A Multi-center, Randomized, Double-blind, Placebo-controlled, 24 Months Study in Patients With Amnestic Mild Cognitive Impairment or Very Mild Alzheimer's Disease to Investigate the Safety, Tolerability and Immune Response of Repeated Subcutaneous Injections of ABvac40
Phase: PHASE2
Conditions: Mild Cognitive Impairment, Alzheimer Disease
Sponsor: Araclon Biotech S.L.

Official Title: 
A Multi-center, Randomized, Double-blind, Placebo-controlled, 24 
months Study in Patients with amnestic Mild Cognitive Impairment or 
Very Mild Alzheimer’s Disease to Investigate the Safety, Tolerability and 
Immune Response of Repeated Subcutaneous Injections of ABvac40. 
NCT Number: 
NCT03461276 
Document Date: 
Protocol Version 5.0; 22 May 2020 
 

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Page 1 of 121  
Clinical Study Protocol 
Protocol Title: 
 
A Multi-center, Randomized, Double-
blind, Placebo-controlled, 24 months Study 
in Patients with  amnestic Mild Cognitive 
Impairment or Very Mild Alzheimer’s 
Disease to Investigate the Safety, 
Tolerability and Immune Response of 
Repeated Subcutaneous Injections of 
ABvac40. 
Investigational Product: 
 
ABvac40 
Sponsor’s Name and Address: 
 
ARACLON BIOTECH, S.L. a GRIFOLS 
company, 
Vía de la Hispanidad, 21 
50009 Zaragoza, Spain 
 
Sponsor’s Telephone Number: 
 
 
 
Study Number/Protocol Version 
Number/Date: 
 
AB1601 
Version V5.0 SPA including Amendment 3 
22 of May 2020 
Previous version 
 
Version V4.0 SPA including Amendment 2 
23 of July 2018 
Additional Identifier 
 
 
EUDRACT Number: 
 
2016-004352-30  
 
IND/CTA Number 
 
NA 
Development Phase: 
 
Phase 2 
 
Confidentiality Statement: 
The following confidential information is the property of Araclon-Grifols.  
As long as the information contained in this protocol has not been 
published, it may only be used after permission has been obtained from 
Araclon-Grifols.  It is not possible to make reproductions of all or sections 
of this protocol. Commercial use of the information is only possible with the 
permission of the proprietor and is subject to a license fee.

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PRINCIPAL INFORMATION CONTACT 
Sponsor  
Araclon Biotech, S.L. a Grifols company 
Vía Hispanidad, 21 
50009 Zaragoza, España 
Tel.: 
 
 
 
 
Organizations authorized by the Sponsor  
Contract Research Organization 
 
 
 
 
Tel.: 
 
Fax: 
 
 
Sponsor´s scientific personnel  
 
 Vía Hispanidad, 21 
50009 Zaragoza, España 
Tel.: 
 
 
 
 Vía 
Hispanidad, 21 
50009 Zaragoza, España 
Tel.: 
 
 
 
Sponsor Medical Advisor 
 
 
 
Germans Trías i Pujol Hospital 
Tel.: 
 
email: 
 
 
 
 
 
 
C/ Gran Vía Carles III, 85 bis 
08028 Barcelona 
Tel. 
 
Fax. 
 
email: 
 
 
Co-Investigator of the study 
  
  
C/ Gran Vía Carles III, 85 bis 
08028 Barcelona  
 
Tel.: 
 
Fax: 
 
E-mail: 
 

Protocol AB1601 V5.0 SPA including Amendment 3 
22-05-2020 
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Page 4 of 121  
PROTOCOL SYNOPSIS 
Title of Study: 
A Multicenter, Randomized, Double-blind, Placebo-controlled, 24 months Study in Patients 
with amnestic Mild Cognitive Impairment or Very Mild Alzheimer´s Disease to Investigate 
the Safety, Tolerability and Immune Response of Repeated Subcutaneous Injections of 
ABvac40. 
Study Number: 
AB1601 
Phase:  
Confirmatory Phase 2 clinical trial. 
Study Objectives: 
 
Part A (Randomized, double-blind, placebo-controlled – 18 to 24 months follow-up): 
Primary Safety Objective  
- 
To evaluate the safety and tolerability of repeated doses of ABvac40 in a population of 
patients with amnestic Mild Cognitive Impairment (a-MCI) or very mild Alzheimer’s 
disease (vm-AD). 
 
Primary Efficacy Objective (immunogenicity) 
- 
To assess the immune response produced during the study by repeated doses of 
ABvac40 in a population of a-MCI or vm-AD. 
 
Secondary (Exploratory) Efficacy Objectives  
- 
To characterize the immune response elicited by repeated doses of ABvac40 in a 
population of a-MCI or vm-AD. 
- 
To assess the changes in the disease biomarkers elicited by ABvac40 in the overall 
study population. 
- 
To assess the changes in cognition and quality of life elicited by ABvac40 in the overall 
study population. 
 
Part B (ABvac40 delayed start, open label [Part A assignment will remain blinded for 
investigators and patients] – 18 months follow-up): 
Exploratory Safety Objective  
- 
To evaluate the safety and tolerability of repeated doses of ABvac40 after delayed start 
in patients receiving placebo during Part A, and the long-term safety and tolerability of 
ABvac40 in patients receiving a booster after their Part A vaccination scheme. 
 

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Exploratory Efficacy Objectives  
Immunogenicity 
- 
To assess the immune response produced by repeated doses of ABvac40 after delayed 
start in patients receiving placebo during Part A. 
- 
To assess the immune response triggered by a second ABvac40 booster in patients 
receiving ABvac40 during Part A. 
Other 
- 
To assess the changes in the disease biomarkers elicited by ABvac40 in the overall 
study population. 
- 
To assess the changes in cognition and quality of life elicited by ABvac40 in the overall 
study population and according to the treatment scheme during Part A and B. 
- 
To assess the immunological memory, characterizing the immune response ex vivo 
elicited by the booster in patients who have received ABvac40 during Part A.  
- 
To assess the potential relationship between antibody titration, biomarkers and 
cognitive state. 
- 
To define the optimal ABvac40 treatment scheme.  
Overall Study Design and Description:  
A multi-center, prospective, longitudinal, randomized, double-blind, placebo-controlled, two 
parallel treatment groups (verum and placebo), confirmatory phase 2 clinical trial has been 
designed (Part A). 
Additionally, a delayed-start vaccination, open label (Part A assignment will remain blinded 
for investigators and patients) extension will start after at least 18 months of Part A initiation 
(Part B). 

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OVERALL STUDY DESIGN 
 
Part A: 
Screening 
 
 
week -8 
0 
4 
8 
12 
16 
 
24 
 
 
 
42 
 
50 
 
 
 
 
 
77 
 
 
 
 
 
104 
Visits 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Verum or 
Placebo 
 
  
MRI 
. 
   
 
 
a-PET 
. 
 
 
CSF 
 . 
 
 
NPB 
 
 
Part B: 
Week 
0* 
4 
8 
12 
16 
 
24 
 
 
 
42 
 
50 
 
 
 
 
 
77 
Visits 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Verum  
or placebo 
 
MRI 
. 
   
 
 
a-PET 
. 
 
 
CSF  
 
 
NPB 
 
*At least 18 months after initiating Part A 
†A MRI will be performed before first vaccination of Part B only if the previous MRI was performed more than 6 months (±15 days) before V1B 
† 

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STUDY SCHEME 
Part A: 
 
Scree
ning 
Month 
-2 
0 
1 
2 
3 
4 
5 
6 
7 8 
9 
10 
11 
12 
…
15 
…18 …21 
…
24 
Week 
-8 
0 
0 
2 
4 
4 
6 
8 
8 
10 12 12 
14 
16 
16 
18 
 
24 
 
 
 
40 
42 
42 
44 
 
50 
 
65 
 77  90  104 
Day 
-60 
-3 
/0* 
3 
±3 
14 
±3 
28 
±3 
31 
±3 
42 
±3 
56 
±3 
59 
±3 
70 
±3 
84 
±3 
87 
±3 
98 
±3 
112 
±3 
115 
±3 
126 
±3 
 
168 
±7 
 
 
 280 
±7 
294 
±7 
297 
±7 
308 
±7 
 
350 
±15 
 
455 
±15 
 539 
±15 
 630 
±15 
 
728 
±15 
Visit Nº 
(T=by phone) 
0† 
1* 
Vc 
2 
(T) 
3 
Sc 
4 
Vc 
5 
(T) 
6 
Sc 
7 
Vc 
8 
(T) 
9 
Sc 
10 
Vc 
11 
(T) 
12 
Sc 
13 
Vc 
14 
(T) 
15 
Sc 
16 
Int 
6m 
17 
Sc 
18 
Vc 
19 
(T) 
20 
Sc  
21 
Sc 
22 
(T) 
23 
Sc 
24 
(T) 
25 
 FV 
Informed Consent 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vaccination 
ABvac40/placebo 
 
* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
§ 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History, 
Height (only at 
screening) 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight, BP, HR, RR, Tº 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical and 
neurological exam 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neuropsych. Battery 
and IGE (exc. V0/V23) 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Quality of Life EQ-
5D5L 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eletrocardiogram 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
#
 
 
 
 
 
#
 
 
#
 
 
#
 
Urine Analysis (test 
strip) 
2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ApoE Genotyping 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hemogram 
2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biochemistry 
2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biological Activity 
2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRI 
3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a-PET 
4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CSF 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
Medication 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRI: Magnetic Resonance Imaging; a-PET: Amyloid PET; CSF: Cerebrospinal fluid; EKG: Electrocardiogram; exc.: except; IGE: Investigator Global Evaluation; NPB: Neuropsychological 
battery; FV: final visit; Vc: Vaccination; Sc: Safety control; Int: Interim analysis; T: Telephone call; RR: respiratory rate: Tº: body temperature 

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†The Screening Visit (V0) should be performed in 4 separate days: 
1Day 1 of V0 (V0a):  
- Signature of informed consent and verification of inclusion and exclusion criteria; medical history, vital signs, physical and neurological exam, 
neuropsychological battery, EKG, concomitant medication for AD and other diseases and delivery of Patient Card and Patient Diary; the scanned 
EKG must be sent to the Medical Advisor and no further assessments can be made to the subject until the approval is received at the center. 
- If the patient meets all neuropsychological criteria, once the EKG has been approved by the Medical Advisor, the Day 2 of V0 (V0b) can be 
scheduled 
2Day 2 of V0 (V0b): 
- Urine analysis and blood sample extraction (for hemogram, biochemistry and biological activity) 
- If no abnormal findings are found in the blood and urine tests, the Day 3 of V0 (V0c) can be scheduled. 
3Day 3 of V0 (V0c):  
- Magnetic Resonance Imaging 
- Once the MRI has been approved by the MRI Central Reader, the Day 4 of V0 (V0d) can be scheduled 
4Day 4 of V0 (V0d):  
- a-PET 
- Once the a-PET has been approved by the a-PET Central Reader, the patient can be randomized and the first day of V1 can be scheduled (a 
minimum of 4 days later, so that the appropriate material for CSF extraction and the investigational medicinal product (IMP) can be received at 
the center). 
* The Inclusion Visit (V1) should be performed in 2 separate days; the vaccination should take place at least 3 days after the CSF extraction, or the 
time needed until resolution of any AE occurring after the CSF extraction, whichever is longer (to avoid interference with the assessment of AEs 
related to the vaccination), with a maximum of 10 days after the urine and blood sample extraction: 
 Day 1 of V1 (V1a):  
- Urine analysis, blood sample extraction (for ApoE genotyping, hemogram, biochemistry and biological activity) and CSF collection  
 Day 2 of V1 (V1b):  
- Physical and neurological exam, neuropsychological battery and IGE, quality of life, vital signs (before vaccination), vaccination, vital signs 
(after vaccination), concomitant medication and AEs. 
 A telephone control interview will take place within the first week (3± 3 days) after each vaccination visit and at V22 and V24.  
 A safety visit will be scheduled two weeks after each vaccination and at V17 and V23. 
 Blood samples will be collected at every safety control visit for safety control and characterization of immune response. 
 Study visits should take place at the Days indicated above, within the following windows: 
- 
During first 6 months: ± 3 days  
- 
Between month 6 and month 12: ± 7 days 
- 
Between month 12 and month 24: ± 15 days 
 If a visit takes place out of window, the patient should be visited as soon as possible; For the five firsts immunizations the minimum interval 
between vaccinations must be 25 days and the maximum interval must be 31 days; if one vaccination is delayed for any reason, the next dose 
must be re-scheduled to fit this therapeutic window. 
# In this visit the scanned EKG must be sent to the Medical Advisor for review. 

