRQ LQ WKH FRQWURO VKDP JURXS DIWHU
VWRSSLQJWKH)HQZDOGHYLFHWKHDOEXPLQOLQHZLOOEHUHPRYHG7KLVZLOODOORZVLPSO\E\
JUDYLW\ WKHDOEXPLQ ERWWOHVWR HPSW\ DQG WKH OLTXLG ZLOO EH FROOHFWHG LQ WKH UHVHUYRLU
PDLQWDLQLQJWKHFORVHGFLUFXLWRIWKHZKROHSURFHGXUH)LJXUH
'LVFRQQHFWLRQ IURP WKH SODVPDSKHUHVLV NLW ZLOO EH VLPXODWHG )LJXUH  'XULQJ WKH
VLPXODWHG GLVFRQQHFWLRQ WKH SDWLHQWV DJDLQZLOO EH LQVWUXFWHGWR WXUQ WKHLU KHDG LQ WKH
RSSRVLWHGLUHFWLRQDQGLWZLOOEHFRYHUHGZLWKDVWHULOHFORWK
)LJXUH6KDPFRQQHFWLRQWRSHULSKHUDOYHQRXVOLQH


9HUVLRQWK'HF
6KDP0DQXDO



&RQILGHQWLDO
RI
3RVWSODVPDSKHUHVLVEORRGVDPSOHVZLOOEHREWDLQHGDQGWKHQWKHSHULSKHUDOYHQRXVOLQH
ZLOOEHUHPRYHG9LWDOVLJQVZLOOEHPHDVXUHGRQFHDJDLQDQGWKHSDWLHQWZLOOEHOHWWR
UHVWDQGUHFRYHUIURPWKHSODVPDSKHUHVLVSURFHGXUHIRUDSSUR[LPDWHO\PLQXWHV

/RZYROXPHSODVPDH[FKDQJHZLWK,9,*
3OHDVHZDWFKWKHYLGHRHQWLWOHG³6KDPSURFHGXUHV/93()OHERJDPPD',)´
7KH /93( ZLWK ,9,* LQIXVLRQ LV YHU\ VLPLODU WR WKH /93( ZLWK DOEXPLQ LQIXVLRQ
7KHUHIRUHWKHH[DFWVDPHVHWXSRIWKH)HQZDOGHYLFHDQGVLPXODWHGFRQQHFWLRQZLOOEH
XVHGDVLWZDVH[SODLQHGLQWKHVHFWLRQDERYH
7KHPDLQGLIIHUHQFHRFFXUVWKDWDIWHURQHUXQQLQJF\FOHRIWKH)HQZDOGHYLFHVRPHH[WUD
VWHSVZLOOEHDGGHGVLQFHDSHUIXVLRQSXPSLVQHHGHGWRLQIXVH,9,*

6KDPORZYROXPHSODVPDH[FKDQJHSURFHGXUHZLWK,9,*
)LUVW DIWHU VWRSSLQJ WKH )HQZDO GHYLFH WKH GLVFRQQHFWLRQ IURP WKH SODVPDSKHUHVLV NLW
ZLOOEHVLPXODWHG'XULQJWKHVLPXODWHGGLVFRQQHFWLRQWKHSDWLHQWVZLOOEHLQVWUXFWHGWR
WXUQWKHLUKHDGLQWKHRSSRVLWHGLUHFWLRQDQGLWZLOOEHFRYHUHGZLWKDVWHULOHFORWK
6HFRQGDPDVNHGVDOLQHVROXWLRQERWWOHRUEDJXVHGDVVKDP,9,*YLDOZLOOEHSODFHGDW
WKH WRS RI WKH ,9,* SHUIXVLRQ SXPS 7KH ,9,* SHUIXVLRQ SXPS ZLOO EH VHWXS DQG DQ
)LJXUH1RUHDOFRQQHFWLRQLVSHUIRUPHGLQVKDP/93(
)LJXUH6KDPDOEXPLQLQIXVLRQ


9HUVLRQWK'HF
6KDP0DQXDO



&RQILGHQWLDO
RI
)LJXUH6KDP,9,*SHUIXVLRQNLWFRQQHFWLRQWRSHULSKHUDOYHQRXVOLQH
HPSW\EDJZLOOEHFRQQHFWHGWRWKHSHUIXVLRQNLWWRFROOHFWWKHVDOLQHVROXWLRQFRPLQJRXW
IURPWKHSHUIXVLRQSXPS
7KLUGDVLPXODWHGFRQQHFWLRQRIWKH,9,*SHUIXVLRQSXPSWRWKHSHULSKHUDOYHQRXVOLQH
ZLOOEHSHUIRUPHG$VEHIRUHWKHSHUIXVLRQNLWWXELQJZLOOEHSODFHGQH[WWRSHULSKHUDO
YHQRXVOLQHDQGLWZLOOEHVHFXUHGZLWKVXUJLFDOWDSH$GGLWLRQDODGKHVLYHJDX]HZLOOEH
SODFHGDQGDVWHULOHFORWKZLOOFRYHUWKHSDWLHQW¶VDUP)LJXUH'XULQJWKHVLPXODWHG
FRQQHFWLRQWKHSDWLHQWVZLOOEHLQVWUXFWHGWRWXUQWKHLUKHDGLQWKHRSSRVLWHGLUHFWLRQDQG
LWZLOOEHFRYHUHGZLWKDVWHULOHFORWK
)RXUWK WKH ,9,* SHUIXVLRQ SXPS ZLOO EH SURJUDPPHG E\ WKHQXUVH WR SURFHHG ZLWK D
UHDOLVWLF ZRUNLQJ VWDWXV ZLWK WKH DSSURSULDWH UDWH IRU LQWUDYHQRXV LQIXVLRQ 7KH ,9,*
SHUIXVLRQSXPSZLOOEHUXQQLQJIRUDSSUR[LPDWHO\PLQXWHV
$IWHUVWRSSLQJWKH,9,*SHUIXVLRQSXPSWKHGLVFRQQHFWLRQIURPWKHSHUIXVLRQNLWZLOOEH
VLPXODWHG'XULQJWKHVLPXODWHGGLVFRQQHFWLRQWKHSDWLHQWVZLOOEHLQVWUXFWHGWRWXUQWKHLU
KHDGLQWKHRSSRVLWHGLUHFWLRQDQGLWZLOOEHFRYHUHGZLWKDVWHULOHFORWK
3RVWSODVPDSKHUHVLVEORRGVDPSOHVZLOOEHREWDLQHGDQGWKHQWKHSHULSKHUDOYHQRXVOLQH
ZLOOEHUHPRYHG9LWDOVLJQVZLOOEHPHDVXUHGRQFHDJDLQDQGWKHSDWLHQWZLOOEHOHWWR
UHVWDQGUHFRYHUIURPWKHSODVPDSKHUHVLVSURFHGXUHIRUDSSUR[LPDWHO\PLQXWHV