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§ All patients who will attend their V18 after May 2020 must be tested for COVID-19 by PCR (Polymerase chain reaction test) method before receiving 
the study medication. A specific informed consent form (ICF) must be signed by the applicable patients authorizing this test (see Section 6.1.1.1 for 
further details) 
 
 Part B: 
 
Part B 
Month 
0† 
1 
2 
3 
4 
5 
6 
7 8 
9 
10 
11 
12 
… 
18 
Week 
0 
0 
2 
4 
4 
6 
8 
8 
10 12 12 
14 
16 
16 
18 
 
24 
 
 
40 
42 
42 
44 
 
50 
 
77 
Day 
-3 
/0* 
3 
±3 
14 
±3 
28 
±3 
31 
±3 
42 
±3 
56 
±3 
59 
±3 
70 
±3 
84 
±3 
87 
±3 
98 
±3 
112 
±3 
115 
±3 
126 
±3 
 
168 
±7 
 
 
280 
±7 
294 
±7 
297 
±7 
308 
±7 
 
350 
±15 
 
539 
±15 
Visit Nº 
(T=by phone) 
1B* 
Vc 
2B 
(T) 
3B 
Sc 
4B 
Vc 
5B 
(T) 
6B 
Sc 
7B 
Vc 
8B 
(T) 
9B 
Sc 
10B 
Vc 
11B 
(T) 
12B 
Sc 
13B 
Vc 
14B 
(T) 
15B 
Sc 
16B 
Sc 
17B 
Sc 
18B 
Vc 
19B 
(T) 
20B 
Sc  
21B 
Sc 
22B 
EOS 
Informed Consent 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vaccination ABvac40/placebo§ 
* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight, BP, HR, RR, Tº 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical and neurological exam 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neuropsych. Battery and IGE  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Quality of Life EQ-5D5L 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eletrocardiogram 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
#
 
 
 
 
 
#
 
 
Urine Analysis (test strip) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hemogram 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biochemistry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biological Activity 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRI 
   ‡
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a-PET 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CSF 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medication 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRI: Magnetic Resonance Imaging; a-PET: Amyloid PET; CSF: Cerebrospinal fluid; EKG: Electrocardiogram; exc.: except; IGE: Investigator Global Evaluation; NPB: Neuropsychological 
battery; EOS: end of study; Vc: Vaccination; Sc: Safety control; T: Telephone call; RR: respiratory rate: Tº: body temperature 
 
† At least 18 months after initiating Part A 
* The First Visit of Part B (V1B) will take place only when the results of the last MRI test performed (either at V21 or V25 or before first vaccination of 
Part B‡) are available and support the vaccination.   
‡ A MRI will be performed before first vaccination of Part B only if the previous MRI was performed more than 6 months (±15 days) before V1B. 

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Page 10 of 121  
 A telephone control interview will take place within the first week (3 ±3 days) after each vaccination visit.  
 A safety visit will be scheduled two weeks after each vaccination and at V17B. 
 Blood samples will be collected at every safety control visit for safety control and characterization of immune response. 
 Study visits should take place at the Days indicated above, within the following windows: 
- 
During first 6 months: ± 3 days  
- 
Between month 6 and month 12: ± 7 days 
- 
Between month 12 and month 18: ± 15 days 
 If a visit takes place out of window, the patient should be visited as soon as possible; For the five first immunizations the minimum interval 
between vaccinations must be 25 days and the maximum interval must be 31 days; if one vaccination is delayed for any reason, the next dose 
must be re-scheduled to fit this therapeutic window. 
# In this visit the scanned EKG must be sent to the Medical Advisor for review 
§ All patients must be tested for COVID-19 during the Part B vaccination visits before receiving the study medication (see Section 6.1.1.2 for further 
details) 
 
 

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Phases in the study: visits, assessments and dates: 
Part A: 
The Part A of the study will last for up to 104 weeks (from V0 to V25) and at least 18 months 
(up to V23) during which the patients will receive five monthly (every four weeks) 
immunizations plus a booster shot. During the study, two interim analyses (Int) will be 
performed to assess safety, tolerability and biological activity of the treatment (including data 
from the collected disease biomarkers at each of them). These analyses will be reviewed by an 
independent Data Safety Monitoring Board (DSMB). The first Int will be carried out once the 
first 30 patients have completed the 24-week visit (Int-6m) and the second one once all patients 
have completed the 24-week visit (Int-6m, eight weeks after the fifth monthly immunization) 
or in October 2020, whichever occurs first.. The double blinding of the study will be 
maintained throughout these two Int. Additional DSMB reviews may be made ad hoc in the 
event of safety issues. 
Additionally, after all patients complete their 18-months visit (V23), a statistical analysis will 
be performed to determine whether the Part B of the study should be discontinued. 
 
Within the first week (3± 3 days) after each vaccination visit, a telephone control interview 
will take place.   
Two weeks after each vaccination, and at 40, 50, 77 and 104 weeks there will be a safety visit 
consisting on: 
 Physical and neurological examination (assessment of vital signs; electrocardiogram 
in five visits: V0, V16, V21, V23 and the final visit (V25); body biometrics; collection 
of adverse events and concomitant medication) at all face to face visits (V0, V1, V3, 
V4, V6, V7, V9, V10, V12, V13, V15, V16, V17, V18, V20, V21, V23 and V25; and 
PDV, if applicable).  
 Blood collection for safety control and measurement of biological activity at visits: 
V0, V1, V3, V6, V9, V12, V15, V16, V17, V20, V21, V23 and V25 
 A MRI at visits V0, V9, V16, V17, V21 and V25. 
At the screening visit (V0), the participants will receive an amyloid-PET scan. Subjects will 
undergo additional amyloid-PET scan at V21 and final visit (V25) for the assessment of 
amyloid burden. The subject will receive lumbar puncture for CSF analysis at baseline (V1), 
V21 and at the final visit (V25) for the assessment of changes in CSF biomarkers.  
 
Part B: 
The Part B of the study will last for 18 months (from V1B to V22B). The scheme of visits will 
mirror the Part A scheme.  
The first visit of Part B (V1B) will take place at least 18 months after the patient started Part 
A (i.e. he/she should have completed V23 of Part A to enter Part B).  
The patients randomized to the placebo group during Part A will receive five monthly (every 
four weeks) immunizations with ABvac40 plus a booster shot after 6 months (Delayed start 
group), whereas the patients randomized to the Verum group during Part A will receive placebo 
following this schedule, except in V13B, where they will receive an ABvac40 booster shot

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Page 12 of 121  
(Booster group). Given the extended inclusion period of Part A, the V13B booster will take 
place at different timepoints relative to the patients’ last immunization. For the analysis, they 
will be grouped in 2 periods: 12± 3 months and 18± 3 months after their last Part A 
immunization. 
Within the first week (3± 3 days) after each vaccination visit, a telephone control interview 
will take place.   
Two weeks after each vaccination, and at 40 and 50 weeks there will be a safety visit consisting 
on: 
 Physical and neurological examination (assessment of vital signs, body biometrics and 
collection of adverse events and concomitant medication at all face to face visits (V1B, 
V3B, V4B, V6B, V7B, V9B, V10B, V12B, V13B, V15B, V16B, V17B, V18B, V20B, 
V21B and V22B, if applicable; electrocardiogram only in three visits: V16B, V21B 
and V22B).  
 Blood collection for safety control and measurement of biological activity at visits: 
V1B, V3B, V6B, V9B, V12B, V15B, V16B, V17B, V20B, V21B and V22B. 
 A MRI at visits V9B, V16B, V17B, V21B and V22B.  
o A MRI will be performed before first vaccination of Part B only if the previous 
MRI was performed more than 6 months (±15 days) before V1B 
Patients will undergo an amyloid-PET scan at V21B for the assessment of amyloid burden. 
The patients will receive lumbar puncture for CSF analysis at V21B for the assessment of 
changes in CSF biomarkers. 
Study Population: 
Patients with amnestic Mild Cognitive Impairment (a-MCI) or very mild Alzheimer's Disease 
(vm-AD).  
Number of Subjects Planned: 
To ensure the primary safety and efficacy endpoints of the study a minimum of 60 subjects 
with a-MCI or vm-AD per treatment group (verum and placebo) are required. The amyloid-
PET positive and amyloid-PET negative patients will be independently randomized following 
a ratio 1:1 between verum and placebo (Part A). Thus, the study contains two treatment groups.
To ensure the primary efficacy endpoint with a potency of 85%, at least 15 subjects per 
treatment group (verum and placebo; 30 in total) are required to complete the study. Since a 
total of 120 subjects will be initially included in the study and we estimate ~40% dropouts 
along the clinical trial, 70 are expected to complete the Part A of the protocol.  
The patients’ recruitment will be competitive until the required number of patients is 
completed. Approximately 22 international centres will be involved: Spain (17 sites), France 
(3 sites), Sweden (1 site) and Italy (1 site).  

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Page 13 of 121  
Diagnosis and Main Criteria for Inclusion: 
The study population will consist of patients of both sexes with a-MCI or VM-AD, who meet 
all the selection criteria and give their informed consent to collaborate in the study, after being 
informed. The inclusion of each participant will be controlled by the principal investigator of 
each center. 
Inclusion Criteria: 
A subject must meet all the following inclusion criteria: 
1. Male or female between 55 and 80 years of age, both inclusive, at the time of signing 
informed consent. 
2. The patient (or legal representative, if applicable) and a close relative/caregiver must 
read the subject information sheet, agree to participate in the clinical trial and sign the 
informed consent form (the patient and a close relative/caregiver). 
3. Presence of a stable caregiver to attend the patient study visits. 
4. Mini-Mental Status Examination (MMSE) score between 24 and 30 points (inclusive), 
according to age and education level.  
5. Clinical Dementia Rating (CDR) scale scoring 0.5.  
6. Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Score 
on the Delayed Memory Index (DMI) of 85 or lower.  
7. The results of the patient’s MRI brain scan must be concordant with the diagnosis of  
clinical a-MCI or vm-AD according to the following criteria: Scheltens scale, and 
measurement of white matter and past haemorrhages. 
8. If the patient is receiving treatment for AD, must have been stable during the two 
months before the selection visit.  
9. Treatment for concomitant diseases must be stable during the previous month before 
the treatment of the study. 
10. Positive assessment of the candidate by the investigator for complying with the 
requirements and procedures of the study.  
Exclusion Criteria:  
A subject meeting any of the following exclusion criteria is NOT eligible for participation in 
the study. 
1. Known allergy to components of the vaccine or prior history of anaphylaxis, a severe 
allergic reaction or a history of hypersensitivity to any component of the formulation. 
Allergy to fish or shellfish. 
2. Active infectious disease (i.e. hepatitis B, C). Positive syphilis serology. 
3. History or presence of autoimmune disease, except mild eczema, rhinitis or psoriasis.  
4. Presence or history of immunodeficiency (i.e. HIV). 
5. Significant kidney and/or liver disease, as defined by plasma creatinine  2.5 mg/dL 
(221 mol/l) and/or total bilirubin > 3 mg/dL (51.3 mol/l) measured at the local site 
laboratory.  
6. History of asthma or reactive airway disease with bronchospasm in the last 6 months, 
or currently on regular treatment. 
7. Major uncontrolled systemic condition (e.g. diabetes, congestive heart failure, 
hypertension).

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8. History of cancer (≤5 years since the last specific treatment). Exceptions: basocellular 
carcinoma. 
9. Significant alterations in hematological, biochemical or urine analytical parameters, 
particularly those relating to levels of vitamin B12, folic acid or thyroid tests.  
10. History of any other central nervous system disorder, degenerative or non-degenerative 
neurological or psychiatric condition that, in the investigator's opinion could be the 
cause of the dementia, or could explain the cognitive impairment, or that might interfere 
with cognitive function directly or by its treatment. 
11. Geriatric Depression Scale (GDS; abbreviated version), score >5 
12. Has a “yes” answer to C-SSRS suicidal ideation items 4 or 5, or any suicidal behavior 
within 6 months before Screening, or has been hospitalized or treated for suicidal 
behavior in the past 5 years before Screening. 
13. History or signs of cerebrovascular disease (ischemic or haemorrhagic stroke, transient 
ischemic attack), or diagnosis of possible, probable or clear vascular dementia 
according to NINDS-AIREN criteria.      
14. Presence on MRI of a relevant pattern of microvascular disease (Leukoaraiosis, 
Fazekas score ≥2 in the deep white matter scale or ≥4 in the global score) or more than 
one lacunar or territorial infarcts. Any other MRI finding that, in the opinion of the 
investigator, might be a relevant contributing cause of subject´s cognitive impairment. 
Presence of up to 3 microhemorrhages will be acceptable. 
15. History of bleeding disorder or predisposing conditions, blood clotting or clinically 
significant abnormal results on coagulation profile at Screening, as determined by the 
Investigator.  
16. Patients being treated with anticoagulants or antiaggregant therapy (aspirin at a 
prophylactic dose ≤ 325 mg daily or clopidogrel at a dose ≤75 mg daily are allowed) 
should not be recruited in the study. 
17. Modified Hachinski Ischemic Scale, score higher than 4. 
18. Surgery (with general anaesthetic) within the previous three months to be included in 
the trial, or programed during the study period.  
19. Treatment within 30 days prior to visit 0 with systemic corticosteroids or other 
immunosuppressant’s. 
20. Vaccination against influenza or any other vaccination within 2 months before first 
IMP dose. 
21. Patients, who have previously been randomized in this trial. 
22. Participation in another clinical trial within the previous 1 month to screening visit, or 
within the previous 12 months after the last dose to the screening visit in the case of 
subjects who participated in trials with a study drug whose intention was to modify the 
progression AD unless documentation of receipt of placebo is available. The patient 
cannot be included in the study if the experimental drug was an immunotherapeutic 
drug, including IVIG or a vaccine against Alzheimer's disease unless documentation of 
receipt of placebo is available.   
23. Patients with alcohol or drug abuse or dependence. 
24. Absolute (having a pacemaker or implantable defibrillator) or relative (bare metal stent 
or stent implanted in the last six months) contraindications to MRI examination. 
Feeling of claustrophobic do not let perform MRI or PET scan. 

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25. Patients unlikely to comply with the protocol (e.g., unable to return for follow-up 
visits). 
26. Women of childbearing potential, pregnant or nursing. 
Note: All women will be considered to be of childbearing potential unless they are postmenopausal 
(amenorrheic for at least 12 consecutive months, in the appropriate age group, and without other known 
or suspected cause) or have been sterilized surgically (i.e. bilateral tubal ligation, total hysterectomy, or 
bilateral oophorectomy, all with surgery at least 1 month before dosing) 
27. Significant alterations in the EKG that are associated with an added risk for the patient.
Investigational Product, Dose and Mode of Administration 
 
Study Medication 
Name: ABvac40  
Active ingredient: Conjugated Aβx-40 to KLH 
Transporter: Phosphate buffer containing 0.35% aluminium hydroxide (adjuvant)   
Pharmaceutical Form: Injection ready vials 
Posology: Part A: Verum group: Six administrations: the first five administered once every 
4 weeks (28±3 days) and the sixth at week 42 (V18), 26 weeks after the fifth immunization. 
Each administration consists of 1mL injection of ABvac40 (containing 0.2 mg of Abetax-
40). 
Part B: Delayed start group: Six administrations: the first five administered once every 4 
weeks (28±3 days) and the sixth at week 42 (V18B), 26 weeks after the fifth immunization.
Booster group: One administration at week 16 (V13B).  
Each administration consists of 1mL injection of ABvac40 (containing 0.2 mg of Abetax-
40). 
Method of administration: Subcutaneous injection. 
Duration of Treatment: 
The participation in the study for each patient will last between 36 and 42 months (Part A + 
Part B). They will be exposed to the study’s drug for an initial period of 16 weeks (V1 to V13 
[Part A – Verum group] or V1B to V13B [Part B – Delayed start group]). After 6 months, they 
will receive the 6th vaccination (V18/V18B). Only the patients assigned to the Verum group 
in Part A will receive a 7th vaccination at V13B. 
Reference Therapy, Dose and Mode of Administration 
Comparator 
Name: Placebo 
Active ingredient: None 
Transporter: Phosphate buffer containing 0.35% aluminium hydroxide (adjuvant)   
Pharmaceutical Form: Injection ready vials 
Posology: Part A: Placebo group: Six administrations: the first five administered once 
every 4 weeks (28±3 days) and the sixth at week 42 (V18), 26 weeks after the fifth. Each 
administration consists of 1mL injection of ABvac40 vehicle. 

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Part B: Booster group: Five administrations: the first four administered once every 4 weeks 
(28±3 days) and the fifth at week 42 (V18B), 30 weeks after the forth. Each administration 
consists of 1mL injection of ABvac40 vehicle. 
Method of administration: Subcutaneous injection. 

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Key Study Variables: 
Part A: 
Primary Safety Variable: 
The rate (%) of Adverse Events (AEs).   
Primary Efficacy Variable: 
Maximal increment of specific anti-Aβ40 antibody signal (antibody titers estimated by 
ELISA (signal optical density (OD) values) in each subject with regard to the pre-treatment 
visit (either V0 or V1) 
Secondary Safety Variables: 
Other secondary safety endpoints will be evaluated, including:     
- 
withdrawal criteria (continuation decision) 
- 
number of withdrawn patients due to adverse events (AEs); cause of withdrawal  
- 
serious adverse events (SAEs)  
- 
physical  and neurological examination 
- 
concomitant medication 
- 
vital signs (blood pressure, heart rate, respiratory rate, body temperature), body 
mass (weight, height). 
- 
brain MRI  
- 
electrocardiogram (EKG) 
- 
analytical haematology, toxicology (reactive protein), biochemistry, coagulation, 
serology and urine test strip results. 
Secondary Efficacy Variables: 
- 
Characterization of the immune response:   
o Levels of anti-KLH and anti-Aβ42 antibodies in plasma  
o Level of anti-Aβ40 antibodies in CSF  
o Levels of cytokines in plasma including IL-2, IL-4, IL-5, IL-6, IL-10, IL-
13, IL-15, TNF-α and IFN-γ. 
o Analysis of the peripheral blood cell subsets by immunophenotyping. 
o Levels of antibody secreting cells and cytokine-secreting cells (including 
IFN-γ, TNF-α and IL-13)  
- 
Assessment of disease biomarkers: 
o Levels of Aβ peptides in plasma  
o Cortical fibrillary amyloid deposition assessed by PET scans. 
o Levels of CSF biomarkers (Aβ42, Tau, P-tau, neurofilament light and 
neurogranin) and other Aβ peptide species 
o Brain volumetric and atrophy of the hippocampus using magnetic 
resonance imaging 
- 
Assessment of cognition and quality of life: 
o Mini Mental State Examination (MMSE) 
o Clinical Dementia Rating scale (CDR)  
o Repeatable Battery for the Assessment of Neuropsychological Status 
(RBANS) 
o Alzheimer’s Disease Cooperative Study – Activities of Daily Living, Mild 
Cognitive Impairment (ADCS-ADL MCI)

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o Columbia Suicide Severity Rating Scale (C-SSRS) 
o Trail Making Test (TMT) 
o Investigator Global Evaluation (IGE) 
o Euroqol 5 Dimensions (EQ-5D-5L)   
 
Part B: 
Exploratory Safety Variables: 
- 
Rate (%) of AEs   
- 
Withdrawal criteria (continuation decision) 
- 
Number of withdrawn patients due to AEs; cause of withdrawal  
- 
SAEs  
- 
Physical and neurological examination 
- 
Concomitant medication 
- 
Vital signs (blood pressure, heart rate, respiratory rate, body temperature), body mass 
(weight, height). 
- 
Brain MRI  
- 
EKG 
-  Analytical haematology, toxicology (reactive protein), biochemistry, coagulation, 
serology and urine test strip results 
Exploratory Efficacy Variables: 
- 
Maximal increment of specific anti-Aβ40 antibody signal (antibody titers estimated by 
ELISA (signal OD values) in each patient with regard to the pre-treatment visit (either 
V0/V1 [Booster group] or V1B [Delayed start group]). 
- 
Characterization of the immune response:   
o Level of anti-Aβ40 antibodies in CSF 
o Levels of antibody secreting cells  
- 
Assessment of disease biomarkers: 
o Levels of Aβ peptides in plasma  
o Cortical fibrillary amyloid deposition assessed by PET scans. 
o Levels of CSF biomarkers (Aβ42, Tau, P-tau, neurofilament light and 
neurogranin) and other Aβ peptide species  
o Brain volumetric and atrophy of the hippocampus using magnetic resonance 
imaging 
- 
Assessment of cognition and quality of life: 
o MMSE 
o CDR scale  
o RBANS 
o ADCS-ADL MCI 
o C-SSRS 
o TMT 
o IGE 
o EQ-5D-5L 