9HUVLRQWK'HF
6KDP0DQXDO



&RQILGHQWLDO
RI
9HU\ LPSRUWDQW WKLV PDQXDO PXVW EH DFFRPSDQLHG E\ D
'9' ZLWK WKHYLGHRV VKRZLQJ WKH SURFHGXUHV GHVFULEHG LQ
LW3OHDVHUHIHUWRWKRVHYLGHRVWRYLVXDOO\IROORZWKHGHWDLOV
DFFRUGLQJWRWKHLQGLFDWLRQVJLYHQLQWKHVHLQVWUXFWLRQV
,I\RXDUHWRXVHDSHULSKHUDOFDWKHWHUIRU)XOO3ODVPD([FKDQJH)3(
\RXZLOOUHFHLYHD'9'ZLWKVKRUWYLGHRVIRUWKHVKDPSURFHGXUHV
 6KDPSURFHGXUHV)3($OEXWHLQSHULSKHUDODFFHVV
 6KDP SURFHGXUHV /RZ 9ROXPH 3ODVPD ([FKDQJH /93( 
$OEXWHLQ
 6KDPSURFHGXUHV/93()OHERJDPPD',)
,I\RXDUHWRXVHDFHQWUDOFDWKHWHUIRU)3(\RXZLOOUHFHLYHD'9'ZLWK
VKRUWYLGHRV
 6LPXODWHGMXJXODUFHQWUDOFDWKHWHULPSODQWDWLRQ
 6KDPSURFHGXUHV)3($OEXWHLQFHQWUDODFFHVV
 6KDP SURFHGXUHV /RZ 9ROXPH 3ODVPD ([FKDQJH /93( 
$OEXWHLQ
 6KDPSURFHGXUHV/93()OHERJDPPD',)






















APPENDIX  10 




HYPOVOLEMIA GUIDELINE


$0%$56WXG\
/93(6DOLQH6ROXWLRQ
6(3
9HUVLRQ

$0%$5
3URWRFRO1XPEHU,*

5HFRPPHQGDWLRQVIRUSUHYHQWLQJK\SRWHQVLRQUHODWHG
HYHQWVLQ/RZ9ROXPH3ODVPD([FKDQJHSURFHGXUHV
,QIXVLRQRIVDOLQHVROXWLRQDQGDGMXVWPHQWRIUHPRYHG
SODVPDYROXPHLQORZZHLJKWSDWLHQWV

'DWH6(3
6LWH $OO6LWHV6SDLQDQG86
,QIXVLRQRIVDOLQHVROXWLRQ
7KLVUHFRPPHQGDWLRQLVRQO\DSSOLFDEOHWRWKH/93(SURFHGXUHVZLWK$OEXWHLQ
,Q/93(ZLWK$OEXWHLQLQIXVLRQDYROXPHRIPORISODVPDLVH[WUDFWHGGXULQJ
WKHSURFHGXUHGHSHQGLQJRQWKHSDWLHQW¶VZHLJKW+RZHYHUEDVHGRQWKHSDWLHQW¶VZHLJKW
DQGRUWUHDWPHQWDUPRQO\DYROXPHRIPORI$OEXPLQLVLQIXVHGGXULQJWKH
SURFHGXUH'XHWRWKHGLIIHUHQFHLQYROXPHVDOLQHVROXWLRQFDQEHLQIXVHGWRUHGXFHWKH
ULVNRIK\SRWHQVLRQUHODWHGHYHQWV
+RZWRSURFHHGIRUWKH/93(ZLWK$OEXWHLQLQIXVLRQ
 3HUIRUPSODVPDFROOHFWLRQUHJXODUO\
 ,QIXVH$OEXWHLQUHJXODUO\
 0HDVXUHYLWDOVLJQVDIWHULQIXVLRQ
 &ROOHFWEORRGVDPSOHVIRUODERUDWRU\WHVWV
 ,QIXVHVDOLQHVROXWLRQDVUHFRPPHQGHGLQWDEOHVHHEHORZ
 0HDVXUHYLWDOVLJQVDIWHUVDOLQHLQIXVLRQ
$GMXVWPHQWRIUHPRYHGSODVPDYROXPHLQSDWLHQWVZKRZHLJKWOHVVWKDQOEV
7KLV UHFRPPHQGDWLRQ LV DSSOLFDEOH WR $// /93( SURFHGXUHV $OEXWHLQ DQG
)OHERJDPPD',)
,QWKRVHSDWLHQWVZKRVHZHLJWKLVOHVVWKDQOEVWKHYROXPHRISODVPDWRUHPRYHZLOO
EHSURSRUWLRQDOWRWKHDFWXDOZHLJKWDQGFDOFXODWHGDFFRUGLQJWRWKHIROORZLQJIRUPXOD


$0%$56WXG\
/93(6DOLQH6ROXWLRQ
6(3
9HUVLRQ

OEV
P/
[
OEV
:HLJKW
P/
FROOHFW
WR
YROXPH
3ODVPD






=
VHHWDEOHEHORZDVZHOO
)RUH[DPSOHIRUDSDWLHQWZHLJKWLQJOEV
P/
OEV
P/
[
OEV
P/
FROOHFW
WR
YROXPH
3ODVPD






≈
=
7DEOH5HPRYDODQGUHSODFHPHQWYROXPHGXULQJ/93(
5(029$/$1'5(3/$&(0(1792/80('85,1*/93(
3DWLHQW
ZHLJKW
3ODVPDFROOHFWHG
$OEXWHLQWRLQIXVH
GHSHQGLQJRQWKH
WUHDWPHQWDUP