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Study Assessments and Procedures: 
Medical  Evaluation:  
To be performed at all visits, except telephone interviews. Consists on the following tests:  
 Physical and neurological examination 
 Vital Signs 
 Electrocardiogram (EKG) (at visits V0, V16, V21, V23 and V25 [Part A], and at V16B, 
V21B and V22B [Part B]) (at all visits, except V22B, assessed centrally by the Medical 
Advisor) 
 Body biometrics 
Neuropsychological tests: 
Throughout the study, a series of neuropsychological tests will be performed. 
Part A:  
At the pre-selection (V0) MMSE, CDR and RBANS will be performed to decide if the 
participants meet inclusion criteria. In the baseline (V1), Int-6m (V16), V21, V23 and final 
visit (V25) the complete Neuropsychological battery and the test for quality of life will be 
performed as per the following table: 
 
 
Part B: 
At V16B, V21B and V22B visits, the complete Neuropsychological battery will be performed. 
In addition, the test for quality of life will be performed in V21B. 
Blood tests: 
 Complete blood analysis for safety and characterization of immune response:  
Part A: V0, V1, V3, V6, V9, V12, V15, V16, V17, V20, V21, V23 and V25. Part B: 
V1B, V3B, V6B, V9B, V12B, V15B, V16B, V17B, V20B, V21B and V22B. 
 Genotype ApoE (to be carried out in V1 [Part A]) 
Assessment of autoimmunity markers (to be held in V0, V21 and V25 [Part A] and V21B [Part 
B]): Antinuclear antibodies 
 Native anti-DNA antibodies 
 Anti-thyroglobulin antibodies 
 Anti-TPO antibodies
Neuropsychological Battery
V0 
Screening   
Week -8
V1           
Baseline      
Week 0
V16             
Int-6m
Week 24 
V21       
Int-12m
Week 52
V23       
Week 77
V25         
Final visit 
Week 104
MMSE (24-30 at inclusion)
X
-  
X
X
X
X
CDR (global score of 0.5 at inclusion)
X
-  
X
X
X
X
RBANS (score ≤ 85 at inclusion)
X
-  
X
X
X
X
COLUMBIA-SSRS (no answer "YES" in item 
4 or 5 at inclusion)
X
-  
X
X
X
X
ADCS-ADL MCI
-  
X
X
X
X
X
TMT-B
-  
X
X
X
X
X
GDS abbreviated (score≤ 85 at inclusion)
X
-  
-  
-  
-  
-  
IGE
-  
X
X
X
-  
X
Quality of Life Tests
EQ-5D-5L
-  
X
-  
X
-  
X
Neuropsychological tests

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Urine Analysis: 
 A urine analysis will be done at visits V0, V1, V3, V6, V9, V12, V15, V16, V17, V20, 
V21, V23 and V25 (Part A) and V3B, V6B, V9B, V12B, V15B, V16B, V17B, V20B, 
V21B and V22B (Part B). Urine samples will be analysed locally with a test strip. If 
no relevant abnormalities are found, local results will be collected in the eCRF (and 
corresponding source document). If any abnormality is found, the urine sample will be 
sent to central laboratory for reanalysis. 
The Sponsor Medical Advisor:  
 The Medical Advisor will review all EKGs centrally, and will inform the sites about 
any abnormal finding. 
 Medical Monitor 24/7 
Neuroimaging: 
 Brain MRI at visits:  
Part A: V0, V9, V16, V17, V21 and V25  
Part B: V1B (only in the absence of a MRI performed within 6 months (±15 days)), 
V9B, V16B, V17B, V21B and V22B. 
 MRI Central Reader will issue his assessment after every MRI (except V22B). This 
assessment will be taken into account for subjects’ eligibility and /or continuity. In 
V22B will be performed a MRI to identify any long-term safety issue. 
 Amyloid-PET evaluation at visits V0, V21 and V25 (Part A) and V21B (Part B). 
CSF collection for the following analysis at 
Part A: V1, V21 and at visit V25. Part B: V21B 
 Total proteins 
 Glucose 
 Albumin  
 Assessment of biomarkers (Aβ42, tau, P-tau, neurogranin,  neurofilament light and 
other Aβ peptide species)  
 Assessment of anti-Aβ antibodies 
 Treatment: 
 Vaccination (at visits V1, V4, V7, V10, V13 and V18 [Part A] and V1B, V4B, V7B, 
V10B, V13B and V18B [Part B]) 
 
Medical History (at all visits): 
 Relevant past and concomitant diseases 
 Adverse events 
 Concomitant medication 

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Statistical Methods: 
Part A: 
Primary Safety Analysis: 
The primary safety variable is the frequency (%) of Adverse Events (AEs) over the course of 
the study. The primary safety endpoint will be analyzed descriptively in the Safety population.
The hypothesis for the primary endpoint for safety is that ABvac40 will be safe for human 
administration, according to the observed pattern of AEs. 
The trial will be considered satisfactory if the pattern of AEs (overall or grouped as 
neurological, psychiatric or cardiovascular) is consistent with a good safety and tolerability 
profile of ABvac40 for human administration at the final of the study. 
For this primary safety analysis, the amyloid-PET negative and the amyloid-PET positive 
subjects will be pooled together.  
Primary Efficacy Analysis (immunogenicity): 
The primary efficacy variable is the maximal increment of specific anti-Aβ40 antibody signal 
(antibody titers estimated by ELISA [signal OD values]) in each subject with regard to the pre-
treatment visit (either V0 or V1). For this primary efficacy analysis, the amyloid-PET negative 
and the amyloid-PET positive subjects will be pooled together. 
The trial will be considered successfully confirmatory regarding efficacy (immunogenicity) of 
ABvac40 if the average maximal increment (MΔ) of anti-Aβ40 antibody signal (OD in ELISA) 
in the verum group is >0 OD than the average MΔ in the placebo group. 
Secondary Safety Analysis: 
The safety and tolerability analysis will be based on the safety population, comprising all 
subjects who took at least one dose of study medication. For this secondary safety analysis, the 
amyloid-PET negative and the amyloid-PET positive subjects will be pooled together. 
Safety and tolerability assessments will be based on the following parameters: 
- 
withdrawal criteria. 
- 
number of withdrawn patients due to adverse events (AEs); cause of withdrawal  
- 
serious adverse events (SAEs)  
- 
physical and neurological examination  
- 
concomitant medication 
- 
vital signs (blood pressure, heart rate, respiratory rate, body temperature), body 
mass (weight, height). 
- 
brain MRI  
- 
electrocardiogram (ECG or EKG) 
- 
analytical haematology, immunology, toxicology (reactive protein, cytokines, T 
cell activation), biochemistry, coagulation, serology and urine test strip results. 
The number (%) of withdrawals due to AEs and the reason(s) for these withdrawals will be 
summarized using appropriate descriptive statistics. 
All adverse events, results from physical and neurological examinations, results of new onset 
and/or worsening of signs found from physical examination, safety analytics, vital signs and 
EKG recorded during the study will be presented in tables by treatment group, and frequencies 

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by system-organ class will be calculated. These results will be analyzed descriptively and 
incidences summarized. 
Blood pressure, heart rate, respiratory rate, body temperature, body mass and analytic 
parameters as well as changes from baseline will be analyzed using descriptive statistics for 
each measured time point and for the end point (defined as the last observation available). 
Patient demographics, baseline characteristics, general treatment for AD and concomitant 
medication will be analyzed using descriptive statistics. 
As an exploratory analysis, the incidence of AEs (overall or grouped as neurological, 
psychiatric or cardiovascular) will be compared between the group receiving the active 
treatment (ABvac40) and the control group receiving placebo. 
Secondary Efficacy Analysis: 
The trial will be considered satisfactory if the difference of the average maximal increment 
(MΔ) of anti-Aβ40 antibody signal (OD in ELISA) in the treated group is > 1.778 OD than the 
average MΔ in the placebo group; the difference that was reached between both groups in the 
phase I clinical trial of ABvac40. 
Secondary efficacy variables will be analyzed in an exploratory manner, using descriptive 
statistics. The secondary efficacy variables regarding assessment of disease biomarkers and 
cognition will be analyzed in the overall group and separately in the amyloid-PET negative 
(verum and placebo) and the amyloid-PET positive (verum and placebo) subjects. 
Statistical comparison between groups of treatment (placebo/treatment) will be done for each 
time point and for the end point (defined as the last observation available). 
The change from baseline in absolute value will be analyzed for each time point and for the 
end point (defined as the last observation available). 
Mixed-model repeated-measures (MMRM) analyses will be performed for all the primary and 
secondary efficacy variables (section 7.1) to assess between-group differences in change scores 
from baseline (V0/V1) to 12-months visit (V21), and separately to the final visit (V25). Patient 
demographics, baseline characteristics, general treatment for AD and concomitant medication 
will be analyzed using descriptive statistics. 
 
Part B: 
The analyses for Part B will mirror the analyses of Part A, without testing any hypothesis. The 
detailed statistical analyses will be described in the Statistical Analysis Plan. 
 
Determination of Sample Size: 
This trial is intended as a confirmatory assay for the primary safety and primary efficacy 
variables. 
For the safety primary endpoint, the sample size may be calculated to ensure ≥95% probability 
of detecting an adverse event that occurs with a rate of at least 5% within the ABvac40 treated 
dose cohort. Under these assumptions, a minimum of 60 patients in the active dose group will 
be needed (and 60 in the placebo group). 

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This sample size (60 patients in the active group and 60 in the placebo group), considering 
~40% dropouts along the clinical trial, will imply that approximately 70 patients will complete 
the study. These 70 patients will have greater than 85% power to detect a treatment increment 
of 1.778 (the one found in ABvac40 Phase I trial) in maximum change from baseline in anti-
Aβ40 antibody signal (OD in ELISA without preadsorption) between the active group and 
placebo group, using a one-sided T test at a significance level of 0.025 (and considering 
standard deviations of 2.0 and 1.0 in the active and placebo groups, respectively). The study 
will not be powered to demonstrate efficacy in clinical or other biomarker outcomes. 
 
Anticipated study duration: 
First Patient In: February 2018 
Last Patient In: September 2019 
Last Patient Out (Part B): May 2022 
Thus, the expected duration of the trial is 51 months, from February 2018 to May 2022. 