6DOLQH6ROXWLRQWR
LQIXVH
DUP	
)XOOGRVH
DUP
òGRVH
DUP	
OEV
$GMXVWHG9ROXPH
PO
PO

PO
OEV
PO
PO
PO

PO
OEV
PO
PO
PO

PO
OEV
PO
PO
PO

PO
3ODVPDYROXPHWRFROOHFWPO 3DWLHQWZHLJKWLQOEV;POOEV
7KHVHSURFHGXUHVDUHQRWOLVWHGLQWKHSURWRFRODQGWKH\DUHUHFRPPHQGHGWREH
SHUIRUPHGDWWKHGLVFUHWLRQRIWKH,QYHVWLJDWRUVDQG3ODVPDSKHUHVLV7HDPV
)LQDOO\DVLQUHJXODUDSKHUHVLVSUDFWLFHLWLVUHFRPPHQGHGWKDWSDWLHQWVEHSODFHGLQ
7UHQGHOHPEXUJSRVLWLRQIRU$///93(SURFHGXUHV
6LJQDWXUHBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBB
1DPHRI3HUVRQ
-REWLWOH
6LJQDWXUHBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBB
1DPHRI3HUVRQ
-REWLWOH
6LJQDWXUHBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBB
1DPHRI3HUVRQ
-REWLWOH





















APPENDIX  11 




FEVER MANAGEMENT GUIDELINE


$0%$56WXG\

)HYHU0DQDJHPHQW*XLGHOLQH
'(&
9HUVLRQ

$0%$5
3URWRFRO1XPEHU,*

*XLGHOLQHWRPDQDJHIHYHUGXULQJIXOOSODVPDH[FKDQJH)3(
SHULRGLQSDWLHQWVZLWKDFHQWUDOOLQH
 8SRQWKHGHWHFWLRQRIIHYHUWKHSDWLHQWRUWKHFDUHJLYHUZLOOFDOOWKH,QYHVWLJDWRUDQGZLOO
JR WR D QHDUE\ (PHUJHQF\ 5RRP (5 KRVSLWDO GHSHQGLQJ RQ HDFK VLWH WKH UHIHUHQFH
KRVSLWDOZLOOEHGLIIHUHQW
 ,QWKH(5DQDQDPQHVLVDQGDFRPSOHWHSK\VLFDOH[DPLQDWLRQZLOOEHGRQHIRFXVHGRQ
LQYHVWLJDWLQJDQ\SRWHQWLDOLQIHFWLRQIRFXV$VDURXWLQHDQHOHFWURFDUGLRJUDPWKRUDFLF
;UD\EORRGWHVWZLWKEORRGFRXQWEDVLFELRFKHPLVWU\DQGDFXWHSKDVHUHDFWDQWVXULQH
DQDO\VLVDQGXULQHFXOWXUHVKRXOGEHGRQH
 ,QFDVHSDWLHQW¶VWHPSHUDWXUHLVKLJKHUWKDQ&)EORRGFXOWXUHIURPWKHFHQWUDO
OLQHDQGSHULSKHUDOEORRGZLOOEHFROOHFWHG7KHPLFURELRORJLVWVKRXOGEHDVNHGWRLQIRUP
DV TXLFN DV SRVVLEOH DERXW DQ\ PLFURRUJDQLVP JURZWK IURP ERWK WKH SHULSKHUDO DQG
FHQWUDOVDPSOHVDQGWKHWLPHGLIIHUHQFHLIDQ\EHWZHHQERWK
 :LWK WKH LQIRUPDWLRQ REWDLQHG GXULQJ WKH DQDPQHVLVWKH SK\VLFDO H[DPLQDWLRQ DQG WKH
DGGLWLRQDOWHVWVGRQHLQWKH(5VLWXDWLRQVFDQEHFRQVLGHUHG
D
7KHUH DUH LQIHFWLRQ VLJQV RI VRIW WLVVXHV LQ WKH FDWKHWHU LQVHUWLRQ DUHD EXW QR
RWKHUDSSDUHQWLQIHFWLRXVIRFL,QWKLVFDVHWKHLQWHUYHQWLRQZLOOEHDFFRUGLQJWR
WKHIROORZLQJV\VWHPLFLQYROYHPHQWJUDGH
L ,IWKHUHDUHQRFOLQLFDORUDQDO\WLFDOGDWDRIV\VWHPLFLQYROYHPHQW WKH
SDWLHQW FDQ EH GLVFKDUJHG DQG WKH FXWDQHRXV LQIHFWLRQ FDQ EH WUHDWHG
HPSLULFDOO\ZLWKDPR[LFLOOLQDQGFODYXODQLFDFLGDWDGRVHRI
PJWLPHVSHUGD\GXULQJRQHZHHN
$GLIIHUHQWDQWLELRWLFDFWLYHDJDLQVWWKHPDLQPLFURRUJDQLVPVUHVSRQVLEOH
RI FXWDQHRXV DURXQGFDWKHWHU EDFWHULDO LQIHFWLRQV FDQ EH XVHG 7KH
,QYHVWLJDWRUZLOOFRQWDFWWKHSDWLHQWE\SKRQHIUHTXHQWO\7KHSDWLHQWZLOO


$0%$56WXG\

)HYHU0DQDJHPHQW*XLGHOLQH
'(&
9HUVLRQ

EH JLYHQ D 7HPSHUDWXUH /RJ )RUP ZKLFK ZLOO EH FRPSOHWHG E\ WKH
FDUHJLYHU
LL ,I WKHUH LV KLJK IHYHU !& !) DQG V\VWHPLF LQYROYHPHQW
XQFRQVFLRXVQHVVWDFK\FDUGLDK\SRWHQVLRQWKHSDWLHQWVKRXOGEHDGPLWWHG
WR WKH KRVSLWDO 7KH FDWKHWHU VKRXOG EH UHPRYHG DQG WKH SDWLHQW ZLOO EH
WUHDWHGZLWKDEURDGVSHFWUXPHPSLULFDQWLELRWLFZKLOHZDLWLQJWKHFXOWXUH
UHVXOWV 7KH WUHDWPHQW UHJLPHQ VKRXOG FRYHU WKH PRVW IUHTXHQW EDFWHULD
UHODWHG WR FDWKHWHU LQIHFWLRQV IRU H[DPSOH 0HURSHQHP XOWUDEURDG
VSHFWUXPLQMHFWDEOHDQWLELRWLF
0HURSHQHPJ,9HYHU\KRXUVOLQH]ROLGPJ,9HYHU\KRXUV
$IWHUZDUGVWKHWUHDWPHQWZLOOEHDFFRUGLQJWRWKHDQWLELRJUDPUHVXOWV7KH
FDWKHWHUUHPRYDOLQYROYHVVXEMHFW¶VVWXG\ZLWKGUDZQ
E 7KHUH LV WKH H[LVWHQFH RI FOLQLFDO DQG DQDO\WLFDO GDWD RI DQ LQIHFWLRXV IRFXV
RWKHUWKDQWKHFDWKHWHU$Q87,XULQDU\WUDFWLQIHFWLRQDUHVSLUDWRU\LQIHFWLRQ
RU RWKHU LQIHFWLRXV IRFXV LV GLDJQRVHG ,Q WKLV FDVH WKH SDWLHQW ZLOO EH WUHDWHG
DFFRUGLQJWRWKHLQYROYHPHQWJUDGH
L ,I WKH SDWLHQW LV LQ JRRG JHQHUDO FRQGLWLRQ GRHV QRW KDYH KLJK IHYHU
WKHUH LV QR XQFRQVFLRXVQHVV DQG WKH LQIHFWLRQ FDQ EH WUHDWHG RXW RI WKH
KRVSLWDO LQ VDIH FRQGLWLRQV SDWLHQW FDQ EH GLVFKDUJH ZLWK DQ HPSLULF
DQWLELRWLFWUHDWPHQW,WLVPDQGDWRU\WRGDLO\IROORZWKHSDWLHQWE\SKRQH
DQG WR EH LQ FRQWDFW ZLWK WKH PLFURELRORJLVW ZKR ZLOO LQIRUP DERXW WKH
FXOWXUHUHVXOWV,IDIWHUKRXUVWKHSDWLHQWFRQGLWLRQKDVLPSURYHGWKH
SDWLHQW VKRXOG FRQWLQXH ZLWK WKH WUHDWPHQW UHJLPHQ LI WKHUH LV QR
LPSURYHPHQWRUWKHUHLVDZRUVHQLQJRIWKHSDWLHQWFRQGLWLRQLWVKRXOGJR
DJDLQWRWKHUHIHUHQFH(5KRVSLWDOWRJHWDUHHYDOXDWLRQ
LL ,IWKHSDWLHQWLVLQEDGJHQHUDOFRQGLWLRQKDVKLJKIHYHUKHPRG\QDPLF
HIIHFWV XQFRQVFLRXVQHVV RU WKH LQIHFWLRQ LV VHYHUH IRU H[DPSOH
SQHXPRQLDWKHSDWLHQWVKRXOGEHDGPLWWHGWRWKHKRVSLWDODQGEHWUHDWHG
7UHDWPHQW ZLWK HPSLULF DQWLELRWLFV LV VWDUWHG ZKLOH ZDLWLQJ WKH FXOWXUH
UHVXOWV
F
7KHSDWLHQWKDVIHYHUDQGWKHUHLVQRWFOLQLFDORUDQDO\WLFDOGDWDWKDWVXJJHVWD
GLIIHUHQWLQIHFWLRXVIRFXVRWKHUWKDQWKHFDWKHWHU,QWKLVFDVHWKHSDWLHQWDOZD\V
VKRXOGEHDGPLWWHGWRWKHKRVSLWDODQGUHPDLQXQGHUREVHUYDWLRQ
7KHUHDUHSRVVLEOHVFHQDULRV
L ,IWKHSDWLHQWLVLQJRRGJHQHUDOFRQGLWLRQWKHWUHDWPHQWFDQZDLWXQWLO
WKH FXOWXUH UHVXOWV DUH REWDLQHG $ QHJDWLYH EORRG DQG FDWKHWHU FXOWXUH


$0%$56WXG\

)HYHU0DQDJHPHQW*XLGHOLQH
'(&
9HUVLRQ

UHVXOWV UXOHV RXW D FDWKHWHU LQIHFWLRQ DV D IRFXV ,I WKH JRRG JHQHUDO
FRQGLWLRQ UHPDLQV WKH SDWLHQW FRXOG EH GLVFKDUJHG DQG EH FRQWUROOHG E\
SKRQH ,I WKH EORRG DQG FDWKHWHU FXOWXUH UHVXOWV DUH SRVLWLYH WKH FDWKHWHU
VKRXOGEHUHPRYHGDQGWKHEDFWHULDOLQIHFWLRQVKRXOGEHWUHDWHG
,Q DQ\ FDVH ERWK VLWXDWLRQV UHTXLUH SDWLHQW¶V DGPLVVLRQ XQWLO WKH FXOWXUH
UHVXOWVDUHREWDLQHG
,I WKH UHPRYDO RI WKH FDWKHWHU LV UHTXLUHG WKLV LQYROYHV VXEMHFW¶V VWXG\
ZLWKGUDZQ
LL ,I WKH SDWLHQW LV LQ EDG JHQHUDO FRQGLWLRQ HYHQ LI WKHUH LV QR ORFDO
LQIHFWLRQ DURXQG WKH FDWKHWHU¶V LQVHUWLRQ SRLQW WKH FDWKHWHU VKRXOG EH
UHPRYHGDQGEURDGVSHFWUXPDQWLELRWLFWKHUDS\VKRXOGEHVWDUWHG
7KHUHFRPPHQGHGWUHDWPHQWLV
0HURSHQHPJ,9HYHU\KRXUVOLQH]ROLGPJ,9HYHU\KRXUV
ZKLOHZDLWLQJWKHFXOWXUHUHVXOWV
7KHFDWKHWHUUHPRYDOLQYROYHVVXEMHFW¶VVWXG\ZLWKGUDZQ
 7KH DQWLELRWLF SURWRFRO LV D UHFRPPHQGDWLRQ <RX FDQ IROORZ RWKHU SURWRFROV WDNLQJ LQWR
DFFRXQWWKDW

:HVKRXOGLQFOXGHWUHDWPHQWIRUDOOVNLQEDFWHULDXVXDOO\LQYROYHGLQFXWDQHRXVLQIHFWLRQV

:HVKRXOGDOVRLQFOXGHWUHDWPHQWIRUDQDHURELFEDFWHULD

7KH FDWKHWHU RI WKHVH SDWLHQWV DUH PDQLSXODWHG ZHHNO\ WKHUHIRUH ZH VKRXOG LQFOXGH
WUHDWPHQWIRUQRVRFRPLDOEDFWHULD
0HURSHQHPLVUHFRPPHQGHGEHFDXVHLWLVDFDUEDSHQHPDQGLQFOXGHVDKLJKQXPEHURI JUDP
QHJDWLYHDQDHURELFDQGQRVRFRPLDOEDFWHULDFRYHUDJH
7RLQFOXGHWKHUHVWRIWKHJUDPSRVLWLYHEDFWHULDFRYHUDJH/LQH]ROLGLVUHFRPPHQGHGEHFDXVHLW
LVHDVLHUWRKDQGOHWKDQYDQFRP\FLQ
0HURSHQHP¶VDGYHUVHHYHQWVDUHGLDUUKHDJDVWURLQWHVWLQDOGLVFRPIRUWDQGWUDQVDPLQDVHLQFUHDVH
5HJDUGLQJ /LQH]ROLG WKH PRVW IUHTXHQW DGYHUVH HYHQWV DUH FXWDQHRXV UDVK GLDUUKHD DQG
JDVWURLQWHVWLQDOGLVFRPIRUWDQGLQUDUHRFFDVLRQWKURPERF\WRSHQLD