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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL ........................................................................................... 1 
PROTOCOL SYNOPSIS.......................................................................................................... 4 
TABLE OF CONTENTS ........................................................................................................ 24 
LIST OF TABLES: ................................................................................................................. 28 
GLOSSARY AND ABBREVIATIONS ................................................................................. 29 
1 
GENERAL INFORMATION ......................................................................................... 32 
2 
BACKGROUND INFORMATION ............................................................................... 33 
2.1 
Name and Description of the Investigational Product(s) ...................................... 34 
2.2 
Relevant Findings from Nonclinical and Clinical Trials ...................................... 35 
2.3 
Known and Potential Risks and Benefits to Human Subjects .............................. 37 
2.4 
Description of and Justification for the Route of Administration, Dosage 
Regimen, and Treatment Period(s) ....................................................................... 38 
2.4.1 
Administration of Investigational Products ................................................ 38 
2.4.2 
Justification for Selection of Doses/Timing of Investigational Products ... 39 
2.5 
Compliance Statement .......................................................................................... 39 
2.6 
Study Population ................................................................................................... 39 
2.7 
Relevant Data and Literature Review ................................................................... 40 
3 
STUDY OBJECTIVES AND PURPOSE ...................................................................... 44 
3.1 
Part A (Randomized, Double-Bblind, placebo-controlled – 18 to 24 months 
follow-up) ............................................................................................................. 44 
3.1.1 
Safety Objectives ........................................................................................ 44 
3.1.1.1 
PRIMARY SAFETY OBJECTIVE .................................................. 44 
3.1.2 
Efficacy Objectives ..................................................................................... 44 
3.1.2.1 
PRIMARY EFFICACY (IMMUNOGENICITY) OBJECTIVE ...... 44 
3.1.2.2 
SECONDARY (EXPLORATORY) EFFICACY OBJECTIVES .... 44 
3.2 
Part B (ABvac40 delayed start, open label [Part A assignment will remain 
blinded for investigators and patients] – 18 months follow-up) ........................... 44 
3.2.1 
Exploratory Safety Objective ...................................................................... 44 
3.2.2 
Exploratory Efficacy Objectives ................................................................. 45 
3.2.2.1 
IMMUNOGENICITY ....................................................................... 45 
3.2.2.2 
OTHER ............................................................................................. 45 
4 
STUDY DESIGN ............................................................................................................ 46 
4.1 
Endpoints .............................................................................................................. 46 
4.1.1 
Part A .......................................................................................................... 46 
4.1.2 
Part B .......................................................................................................... 47 
4.2 
Study Design and Plan .......................................................................................... 48 
4.2.1 
Part A .......................................................................................................... 48 

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4.2.2 
Part B .......................................................................................................... 52 
4.3 
Measures Taken to Minimize/Avoid Bias ............................................................ 56 
4.3.1 
Subject Numbering ..................................................................................... 56 
4.3.2 
Randomization ............................................................................................ 56 
4.3.3 
Blinding ....................................................................................................... 56 
4.4 
Study Treatments .................................................................................................. 57 
4.4.1 
Treatments to Be Administered .................................................................. 57 
4.4.2 
Labeling of Investigational Product(s) ........................................................ 59 
4.4.3 
Packaging of Investigational Product(s) ..................................................... 59 
4.4.4 
Storage of Investigational Product(s) .......................................................... 59 
4.5 
Expected Duration of Subject Participation in the Study ..................................... 60 
4.6 
Discontinuation Criteria for Individual Subjects and Study ................................. 60 
4.6.1 
Discontinuation Criteria for Individual Subjects ........................................ 60 
4.6.2 
Premature Termination of Study/Closure of Center ................................... 60 
4.7 
Accountability Procedures for Investigational Product(s) .................................... 61 
4.8 
Maintenance of Treatment Randomization Codes ................................................ 62 
4.9 
Data to Be Recorded on the eCRFs ...................................................................... 62 
4.9.1 
Part A .......................................................................................................... 62 
4.9.1.1 
SCREENING PHASE: VISIT V0 (WEEKS -8 TO 0) ..................... 62 
4.9.1.2 
SELECTION AND ACTIVE PHASE: VISITS V1-V21 (WEEKS 
0-50) .................................................................................................. 64 
4.9.1.3 
FOLLOW-UP PERIOD: VISITS V22 - V25 (WEEKS 51 TO 
104) ................................................................................................... 66 
4.9.2 
Part B .......................................................................................................... 66 
4.9.3 
Premature discontinuation visit (PDV) ....................................................... 68 
4.9.4 
Information collected on selection failures ................................................. 68 
5 
SELECTION AND WITHDRAWAL OF SUBJECTS .................................................. 69 
5.1 
Inclusion Criteria .................................................................................................. 69 
5.2 
Exclusion Criteria: ................................................................................................ 70 
5.3 
Subject Withdrawal Criteria ................................................................................. 71 
5.3.1 
Screen Failures ............................................................................................ 71 
5.3.2 
Removal of Subjects ................................................................................... 71 
5.3.3 
Subject Replacement ................................................................................... 72 
5.3.4 
Follow-up of Subjects Withdrawn from Study Treatment ......................... 72 
6 
TREATMENT OF SUBJECTS ...................................................................................... 73 
6.1 
Administration and Timing of Investigational Products for Each  Subject .......... 73 
6.1.1 
COVID-19 Testing ...................................................................................... 74 
6.1.1.1 
PART A ............................................................................................ 74 
6.1.1.2 
PART B ............................................................................................. 74 

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6.2 
Prior and Concomitant Therapy ............................................................................ 75 
6.2.1 
Prohibited Medications Prior to Study Participation .................................. 75 
6.2.2 
Prohibited Concomitant Medications during the Study .............................. 75 
6.2.3 
Restricted Concomitant Medications during the Study .............................. 75 
6.3 
Treatment Compliance .......................................................................................... 76 
7 
ASSESSMENT OF EFFICACY..................................................................................... 77 
7.1 
Efficacy Variables ................................................................................................. 77 
7.1.1 
Part A .......................................................................................................... 77 
7.1.1.1 
PRIMARY EFFICACY VARIABLE ............................................... 77 
7.1.1.2 
SECONDARY EFFICACY VARIABLES ...................................... 77 
7.1.2 
Part B .......................................................................................................... 78 
7.1.2.1 
EXPLORATORY EFFICACY VARIABLES ................................. 78 
7.2 
Methods and Timing for Assessing, Recording, and Analyzing Efficacy 
Parameters ............................................................................................................. 78 
7.2.1 
Observations and Measurements ................................................................ 78 
7.2.1.1 
ASSESSMENT AND CHARACTERIZATION OF THE 
IMMUNE RESPONSE ..................................................................... 79 
7.2.1.2 
ASSESSMENT OF THE AD BIOMARKERS ................................ 79 
7.2.1.3 
ASSESSMENT OF COGNITION AND QUALITY OF LIFE ........ 80 
7.2.2 
Description of Laboratory Tests and Procedures ........................................ 81 
8 
ASSESSMENT OF SAFETY ......................................................................................... 84 
8.1 
Safety Parameters .................................................................................................. 84 
8.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters ............................................................................................................. 84 
8.2.1 
Adverse Events ........................................................................................... 85 
8.2.2 
Clinical Laboratory Evaluations ................................................................. 85 
8.2.3 
Vital Signs and body mass index ................................................................ 86 
8.2.4 
Physical and Neurological Examinations ................................................... 86 
8.2.5 
EKG ............................................................................................................ 87 
8.2.6 
Brain MRI ................................................................................................... 87 
8.2.7 
Patient’s Diary and Patient emergency card ............................................... 87 
8.3 
Procedures for Eliciting Reports of and for Recording and Reporting Adverse 
Event and Intercurrent Illnesses ............................................................................ 88 
8.3.1 
Warnings/Precautions ................................................................................. 88 
8.3.2 
Adverse Event Monitoring .......................................................................... 88 
8.3.3 
Adverse Event Definitions .......................................................................... 88 
8.3.3.1 
ADVERSE EVENTS ........................................................................ 88 
8.3.3.2 
SUSPECTED ADVERSE DRUG REACTIONS/ADVERSE 
REACTIONS .................................................................................... 89 

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8.3.4 
Assessment of Causality of Adverse Event ................................................ 89 
8.3.5 
Severity of Adverse Event or Suspected Adverse Drug Reaction .............. 89 
8.3.6 
Expectedness of Adverse Event or Suspected Adverse Drug Reaction ..... 90 
8.3.7 
Seriousness of Adverse Event or Suspected Adverse Drug Reaction ........ 90 
8.3.8 
Adverse Event Documentation ................................................................... 91 
8.3.9 
Reporting of Serious Adverse Events ......................................................... 92 
8.3.10 
Special safety procedures ............................................................................ 93 
8.3.10.1 
SERIOUS ADVERSE EVENTS OF SPECIAL INTEREST ........... 93 
8.3.10.2 
REACTIONS TO THE VACCINE .................................................. 94 
8.3.11 
Reference safety information ...................................................................... 94 
8.3.11.1 
EXPECTED SERIOUS ADVERSE DRUG REACTIONS ............. 94 
8.3.11.2 
UNEXPECTED SERIOUS ADVERSE DRUG REACTIONS ....... 95 
8.4 
Type and Duration of the Follow-Up of Subjects after Adverse Events .............. 95 
9 
STATISTICS .................................................................................................................. 96 
9.1 
Statistical Methods ................................................................................................ 96 
9.1.1 
Demographic and Baseline Characteristics ................................................ 96 
9.1.2 
Efficacy Analysis (Part A) .......................................................................... 96 
9.1.2.1 
PRIMARY EFFICACY ANALYSIS (IMMUNOGENICITY) ........ 96 
9.1.2.2 
SECONDARY EFFICACY ANALYSIS ......................................... 97 
9.1.3 
Safety Analysis (Part A) ............................................................................. 97 
9.1.3.1 
PRIMARY SAFETY ANALYSIS ................................................... 98 
9.1.3.2 
SECONDARY SAFETY ANALYSIS ............................................. 98 
9.1.4 
Efficacy and Safety Analysis (Part B) ........................................................ 99 
9.1.5 
Interim Analysis (Int) .................................................................................. 99 
9.1.5.1 
DATA SAFETY MONITORING BOARD (DSMB) ..................... 100 
9.2 
Determination of Sample Size ............................................................................ 102 
9.3 
Level of Significance to Be Used ....................................................................... 102 
9.4 
Criteria for Termination of the Study ................................................................. 102 
9.5 
Procedure for Accounting for Missing, Unused, and Spurious Data  (if 
applicable) ........................................................................................................... 103 
9.6 
Reporting Deviation(s) from the Statistical Analysis Plan ................................. 103 
9.7 
Subject Population(s) for Analysis ..................................................................... 103 
10 DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ........................................... 105 
11 QUALITY CONTROL AND QUALITY ASSURANCE ............................................ 106 
11.1 
Monitoring .......................................................................................................... 106 
11.2 
Audit and inspection ........................................................................................... 107 
11.3 
Data Management ............................................................................................... 107 
11.3.1 
Data Documentation ................................................................................. 107 

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11.3.2 
Data processing ......................................................................................... 108 
11.3.3 
Coding ....................................................................................................... 108 
11.3.4 
Data cleaning ............................................................................................ 108 
11.3.5 
Missing and false data ............................................................................... 108 
11.3.6 
Closing the database ................................................................................. 109 
12 ETHICS ......................................................................................................................... 110 
12.1 
Institutional Review Board/Ethics Committee ................................................... 110 
12.2 
Ethical Conduct of the Study .............................................................................. 110 
12.3 
Regulatory Authority Approvals/Authorizations ................................................ 110 
12.4 
Subject Information and Consent ........................................................................ 111 
12.5 
Confidentiality .................................................................................................... 111 
12.6 
Patient health insurance ...................................................................................... 111 
12.7 
Compensation for the subject .............................................................................. 112 
13 DATA HANDLING AND RECORD KEEPING ........................................................ 113 
13.1 
Data Handling ..................................................................................................... 113 
13.2 
Record Retention ................................................................................................ 113 
14 FINANCING AND INSURANCE ............................................................................... 114 
15 PUBLICATION POLICY ............................................................................................ 115 
16 REFERENCES ............................................................................................................. 116 
17 APPENDICES .............................................................................................................. 120 
 