$0%$56WXG\

)HYHU0DQDJHPHQW*XLGHOLQH
'(&
9HUVLRQ

%LEOLRJUDSK\
%DPEDXHU5HWDO6XUIDFH7UHDWHGYHUVXV8QWUHDWHG/DUJH%RUH&DWKHWHUVDV9DVFXODU
$FFHVVLQ+HPRGLDO\VLVDQG$SKHUHVLV7UHDWPHQWV,QWHUQDWLRQDOMRXUQDORIQHSKURORJ\
S
$YDLODEOHDW
KWWSZZZSXEPHGFHQWUDOQLKJRYDUWLFOHUHQGHUIFJL"DUWLG 	WRRO SPFHQWUH]	UHQGHUW\S
H DEVWUDFW>$FFHVVHG)HEUXDU\@
0DNL'*.OXJHU'0	&UQLFK&-7KHULVNRIEORRGVWUHDPLQIHFWLRQLQDGXOWVZLWK
GLIIHUHQWLQWUDYDVFXODUGHYLFHVDV\VWHPDWLFUHYLHZRISXEOLVKHGSURVSHFWLYHVWXGLHV0D\R
&OLQLFSURFHHGLQJV0D\R&OLQLFSS±
$YDLODEOHDWKWWSZZZPD\RFOLQLFSURFHHGLQJVFRPFJLGRL
0HUPHO / D HW DO  &OLQLFDO SUDFWLFH JXLGHOLQHV IRU WKH GLDJQRVLV DQG PDQDJHPHQW RI
LQWUDYDVFXODU FDWKHWHUUHODWHG LQIHFWLRQ  8SGDWH E\ WKH ,QIHFWLRXV 'LVHDVHV 6RFLHW\ RI
$PHULFD&OLQLFDOLQIHFWLRXVGLVHDVHVࣟDQRIILFLDOSXEOLFDWLRQRIWKH,QIHFWLRXV'LVHDVHV6RFLHW\
RI$PHULFDSS±
$YDLODEOHDWKWWSZZZQFELQOPQLKJRYSXEPHG>$FFHVVHG-DQXDU\@
2¶*UDG\ 13 HW DO  *XLGHOLQHV IRU WKH SUHYHQWLRQ RI LQWUDYDVFXODU FDWKHWHUUHODWHG
LQIHFWLRQV&OLQLFDO,QIHFWLRXV'LVHDVHVSS±
$YDLODEOHDW
KWWSZZZSXEPHGFHQWUDOQLKJRYDUWLFOHUHQGHUIFJL"DUWLG 	WRRO SPFHQWUH]	UHQGHUW\S
H DEVWUDFW

)(9(5
,1)(&7,2866,*16
(0(5*(1&<5220
$QDPQHVLV
&RPSOHWH([DPLQDWLRQ
7KRUDFLF;5D\(.*%ORRGDQG8ULQHWHVW%LRFKHPLVWU\
8ULQHFXOWXUHDFXWHSKDVHUHDFWDQWV
,IWHPS!&)3HULSKHUDOEORRGFDWKHWHUFXOWXUH
&87$1(2863(5,&$7+(7(5
,1)(&7,21
¢)HYHU"
¢6\VWHPLFLQYROYHPHQW"
$PR[LFLOOLQDFLG
FODYXODQLF
PJKZHHN
,IDQ\DOOHUJ\RUDO
&LSURIOR[DFLQ
PJK
'LVFKDUJH
3KRQHFRQWURO
$GPLVVLRQ
&DWKHWHUUHPRYDO
(PSLULF7[0HURSHQHP
JK,9/LQH]ROLG
PJK,9
7[ GHSHQGLQJRQ
DQWLELRJUDP
)(9(5:,7+287)2&86
$GPLVVLRQ
¢6\VWHPLF LQYROYHPHQW"
12
:DLWFXOWXUHUHVXOWV
¢326,7,9("
&DWKHWHUUHPRYDO
7[ GHSHQGLQJRQ
FXOWXUHUHVXOWV
'LVFKDUJH
3KRQHFRQWURO
&RQWDFWUHVSRQVLEOH
,QYHVWLJDWRU
<(6
(PSLULF$QWLELRWLF7[
0HURSHQHPJK
,9/LQH]ROLG
PJK,9
&DWKHWHUUHPRYDO
:DLWFXOWXUHVUHVXOWV
'523287
'523287
352%$%/('523287
12
6WUDWLILFDWLRQ
*RRGJHQHUDOFRQGLWLRQ
)HYHU&)
1RKHPRG\QDPLF
LQYROYHPHQW
1RFRQVFLHQFHGLVRUGHU
%DGJHQHUDOFRQGLWLRQ
)HYHU!&)RU
8QFRQVFLRXVQHVVRU
+HPRG\QDPLF
LQYROYHPHQW
(PSLULF$QWLELRWLF7[
'LVFKDUJH
3KRQHFRQWURO
:DLWFXOWXUHVUHVXOWV
¢6\PSWRPVLPSURYHPHQW
K"
(QGRI7[
6WDURYHUWKHGLDJQRVH LQ(5
$GPLVVLRQIRULQIHFWLRQ
7[ VHYHUH
(PSLULF$QWLELRWLF7[
:DLWFXOWXUHVUHVXOWV
<(6
12
'523287
,1)(&7,286)2&8627+(5
7+$17+(&$7+(7(5
<(6
'523287
12
<(6
ƉƉĞŶĚŝǆ ϭϭʹ 'ƵŝĚĞůŝŶĞ ĨŽƌ &ĞǀĞƌ DĂŶĂŐĞŵĞŶƚ
ŽŶĨŝĚĞŶƚŝĂů





















APPENDIX  12 




THROMBOEMBOLIC EVENTS GUIDELINE


$0%$56WXG\

7KURPERHPEROLF(YHQWV*XLGHOLQH
'(&
9HUVLRQ

$0%$5
3URWRFRO1XPEHU,*

*XLGHOLQHIRUWKURPERHPEROLFHYHQWVGXULQJWKHIXOOSODVPD
H[FKDQJH)3(
$ 6XVSLFLRQRIYHQRXVWKURPERVLVUHODWHGWRWKHFDWKHWHU
 ,QFDVHRIFHUYLFDOSDLQQHFNRUVXSHULRUOLPEHGHPDRG\QRSKDJLDRUSXOVDWLQJFHSKDOHD
WKHFDUHJLYHUZLOOFDOOWKH,QYHVWLJDWRUDQGZLOOJRWRDQHDUE\(PHUJHQF\5RRP(5
KRVSLWDOGHSHQGLQJRQHDFKVLWHWKHUHIHUHQFHKRVSLWDOZLOOEHGLIIHUHQW
 ,Q WKH (5 DQ DQDPQHVLV DQG D FRPSOHWH SK\VLFDO H[DPLQDWLRQ DQ HOHFWURFDUGLRJUDP
WKRUDFLF;UD\EORRGWHVWZLWKEORRGFRXQWEDVLFELRFKHPLVWU\DQGFRDJXODWLRQZLOOEH
GRQH
 ,Q FDVH WKH FOLQLFDO HYDOXDWLRQ RI WKH SDWLHQW VKRZV D VSHFLILF FDXVH QRW UHODWHG WR WKH
FDWKHWHUDVWKHVRXUFHRIWKHV\PSWRPVSKDU\QJLWLVIRUH[DPSOHLWZLOOEHVSHFLILFDOO\
WUHDWHG
 ,QFDVHWKHFOLQLFDOHYDOXDWLRQSRLQWVRXWWRZDUGVDWKURPERWLFFRPSOLFDWLRQUHODWHGWR
WKH FDWKHWHU D &7 $QJLRJUDSK\ ZLWK 9HQRXV3KDVH VKRXOG EH GRQH ,W ZLOO DOORZ
LGHQWLI\LQJWKHWKRUDFLFDQGQHFNYHLQV,QFDVHWKLVDQJLRJUDSK\FDQQRWEHSHUIRUPHGD
'RSSOHUHFKRFDUGLRJUDSK\PDGHE\H[SHUWVWDIIZLOOEHGRQH
D
,I WKH UHVXOW LV 1(*$7,9( DQG WKH JHQHUDO FRQGLWLRQ LV JRRG WKH SDWLHQW LV
GLVFKDUJHGDQGZLOOEHFRQWUROOHGE\SKRQHDQGWUHDWHGV\PSWRPDWLFDOO\LIQHHGHG
E ,IWKHUHVXOWLV326,7,9(WKHUHDUHWZRVFHQDULRV
L ,I WKH SDWLHQW KDV IHYHU DQG LQIHFWLRQ VLJQV LQ DGGLWLRQ WR D SURYHG
WKURPERVLVWKHFDWKHWHUVKRXOGEHUHPRYHGDQGWKHSDWLHQWDGPLWWHGWRWKH
(5 3HUIRUP EORRG FXOWXUHV VWDUW DQWLFRDJXODWLRQ WUHDWPHQW DQG EURDG
VSHFWUXPDQWLELRWLFWKHUDS\
0HURSHQHPJK,9/LQH]ROLGPJK,9RUVLPLODU
,IDEDFWHUHPLDLVFRQILUPHGDQHFKRFDUGLRJUDPVKRXOGEHGRQHWRUXOH
RXWLQIHFWLRXVHQGRFDUGLWLV


$0%$56WXG\

7KURPERHPEROLF(YHQWV*XLGHOLQH
'(&
9HUVLRQ

LL ,I WKH &7 $QJLRJUDSK\ ZLWK 9HQRXV3KDVH VKRZV WKURPERVLV VKRZV
WKURPERVLVWKHSDWLHQWKDVQRIHYHUDQGWKHJHQHUDOFRQGLWLRQLVJRRGWKH
FDWKHWHUZLOOEHUHPRYHGDQGWUHDWPHQWZLOOEHVWDUWHGZLWK
(QR[DSDULQPJ.JK6&RUPJ.JK
7KHSDWLHQWZLOOEHGLVFKDUJHGDQGFRQWUROOHGE\SKRQH,WZLOOEHVHQWDV
VRRQ DV SRVVLEOH WR D &OLQLFDO +HPDWRORJLVW ZKR ZLOO DGYLVH WKH SDWLHQW
DERXWWKHORQJRUVKRUWWHUPDQWLFRDJXODQWWKHUDS\
 ,I WKHUH LV FOLQLFDO VXVSLFLRXV RI SXOPRQDU\ HPEROLVP G\VSQHD 2 GHVDWXUDWLRQ
WDFK\FDUGLD V\QFRSH LW VKRXOG EH FRPSOHPHQWHG ZLWK D &7 $QJLRJUDSK\ RI WKH
3XOPRQDU\$UWHULHV$3XOPRQDU\7KURPERHPEROLVP37(FRQILUPDWLRQDOZD\VQHHGV
DQWLFRDJXODWLRQWUHDWPHQWDQGDGPLVVLRQWRWKH(5VHH6HFWLRQ%
 7KH DSSHDUDQFH RI DQ\ WKURPERHPEROLF FRPSOLFDWLRQ DOZD\V PHDQV WKH VXEMHFW LV
ZLWKGUDZQIURPWKHVWXG\
% 3XOPRQDU\WKURPERHPEROLVPVXVSLFLRQ
 ,I D VXEMHFW KDV D VXGGHQ RQVHW RI VKRUWQHVV RI EUHDWK G\VSQHD DQGRU V\QFRSH
WDFK\FDUGLDRUIODQNSDLQWKHFDUHJLYHUZLOOFDOOWKH,QYHVWLJDWRUDQGZLOOJRWRDQHDUE\
(PHUJHQF\ 5RRP (5 KRVSLWDO GHSHQGLQJ RQ HDFK VLWH WKH UHIHUHQFH KRVSLWDOZLOO EH
GLIIHUHQW
 ,Q WKH (5 DQ DQDPQHVLV DQG D FRPSOHWH SK\VLFDO H[DPLQDWLRQ DQ HOHFWURFDUGLRJUDP
WKRUDFLF;UD\EORRGWHVWZLWKEORRGFRXQWEDVLFELRFKHPLVWU\FRDJXODWLRQDQGDUWHULDO
EORRGJDVZLOOEHGRQH
 ,Q FDVH WKH FOLQLFDO HYDOXDWLRQ RI WKH SDWLHQW VKRZV D VSHFLILF FDXVH QRW UHODWHG WR WKH
FDWKHWHUDQGDVWKHVRXUFHRIWKHV\PSWRPVLWZLOOEHVSHFLILFDOO\WUHDWHG
 ,Q FDVH WKH FOLQLFDO HYDOXDWLRQ SRLQWV RXW WRZDUGV D 37( UHODWHG WR WKH FDWKHWHU D &7
$QJLRJUDSK\ ZLWK 9HQRXV3KDVH DOORZLQJ WKH LGHQWLILFDWLRQ RI WKRUDFLF DQG QHFN
YHLQVDQGDOVRD&7$QJLRJUDSK\RIWKH3XOPRQDU\$UWHULHVVKRXOGEHGRQH,QFDVH
WKLV DQJLRJUDSK\ FDQQRW EH SHUIRUPHG D 'RSSOHU HFKRFDUGLRJUDSK\ PDGH E\ H[SHUW
VWDIIZLOOEHGRQH'HSHQGLQJRQWKHUHVXOWVRIWKHWHVWVWKHUHDUHVFHQDULRV
D
,IERWKUHVXOWVDUH1(*$7,9(LWZLOOEHUHHYDOXDWHGWRORRNIRURWKHUFDXVHV,I
DQ\RWKHUFDXVHVDUHIRXQGDQGWKHSDWLHQWLVLQJRRGJHQHUDOFRQGLWLRQWKHSDWLHQW
LVGLVFKDUJHGDQGFRQWUROOHGE\SKRQH