 
LIST OF TABLES: 
TABLE 1: SAFETY AND TOLERABILITY OF ABVAC40 AT PHASE I CLINICAL 
TRIAL ............................................................................................................................. 36 
TABLE 2: OVERALL STUDY DESIGN (PART A) ............................................................ 49 
TABLE 3: SCHEDULE OF STUDY PROCEDURES AND EVENTS (PART A) .............. 50 
TABLE 4: OVERALL STUDY DESIGN (PART B) ............................................................ 52 
TABLE 5: SCHEDULE OF STUDY PROCEDURES AND EVENTS (PART B) ............... 54 
TABLE 6:  TREATMENT TIME POINTS ............................................................................ 57 
FIGURE 1 TREATMENT ADMINISTRATION SCHEDULE SCHEME ........................... 73 
TABLE 7 NEUROPSYCHOLOGICAL TESTS: ................................................................... 81 
TABLE 8. NAME, DESCRIPTION AND LOCATION OF LABORATORY TESTS ......... 82 
 
 
 

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GLOSSARY AND ABBREVIATIONS 
AChEI 
Acetil Cholinesterasa 
AD 
Alzheimer´s Disease 
ADAS-cog  
Alzheimer's Disease Assessment Scale- Cognitive Subscale 
ADCS-ADL 
Alzheimer’s Disease Cooperative Study – Activities of Daily Living 
ADCS-iADL 
Alzheimer's Disease Cooperative Study Activities of Daily Living 
inventory instrumental items 
ADR 
Adverse drug reaction 
AE 
Adverse event 
AEMPS 
Agencia Española de Medicamentos y Productos Sanitarios 
a-MCI 
Amnestic Mild Cognitive Impairment 
ANCOVA 
Analysis of Covariance 
a-PET 
Amyloid PET 
AR 
Adverse reaction 
BL 
Baseline visit 
CDR 
Clinical Dementia Rating scale 
CDR-SB 
Clinical Dementia Rating-Sum of Boxes 
CHMP 
Committee for Medicinal Products for Human Use 
CI 
Confidence interval 
eCRF 
Case report form/electronic case report form 
CRO 
Contract research organization 
CSF 
Cerebrospinal Fluid 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DBP 
Diastolic Blood Pressure 
DSMB 
Data Safety Monitoring Board  
EDC 
Electronic data capture 
EKG 
Electrocardiogram 
EMA 
European Medicines Agency 
EQ-5D 
Euroqol 5 dimensions 
FDA 
Food and Drug Administration 
FV 
Final visit 

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HAV 
Hepatitis A virus 
HBV 
Hepatitis B virus 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH GCP 
International Conference on Harmonization Good Clinical Practice 
IgA 
Immunoglobulin A 
IGE 
Investigator Global Evaluation 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
Int 
Interim analysis 
IMP 
Investigational medicinal product 
IRB/EC 
Institutional Review Board/Ethics Committee 
ITT 
Intent-to-treat 
IV 
Intravenous 
IVIG 
Intravenous Immune Globulin (generic terminology)    
IWG 
International Working Group 
kg 
Kilogram 
KLH 
Keyhole limpet hemocyanin 
LC-MS 
Liquid Chromatography-Mass Spectrometry 
MedDRA 
Medical Dictionary for Regulatory Activities 
M-AD 
Mild Alzheimer´s Disease 
MCI 
Mild Cognitive Impairment 
MCI-DAD 
Mild Cognitive Impairment due to Alzheimer´s Disease 
MMSE 
Mini Mental State Examination 
MMRM 
Mixed-Model Repeated-Measures 
MRI  
Magnetic Resonance Imaging  
m 
Month  
NIA-AA 
National Institute on Aging - Alzheimer´s Association 
NPB 
Neuropsychological battery 
OD 
Optical density 
P-AD 
Prodromal Alzheimer´s Disease 

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PET 
Positron emission tomography 
p-TAU 
Phosphorilated Tau 
RBANS 
Repeatable Battery for the Assessment of Neuropsychological Status 
SAE 
Serious adverse event 
SBP 
Systolic blood pressure 
Sc 
Safety control 
SCR 
Screening visit 
SD 
Standard deviation 
SDCC 
Safety and Data Control Committee  
T 
Temperature / Telephone call 
TEAE 
Treatment-emergent adverse event 
TMT 
Trail Making Test 
US 
United States 
Vc 
Vaccination 
VM-AD 
Very Mild Alzheimer's Disease 
V 
Visit 
WBC 
White blood cell 
 

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1 
GENERAL INFORMATION 
Protocol Title 
A Multi-center, Randomized, Double-blind, Placebo-controlled, 24 months Study in Patients 
with  amnestic Mild Cognitive Impairment or Very Mild Alzheimer’s Disease to Investigate 
the Safety, Tolerability and Immune Response of Repeated Subcutaneous Injections of 
ABvac40. 
 
Sponsor/monitor/technical coordination: Investigators and study administrative 
structure.  
 
Sponsor 
ARACLON BIOTECH, S.L. a GRIFOLS company, 
Vía de la Hispanidad, 21 
50009 Zaragoza, Spain 
 
Study Coordinator Name: 
 
 
 
  
 
Sponsor´s Scientific Personell 
r Araclon Biotech. Zaragoza 
 Araclon Biotech. Zaragoza 
 
Data Safety Monitoring Board  
 
 
 
  
 
Information regarding the Data Safety Monitoring Board (DSMB) is detailed in Section 
9.1.5.1. 
 
 

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2 
BACKGROUND INFORMATION 
The first trial in-humans of ABvac40 (Phase I; registered under EUDRACT nº: 2012-004933-
18) including 24 individuals (16 in verum and 8 placebo) diagnosed with mild to moderate 
Alzheimer’s Disease (AD) showed a good safety and tolerability profile of the investigational 
medicine product (IMP). Additionally, the phase I study explored the immunogenicity of 
ABvac40 which resulted positive in the majority of the individuals belonging to the verum 
group, particularly in those receiving the third immunization included after amending the initial 
two-injection protocol  
Recently, the European Medical Agency (EMA) Committee for Medicinal Products for Human 
Use (CHMP) released a “Draft guideline on the clinical investigation of medicines for the 
treatment of Alzheimer’s disease and other dementias” (EMA/CHMP/539931/2014) which 
reviewed the last conceptual advancements on the natural history of AD. This document 
recognizes the new sets of research diagnostic criteria for AD published by the International 
Working Group (IWG) and the National Institute on Aging - Alzheimer´s Association (NIA-
AA) and admit that from a regulatory perspective both are accepted for diagnosis of AD for 
research purposes and for trial enrichment. However, it is important to note that MCI due to 
AD (MCI-DAD) according to the NIA-AA criteria and those for Prodromal AD (P-AD) as 
published by IWG differ in several aspects, particularly with regard to the mandatory presence 
or not of positive AD biomarkers. 
Additionally the EMA advises to perform phase II trials in the same population expected to be 
targeted at phase III; assumes the usefulness of biomarkers to better characterize the earlier 
stages of the disease; and admits that subjects with MCI-DAD/P-AD and mild AD (M-AD) 
may be studied together. 
Thus, in line with this CHMP document, the present ABvac40 phase II clinical trial will be 
carried out on MCI-DAD/P-AD and/or very mild AD (vm-AD) patients, characterized by their 
amyloid-positron emission tomography (a-PET) neuroimaging profile. 
The present study is aimed to confirm the Phase I safety and immunogenicity results in an 
adequately powered Phase II trial, including a larger population sample and a new batch of the 
IMP. Taken into account the results of Phase I, we will further explore the therapeutic range 
of ABvac40 by increasing the number of immunizations up to 5 administered at monthly 
intervals plus a delayed booster shot. This approach will allow exploring the development of 
the immunological memory to gain an insight on the possible future vaccination schedule. In 
addition, we will address a deeper characterization of the immune response, including the 
exploration of its effects on the biomarkers of β-amyloid (Aβ) cortical pathology and cognitive 
impairment. Taken together these data will be crucial for a founded "go no-go" decision into 
Phase III and an appropriated confirmatory designing. 
In this clinical trial we will follow-up the EMA recommendations about study population and 
the biomarkers selected. The EMA includes the category "prodromal AD/MCI due to AD" in 
its Discussion paper EMA / CHMP / 539931/2014 which will lead to the revision of the current 
legislation on medicinal products for the treatment of AD (EMA / CHMP / 617734/2013). 

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The EMA has published favorable qualification opinions for the use of levels of biomarkers as 
tools for the enrichment of clinical trials with anti-amyloid therapies (EMA / CHMP / SAWP 
/ 893622/2011; and EMA / CHMP / SAWP / 102001/2011). 
In the same line the EMA has issued favorable qualification opinions to the use of PET amyloid 
imaging as a biomarker for enrichment for use in pre-dementia AD clinical trials (EMA / 
CHMP / SAWP / 892998/2011) and the determination of hippocampal atrophy by magnetic 
resonance imaging (MRI) for use in clinical trials for regulatory purpose in pre-dementia stage 
of Alzheimer’s disease (EMA / CHMP / SAWP / 809208 / PET-amyloid 2011). 
 
2.1 
Name and Description of the Investigational Product(s) 
See Section 4.4 Study Treatments for detail. 
Study Medication 
Name: ABvac40  
Active ingredient: Aβx-40 peptide conjugated to keyhole limpet hemocyanin (KLH) 
Transporter: Phosphate buffer containing 0.35% aluminium hydroxide (adjuvant)   
Pharmaceutical Form: vials ready to inject 
Posology: Part A: Verum group: Six administrations: the first five administered once every 
4 weeks (28±3 days) and the sixth at week 42 (V18), 26 weeks after the fifth. Each 
administration consists of 1mL injection of ABvac40 (containing 0.2 mg of Abetax-40). 
Part B: Delayed start group: Six administrations: the first five administered once every 4 
weeks (28±3 days) and the sixth at week 42 (V18B), 26 weeks after the fifth immunization. 
Booster group: One administration at week 16 (V13B).  
Each administration consists of 1mL injection of ABvac40 (containing 0.2 mg of Abetax-
40). 
Method of administration: Subcutaneous injection. 
 
Comparator 
Name: Placebo 
Active ingredient: None 
Transporter: Phosphate buffer containing 0.35% aluminium hydroxide (adjuvant)   
Pharmaceutical Form: Injection ready vials 
Posology: Part A: Placebo group: Six administrations: the first five administered once 
every 4 weeks (28±3 days) and the sixth at week 42 (V18), 26 weeks after the fifth.  
Each administration consists of 1mL injection of ABvac40 vehicle. 

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Part B: Booster group: Five administrations: the first four administered once every 4 
weeks (28±3 days) and the fifth at week 42 (V18B), 30 weeks after the forth.  
Each administration consists of 1mL injection of ABvac40 vehicle. 
Method of administration: Subcutaneous injection. 
See section 4.4 Study Treatment for details. 
 