$0%$56WXG\

7KURPERHPEROLF(YHQWV*XLGHOLQH
'(&
9HUVLRQ

E ,Q FDVH D 37( LV GLDJQRVHG WKHSDWLHQW VKRXOG EH DGPLWWHG WR WKH(5 DQG WKH
FDWKHWHUUHPRYHG7UHDWPHQWZLOOEHVWDUWHGZLWK
6RGLXP+HSDULQRUORZPROHFXODUZHLJKWKHSDULQ
:KHQWKHVXEMHFWLVGLVFKDUJHGLWVKRXOGIROORZORZPROHFXODUZHLJKWKHSDULQRU
RUDODQWLFRDJXODWLRQWKHUDS\DQGYLVLWD&OLQLFDO+HPDWRORJLVW
F
,QFDVHDYHQRXVWKURPERVLVEXWQRWD37(LVGLDJQRVHGWKHVXEMHFWZLOOEH
WUHDWHGDVD37(WKHFDWKHWHUZLOOEHUHPRYHGDQGWKHSDWLHQWDGPLWWHGWRWKH(5
$QWLFRDJXODWLRQWUHDWPHQWZLOOEHVWDUWHG$3XOPRQDU\YHQWLODWLRQSHUIXVLRQVFDQ
ZLOOEHGRQHEHFDXVHDGLDJQRVHRI37(LVKLJKO\SUREDEOH
 7KH DSSHDUDQFH RI DQ\ WKURPERHPEROLF FRPSOLFDWLRQ DOZD\V PHDQV WKH VXEMHFW LV
ZLWKGUDZQIURPWKHVWXG\
 7KHFDWKHWHUZLOOEHDOZD\VUHPRYHGH[FHSWLQFDVHRIDQLQWUDDXULFXODUWKURPEXV,ILWLV
VXVSHFWHG DQ(FKRFDUGLRJUDPVKRXOG EH GRQHWR UXOH LW RXW ,W LV D KLJKO\ LQIUHTXHQW
FRPSOLFDWLRQEXWSRWHQWLDOO\VHYHUH7KHEHVWPDQDJHPHQWRIWKLVVLWXDWLRQLVXQFOHDUEXW
FRXOGUHTXLUHXUJHQWFDUGLDFVXUJHU\
,Q WKLV VLWXDWLRQ DQWLFRDJXODWLRQ WUHDWPHQW ZLWK VRGLXP KHSDULQ ZLOO EH VWDUWHG 7KH
FDWKHWHU ZLOOQRWEHUHPRYHGGXHWRWKHKLJKULVNRI HPEROLVPDQGWKH VXEMHFWZLOOEH
XUJHQWO\VHQWWRDKRVSLWDOZKHUHFDUGLDFVXUJHU\FDQEHDVVHVVHG
 7KH DQWLELRWLF SURWRFRO LV D UHFRPPHQGDWLRQ <RX FDQ IROORZ RWKHU SURWRFROV WDNLQJ LQWR
DFFRXQWWKDW

:HVKRXOGLQFOXGHWUHDWPHQWIRUDOOVNLQEDFWHULDXVXDOO\LQYROYHGLQFXWDQHRXVLQIHFWLRQV

:HVKRXOGDOVRLQFOXGHWUHDWPHQWIRUDQDHURELFEDFWHULD

7KH FDWKHWHU RI WKHVH SDWLHQWV DUH PDQLSXODWHG ZHHNO\ WKHUHIRUH ZH VKRXOG LQFOXGH
WUHDWPHQWIRUQRVRFRPLDOEDFWHULD
0HURSHQHPLVUHFRPPHQGHGEHFDXVHLWLVDFDUEDSHQHPDQGLQFOXGHVDKLJKQXPEHURI JUDP
QHJDWLYHDQDHURELFDQGQRVRFRPLDOEDFWHULDFRYHUDJH
7RLQFOXGHWKHUHVWRIWKHJUDPSRVLWLYHEDFWHULDFRYHUDJH/LQH]ROLGLVUHFRPPHQGHGEHFDXVHLW
LVHDVLHUWRKDQGOHWKDQYDQFRP\FLQ
0HURSHQHP¶VDGYHUVHHYHQWVDUHGLDUUKHDJDVWURLQWHVWLQDOGLVFRPIRUWDQGWUDQVDPLQDVHLQFUHDVH
5HJDUGLQJ /LQH]ROLG WKH PRVW IUHTXHQW DGYHUVH HYHQWV DUH FXWDQHRXV UDVK GLDUUKHD DQG
JDVWURLQWHVWLQDOGLVFRPIRUWDQGLQUDUHRFFDVLRQWKURPERF\WRSHQLD