2.2 
Relevant Findings from Nonclinical and Clinical Trials 
For a detailed description of pre-clinical studies in the development of ABvac40 (see 
investigator´s brochure (IB) document). 
ABvac40 has undergone a clinical development program, a phase I clinical trial in humans 
(AB1203) approved by the Agencia Española de Medicamentos y Productos Sanitarios 
(AEMPS) on 24 July 2013, entitled “A randomized, placebo-controlled, parallel group, double-
blinded, single-center phase-I, pilot study to assess tolerability and safety of repeated 
subcutaneous administration of two single-doses of ABvac40 applied to patients with mild to 
moderate Alzheimer's Disease”  
The primary objective of the AB1203 study was to evaluate the safety and tolerability of two 
immunizations with ABvac40, compared to placebo, in 24 patients with mild or moderate 
Alzheimer’s disease, randomly distributed into two distinct groups with a verum: placebo ratio 
of 2:1. Each immunization consisted of injecting subcutaneously one millilitre (1) of ABvac40 
or placebo. The secondary objective was to evaluate in an exploratory manner ABvac40 
biological activity by determining plasma levels of anti-Aß40 antibodies and Aβ peptides.  
An Interim Analysis was carried out with the first 8 randomized patients without disclosing 
the blind of the study. According to the safety and biological activity data obtained in these 
first eight participants who had completed the initial study protocol, it was decided to amend 
the protocol to include an additional injection of ABvac40 (or placebo as corresponded) in the 
remaining sixteen patients. 
This protocol amendment was approved by the Ethics Committee on 2 December 2014 and by 
the AEMPS by administrative silence. This additional injection of ABvac40 (or placebo) was 
administered 29 days after the second administration in the remaining sixteen patients included 
in the trial. 
On July 30th 2015, the final visit to the last participant in the trial was performed. On October 
27th 2015, after the database was closed, the final meeting of the Safety and Data Control 
Committee (SDCC) was held, the trial randomization was unveiled and the AEMPS was 
notified of the end of the clinical trial. 
For a complete description of the Phase I results see the Clinical Study Report. In brief, the 
analysis of the Phase I primary endpoint – to evaluate the safety and tolerability of ABvac40 
immunizations – carried out in the Safety and Intent-to-treat (ITT) populations (24 patients) – 

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showed no statistical significant differences between the control and the treatment group 
regarding the frequency of overall adverse events (AEs) and grouped as neurological, 
psychiatric and cardiovascular (see table 1). There were no AEs leading to discontinuation of 
study treatment. All AEs recorded in the database were of mild severity and no action was 
needed. Of particular relevance, no incident vasogenic edema or sulcal effusion (ARIA-
Edema) was detected throughout the study period and only one cortical micro-hemorrhage 
(ARIA-Hemorrhage) was detected by MRI after the 2º injection in a patient (S002) who at the 
end turned out to belong to the placebo group. 
 
Table 1: Safety and Tolerability of ABvac40 at Phase I Clinical Trial 
 
The analysis of ABvac40 biological activity – carried out in the ITT population (24 patients) 
– showed a significant difference between groups of treatment at the final visit only for the 
mean optical density (OD) without pre-adsorption (representing level of anti-Aβ40 antibodies): 
median of 2.67 (range, 0.7-4.1) in the ABvac40 group and median of 0.60 (range, 0.6-1.3) in 
the placebo group (p=0.0129). Although the level of response had a considerable individual 
component as could be expected, 87.5 % of patients in the verum group were considered 
responders (those which, at any visit, showed a 3 standard deviations (SD) increase in OD with 
regard to the pre-immune sample) a figure which reached 91 % of the population that received 
the 3 immunization shots in the amended protocol. The Mean OD with pre-adsorption indicates 
that over 95% of the signal registered in the plasma samples from the patients treated with 
verum was due to the presence of specific anti-Aβ40 antibodies. 
The other parameters of biological activity analyzed did not were significant different between 
the two groups of treatment at the final visit.  
In summary, the clinical trial was considered satisfactory because the average frequency of 
AEs (overall or grouped as neurological, psychiatric or cardiovascular) was not significantly 
different between the group that received the active treatment (ABvac40) and the placebo 
group. In fact, the incidence of AEs tended to be lower in the active treatment group, 
 
 
 
 
 
 
 
 
Safety and tolerability of ABvac40 at Phase I 
 
Safety / ITT  population (N=24) 
Total (N=24)  
ABvac40 (N=16)  
Placebo (N=8)  
P-value* 
 
%AEs / Patients 
# AEs  
# Patients  
# 
AEs  
# Patients  # AEs # Patients P-value* 
 
Total of AEs  
71 
18 (75.00%)  42 11 (68.75%)  
29 
7 (87.50%) 0.6214 
 
Neurological AEs  
15 
10 (41.67%)  
9 
5 (31.25%)  
6 
5 (62.50%)  0.2038 
 
Psychiatric AEs  
3
3 (12.50%)  
2 
2 (12.50%)  
1 
1 (12.50%) 1.000  
Cardiovascular AEs  
2
2 (8.33%)  
1 
1 (6.25%) 
1 
1 (12.50%) 1.000  
* Fisher's exact test p-value 
 
 
 
 
 
 
 

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particularly with regard to the Neurological and Cardiovascular events. Therefore, the active 
treatment (ABvac40) shows a good safety and tolerability profile. 
Additionally, the first interim analysis of the present ongoing Phase II clinical trial was 
conducted in July 2019, after the first 36 patients have completed their 24-week visit. The 
results showed that ABvac40 has a favorable profile concerning futility criteria, safety and 
immunogenicity data, encouraging the amendment of the study protocol to include the 
delayed-start extension (Part B).  
Encouraged by these results and taking into account that ABvac40 is an active vaccine directed 
specifically against the Aβ-40 peptide, a cross-over for the subjects receiving placebo will be 
offered after they complete their 18-months visit (V23), aiming to obtain additional safety data 
(patient-years of ABvac40 exposure) and to be able to assess its efficacy after a delayed-start.   
Furthermore, the long-term safety and tolerability of ABvac40 in patients receiving a booster 
after their Part A vaccination scheme will be assessed. 
 
2.3 
Known and Potential Risks and Benefits to Human Subjects 
The ABvac40 formula is designed to avoid the known potential risks of immunization against 
AD (meningoencephalitis, microhemorrhages and angiogenic cerebral edema) while 
maintaining an efficient immune response (see IB document). 
In this regard, the immunogen peptide of ABvac40 (Aβx-40) does not contain the epitope 
recognized by T cells whose activation was considered the primary cause of aseptic 
meningoencephalitis in the AN1792 vaccine study. The occurrence of microhemorrhages and 
cerebral edema has been associated with passive immunization but especially antibodies 
(passive immunization) or induced antibodies (active immunization) against the N-terminal of 
Aβ. However, ABvac40 is designed to recognize the C-terminal segment of Aβ. These 
segments are not accessible to antibodies as long as the Aβ molecule is not secreted in body 
fluids. 
Moreover, the ABvac40 formulation contains a Th2 type adjuvant, widely used in vaccines for 
human use, which directs the immune response towards the production of circulating 
antibodies minimizing the pro-inflammatory cell response. 
The safety assumptions on which the design of ABvac40 is based have been upheld by the 
results of the Phase I clinical trial (see Clinical Study Report document) and all experiments 
carried out to date including three formal toxicology tests. 
The potential benefit for participants in the Phase II trial, that we believe to be sufficiently 
substantiated, rests in the fact that the vaccination can elicit an immune response against Aß40 
peptide potentially capable of modifying the course of the disease. We maintain that this 
potential benefit could occur in both the amyloid-PET positive and amyloid-PET negative 
amnestic-MCI and vm-AD patients intended to be recruited for this clinical trial.  

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This idea is mainly supported, firstly, by studies showing that a considerable proportion of 
MCI patients are experiencing accelerated rates of Aβ deposition and cognitive/functional 
decline before reaching current threshold for amyloid positivity [26] and secondly, in reports 
that ~70% of a-MCI that meet the core clinical criteria defined by the eligibility criteria in the 
present clinical trial (independent of their amyloid-PET or CSF Aβ42 status) progress to 
dementia in a 26.6 month follow-up (range 6-68 months) [27]. In those a-MCI and vm-AD 
patients deemed as Aβ-negative, the clinical symptomatology may be driven by soluble Aβ 
isoforms and/or perivascular deposits of Aβ40, not detectable by current Aβ neuroimaging, 
and susceptible to being modified by our anti-Aβ40 treatment. In addition, there is no 
alternative pharmacological treatment approved for these MCI patients who have such a 
gloomy prognosis and the treatments currently available for AD are merely symptomatic; they 
do not alter the course of the disease, and are effective only in a limited percentage of patients 
and for a limited time. Although this situation in no way justifies any excessive risks, assuming 
that ABvac40 has showed a good safety and tolerability profile and anti-Aβ40 specific 
immunogenicity in previous clinical trial (Phase I), participants in the trial and in the future, 
other patients affected by Alzheimer's disease could benefit from this treatment, especially if 
treatment could be offered in the early stages of the disease. 
Furthermore, on the basis of current knowledge, the foreseeable risks of clinical use of the 
ABvac40 vaccine are considered scarce and reasonably controllable. 
In summary from our point of view this ABvac40 clinical trial presents a risk-benefit balance 
that seems positive for both study participants and for society. 
The results of the first interim analysis of the present ongoing Phase II clinical trial bolsters 
this conclusion. 
 
2.4 
Description of and Justification for the Route of Administration, Dosage 
Regimen, and Treatment Period(s) 
2.4.1 
Administration of Investigational Products  
ABvac40 is administered by subcutaneous injection which proved to be well tolerated in 
previous pre-clinical and clinical trials. For this Phase II study, five monthly (every four weeks) 
single-dose injections plus a 6 months (26 weeks) delayed booster of verum (or placebo, as 
corresponds) are planned for the Part A.  
For the Part B, patients receiving placebo in Part A will cross-over to receive verum following 
the aforementioned scheme (Delayed start group), whereas patients receiving verum in Part A 
will receive placebo following the same scheme (except in V13B when they will receive a 
booster of verum) aiming to maintain the blinding for both patients and investigators (Booster 
group). 

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2.4.2 
Justification for Selection of Doses/Timing of Investigational Products 
Pre-clinical trials on rabbits allowed Non-Observed Adverse Effect Level (NOAEL) doses to 
be set for ABvac40 to about 0.1 mg of Abetax-40 / kg of live weight. That NOAEL meant that 
the Human-Equivalent Dose (HED) could be taken to about 0.0322 mg / kg (following 
indications given by the FDA in its “Guidance for Industry Estimating the Maximum Safe 
Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers”), i.e. up 
to 2 mg of the antigenic peptide for a person weighing about 60 kg. 
However, taking account of the nature of ABvac40 (an active vaccine) and the 
recommendations contained in the EMEA / CHMP “Guidelines on Strategies to Identify and 
Mitigate Risks for First-in-Human Clinical Trials” for this first use in humans, it was decided 
to use a dose of 0.2 mg of Abetax-40, i.e. a dose ten times smaller than the HED calculated 
using the NOAEL. 
Consideration must be given to the fact that those guidelines were put in place for healthy 
volunteers, so they may lead to insufficient calculated doses for administering to aged 
individuals who generally suffer from immuno-senescence and could need repeated injections 
to mount a significant immune response. 
Based on the safety and tolerability results of Phase I and pre-clinical investigations (see IB 
document), we think that there is a safe margin for adding in this Phase II trial two further 
monthly inoculations plus the delayed booster shot to the trial, which will allow to expand the 
therapeutic range of ABvac40 and better explore its ability to generate immunological 
memory. 
Additionally, based on the conclusions of the DSMB after the first interim analysis (July 2019), 
an additional booster shot will be administered to the patients receiving verum during the Part 
A of the present trial, aiming to better explore ABvac40 ability to generate immunological 
memory. 
 