$0%$56WXG\

7KURPERHPEROLF(YHQWV*XLGHOLQH
'(&
9HUVLRQ

%LEOLRJUDSK\
%DPEDXHU5HWDO6XUIDFH7UHDWHGYHUVXV8QWUHDWHG/DUJH%RUH&DWKHWHUVDV9DVFXODU
$FFHVVLQ+HPRGLDO\VLVDQG$SKHUHVLV7UHDWPHQWV,QWHUQDWLRQDOMRXUQDORIQHSKURORJ\
S
$YDLODEOHDW
KWWSZZZSXEPHGFHQWUDOQLKJRYDUWLFOHUHQGHUIFJL"DUWLG 	WRRO SPFHQWUH]	UHQGHUW\S
H DEVWUDFW>$FFHVVHG)HEUXDU\@
%XUQV.	0F/DUHQ$&DWKHWHUUHODWHGULJKWDWULDOWKURPEXVDQGSXOPRQDU\HPEROLVP
$FDVHUHSRUWDQGV\VWHPDWLFUHYLHZRIWKHOLWHUDWXUH-RXUQDORIWKH&DQDGLDQ7KRUDFLF
SS±
$YDLODEOH DW KWWSZZZQFELQOPQLKJRYSPFDUWLFOHV30& >$FFHVVHG )HEUXDU\ 
@
'HERXUGHDX 3 HW DO  ,QWHUQDWLRQDO FOLQLFDO SUDFWLFH JXLGHOLQHV IRU WKH WUHDWPHQW DQG
SURSK\OD[LV RI WKURPERVLV DVVRFLDWHG ZLWK FHQWUDO YHQRXV FDWKHWHUV LQ SDWLHQWV ZLWK FDQFHU
-RXUQDORIWKURPERVLVDQGKDHPRVWDVLVࣟ-7+SS±
$YDLODEOHDWKWWSZZZQFELQOPQLKJRYSXEPHG>$FFHVVHG)HEUXDU\@
6WDYURXORSRXORV $ $UHVWL 9 	 =RXQLV &  5LJKW DWULDO WKURPEL FRPSOLFDWLQJ
KDHPRGLDO\VLV FDWKHWHUV $ PHWDDQDO\VLV RI UHSRUWHG FDVHV DQG D SURSRVDO RI D PDQDJHPHQW
DOJRULWKP 1HSKURORJ\ GLDO\VLV WUDQVSODQWDWLRQௗ RIILFLDO SXEOLFDWLRQ RI WKH (XURSHDQ 'LDO\VLV
DQG7UDQVSODQW$VVRFLDWLRQ(XURSHDQ5HQDO$VVRFLDWLRQSS±
$YDLODEOHDWKWWSZZZQFELQOPQLKJRYSXEPHG>$FFHVVHG-DQXDU\@

ƉƉĞŶĚŝǆϭϮʹ 'ƵŝĚĞůŝŶĞĨŽƌƚŚƌŽŵďŽĞŵďŽůŝĐĞǀĞŶƚƐ
Ϳ^ƵƐƉŝĐŝŽŶŽĨǀĞŶŽƵƐƚŚƌŽŵďŽƐŝƐƌĞůĂƚĞĚƚŽƚŚĞĐĂƚŚĞƚĞƌ
&HUYLFDOSDLQQHFNRUVXSHULRUOLPEHGHPDRG\QRSKDJLDRUSXOVDWLOHFHSKDOHD
(PHUJHQF\5RRP
3K\VLFDOH[DPLQDWLRQ
(.*WKRUDFLF;UD\EORRGWHVW
ELRFKHPLVWU\DQGFRDJXODWLRQ
&RPSDWLEOHZLWKWKURPERVLV
&RPSDWLEOHZLWKDQRWKHUGLDJQRVH
$QDOJHVLDDQGWHOHSKRQHFRQWURODW
KRPH
&7$QJLRJUDSK\ZLWK9HQRXV3KDVHRU
'RSSOHUHFKRFDUGLRJUDSK\
1(*$7,9(
326,7,9(
)HYHUDQGLQIHFWLRQVLJQV
1RIHYHUQRULQIHFWLRQGDWD
(5DGPLVVLRQ
&DWKHWHUUHPRYDO
$QWLFRDJXODWLRQ7[
)ROORZXSLQIHFWLRQSURWRFRO
'523287
&DWKHWHUUHPRYDO
7[ ZLWK(QR[DSDULQ6&
PJ.JK
)ROORZXSE\&OLQLFDO
+HPDWRORJLVW
&RQWDFWUHVSRQVLEOH
,QYHVWLJDWRU
'523287

ƉƉĞŶĚŝǆϭϮʹ 'ƵŝĚĞůŝŶĞĨŽƌdŚƌŽŵďŽĞŵďŽůŝĐǀĞŶƚƐ
ͿWƵůŵŽŶĂƌǇ ƚŚƌŽŵďŽĞŵďŽůŝƐŵ ;WdͿƐƵƐƉŝĐŝŽŶ
37(VXVSLFLRQWDFK\FDUGLDVKRUWQHVVRIEUHDWK>G\VSQHD@V\QFRSHRUIODQNSDLQ
(PHUJHQF\5RRP
3K\VLFDOH[DPLQDWLRQ
(.*WKRUDFLF;UD\EORRGWHVWELRFKHPLVWU\
FRDJXODWLRQDQGDUWHULDOEORRGJDV
&RQVLGHURWKHUFDXVHV
3DWLHQWFRQWUROOHGDWKRPHE\SKRQH
%27+
1(*$7,9(
9HQRXV7KURPERVLV
326,7,9(
37(1(*$7,9(
3UHVHQFHRILQWUDDXULFXODU
WKURPEXV"
1RFDWKHWHUUHPRYDO
7[ ZLWKVRGLXPKHSDULQ
&DUGLDFVXUJHU\
'523287
$GPLVVLRQ(5
&DWKHWHUUHPRYDO
7[ ZLWK6RGLXP+HSDULQRU/0:+
PJ.JK
'LVFKDUJHZLWKDQWLFRDJXODQW7[
)ROORZXSE\&OLQLFDO+HPDWRORJLVW
&RQWDFWUHVSRQVLEOH
,QYHVWLJDWRU
'523287
7KRUDFLFDQGQHFN&7$QJLRJUDSK\ZLWK
9HQRXV3KDVHRU'RSSOHUHFKRFDUGLRJUDSK\
&7$QJLRJUDSK\RI3XOPRQDU\$UWHULD
37(
326,7,9(
12
<(6
3XOPRQDU\
YHQWLODWLRQSHUIXVLRQVFDQ