2.5 
Compliance Statement 
This study will be conducted under the conditions described in this protocol and in compliance 
with International Conference on Harmonization Good Clinical Practice (ICH GCP) and all 
applicable regulatory requirements. 
 
2.6 
Study Population 
Patients (between 55-80 years of age) diagnosed either with a-MCI or vm-AD will be included 
in the trial. To ensure the primary safety and efficacy endpoints of the study a minimum of 60 
subjects with a-MCI or vm-AD per treatment group (verum and placebo) are required. The 
amyloid-PET positive and amyloid-PET negative patients will be independently randomized 
following a ratio 1:1 between verum and placebo (Part A). 

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To ensure the primary efficacy endpoint with a potency of 85% at least 15 subjects per 
treatment group (verum and placebo; 30 in total) are required to complete the study. Since a 
total of 120 subjects will be initially included in the study and we estimate ~40% dropouts 
along the clinical trial, 70 are expected to complete the Part A of the protocol.  
Participants in Part A will have to complete their 18-month visit (V23) in order to be eligible 
for the Part B of the study. 
All patients who have participated in Part A, have not presented any drug reaction and have no 
MRI safety issues before the first immunization in Part B, could participate in Part B. 
 
2.7 
Relevant Data and Literature Review 
Anti-Aß immunotherapies  were considered very likely to be effective in the prevention of AD, 
especially if patients are treated before the onset of the disease or in it’s very early stage (for a 
review see reference [1] in section 16). 
However, in the last ten years most phase III clinical trials on anti-amyloid targeting drugs 
have failed to meet their primary endpoints (for recent reviews, see [2, 3]). In general, these 
disappointing results have been attributed to inadequate selection of either the subjects to be 
recruited, the stage of disease to be treated or the trial’s endpoints to be assessed [3, 4]. Thus, 
the amyloid-cascade hypothesis is still leading the field supported by lines of evidence from 
laboratories and clinics worldwide [5]. In line with this, different anti-amyloid monoclonal 
antibodies (crenezumab, ganterezumab, solanezumab) are still being tested in ongoing phase 
III clinical trials, either in prodromal or pre-clinical AD, as disease modifying therapies (see, 
www.clinicaltrials.gov). Of note, it has been recently reported that a human anti-Aβ 
monoclonal antibody (aducanumab) tested in a phase I clinical trial in patients with prodromal 
or mild AD, reduces brain Aβ in a dose- and time-dependent manner. This is accompanied by 
a slowing of clinical decline measured by Clinical Dementia Rating—Sum of Boxes and Mini 
Mental State Examination scores [6]. On the other hand, active immunizations with short Aβ 
fragments have proved to be safer than the fibrillary Aβ1-42 used as immunogen in Wyeth’s 
AN1792 trial. Thus, three active vaccines of this new kind (CAD-106, ACC-10 and AD02) 
have recently completed phase II showing a good safety profile [7-11]. 
Araclon-Grifols has developed an active vaccine directed specifically against the Aβ1-40 
peptide. The reasons supporting this strategy directed against the Aβ1-40 peptide are initially 
based in several papers published in the 90s pointing to the relevance of Abeta 40 for 
Alzheimer’s disease. 
Among the first, is a paper published by Näslund & col [12] who found that Aβ1-40 was the 
predominant variant in sporadic AD whereas the principal variant in non-demented brains was 
Aβ1-42. Furthermore, the ratio Aβ1-40/Aβ1-42 was 10-fold greater on average in brains from 
sporadic AD than in non-demented controls. 
A little later, Wang & col [13] reported that a progressive shift of brain Aβ1-40 and Aβ1-42 
from soluble to insoluble pools and a profound increase in the levels of insoluble Aβ1-40 plays 
mechanistic roles in the onset and/or progression of AD. In line with this, Shin & col [14] 
found that Aβ1-40 but not Aβ1-42 contributes to the experimental formation of Alzheimer 
disease amyloid fibrils in rat brain. 

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Although Aβ1-42 is more hydrophobic and prone to aggregate, Aβ1-40 can indeed produce 
diffusible aggregates which are highly toxic to cells [15]. 
Furthermore, we saw in our laboratory that specific antibodies against Aβ40 were able to label 
intra-cellular neurofibrillary tangle-like structures in the entorhinal and hippocampal cortex of 
AD brains [16]. These Aβx-40 neurofibrillary tangles like structures did not co-localize in the 
same neurons with the tau neurofibrillary tangles. Thus it appears that in AD brains there are 
two different neurodegenerating populations one filled with tau neurofibrillary tangles and 
other filled with C-terminal fragments of Aβx-40 [16]. 
Moreover, we found an outstanding difference between the brains of two patients with Down 
syndrome suggesting that the onset of dementia may be accompanied by the deposition of 
Aβ40 in the parenchyma [17]. 
Other recent studies have reported higher CSF or plasma levels of Aβ40 in AD patients with 
Down syndrome compared to non-dements controls [18-21]. 
Currently, soluble Aβ species (dimers and/or oligomers) are considered to interact with 
synapsis causing alterations in their functional activity leading to cognitive decline and 
eventually dementia. Increased concentration of these soluble isoforms is supposed to precede 
deposition of fibrillary Aβ in senile plaques and would not be detectable by amyloid-PET scans 
[22, 23]. 
Recently, two phase 3 trials (Expedition-1 and -2 sponsored by Lilly), randomized 2,052 
people with mild to moderate AD to receive infusions of Solanezumab or placebo once a month 
for 80 weeks. Although Expedition-1 and -2 overall showed no improvement on the primary 
outcome measures of Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-
Cog)-11 and Alzheimer’s Disease Cooperative Study – Activities of Daily Living (ADCS-
ADL), statistically significant benefits were seen in a pooled analysis of the subgroup of 
patients with mild AD from both trials [24]. 
Supported by these results, Lilly started Expedition-3, in patients with mild AD and 
demonstrated brain amyloid burden (Florbetapir PET scans). Cognition (ADAS-cog 14) was 
set as the single primary outcome and function (Alzheimer's Disease Cooperative Study 
Activities of Daily Living inventory instrumental items (ADCS-iADL)) as a secondary 
outcome. On November 23, 2016, and then at the CTAD 2016 (San Diego, December 2016) 
Lilly announced, that primary and secondary outcome results were trending in the direction of 
a treatment benefit, but effects were small and fell short of statistical significance. 
It is possible that the observed effect favoring Solanezumab in the pooled subpopulation of 
mild AD from Expedition-1 and -2 were lost precisely because of the selection of people with 
demonstrated brain amyloid burden who might have been in a too advanced disease stage as 
to positively respond to the Solanezumab; an antibody specifically targeting soluble Aβ 
isoforms while current radiotracers for PET are uptaken by insoluble fibrillary Aβ aggregates 
deposited in senile plaques. 
Polyclonal antibodies induced after active immunization with ABvac40 binds both soluble and 
insoluble Aβ40 isoforms. Thus, a priori, it cannot be ruled out an effect in patients with MCI 
or vm-AD and a negative amyloid-PET scans (around 50% prevalence [25]). In line with this, 
it has been recently reported that rates of multiple modes of neurodegeneration, cognitive 
decline, and functional decline in MCI patients are observed to accelerate prior to the current 

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threshold for amyloid positivity [26]. Thus, a considerable proportion of patients with MCI 
would not meet inclusion criteria for a clinical trial based on the current threshold for amyloid 
positivity, though on average, they are experiencing cognitive and functional decline 
associated with pre-threshold levels of CSF Aβ42. In fact, these patients would never meet 
criteria for preclinical or prodromal AD during the course of their progression because they 
demonstrated clinically significant cognitive and functional impairment prior to becoming 
amyloid-positive [26]. Furthermore, it has been found that ~70% of a-MCI meeting the NIH-
AA core clinical criteria (required for eligibility in the present clinical trial), progress to 
dementia in a 26.6 month follow-up (range 6-68 months; independently of their amyloid-PET 
or CSF Aβ42 status [27].  
 
Taken together, these results suggest that the Aβ burden required to elicit an MCI profile could 
vary across patients. Some may be susceptible to minimal levels of Aβ deposition, showing 
clinical symptoms at earlier stages of Aβ cerebral pathology, while others would only show 
clinical symptoms after prolonged Aβ deposition.  
Furthermore, we hypothesized that in those a-MCI and vm-AD patients deemed as Aβ-
negative, the clinical symptomatology may be primarily driven by soluble Aβ isoforms and/or 
perivascular deposits of Aβ40, not detectable by current Aβ neuroimaging, and nevertheless 
susceptible to being modified by our anti-Aβ40 treatment. We assume that by making amyloid 
eligibility more liberal, there may be some loss in specificity; however, this loss may be worth 
the gains made by treating a less progressed population. In conclusion, we think that treatment 
with ABvac40 may benefit a-MCI and vm-AD patients, regardless of their amyloid-PET status 
as determined by the currently validated thresholds. 
Nevertheless, it is well know that on average the progression to dementia in amyloid-PET 
negative MCI or vm-AD patients is less probable and significantly slower than in their 
counterparts with demonstrated amyloid burden, and this is why we decided to use this 
biomarker to stratify (not to select or to reject) the subjects for the assessment of the secondary 
exploratory efficacy objectives [28-30].  
Thus, in line with the EMA/CHMP/539931/2014 document (Draft guideline on the clinical 
investigation of medicines for the treatment of Alzheimer’s disease and other dementias) , the 
present ABvac40 phase II clinical trial will be carried out on a-MCI and/or vm-AD patients, 
characterized by their amyloid-PET neuroimaging profile as either Aβ-positives or Aβ-
negatives. Eligible subjects must meet clinical criteria for either a-MCI as defined by the 
National Institute on Aging–Alzheimer’s Association [31] ; or vm-AD as defined by National 
Institute of Neurological and Communicative Diseases and Stroke/Alzheimer’s Disease and 
Related Disorders Association (NINCDS-ADRDA) (see section 2, pag 29). 
Patients will be recruited regardless their amyloid-PET state (positive or negative), which will 
be assessed as per the currently validated visual reading for flutemetamol. The amyloid-PET 
positive and amyloid-PET negative patients will be independently randomized following the 
same verum:placebo ratio of 1:1 [Part A]. 
The amyloid-PET positive and amyloid-PET negative subjects within each treatment group 
will be pooled together for the analysis of safety, tolerability and primary efficacy 
(immunogenicity) variables. However, the secondary efficacy variables regarding assessment 
of disease biomarkers and cognition (section 7.1.2) will be compared between verum and 

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placebo groups both in the overall group and separately in the amyloid-PET positive and 
amyloid-PET negative subjects. 
 
 

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3 
STUDY OBJECTIVES AND PURPOSE 
The purpose of this Phase II study is to confirm in patients with a-MCI or vm-AD the level of 
safety and tolerability obtained in the ABvac40 Phase I clinical trial in patients with mild to 
moderate AD. In addition, the study is aimed to better characterize the immune response 
elicited by ABvac40 and to explore its effects on AD biomarkers. 
 
3.1 
Part A (Randomized, Double-Bblind, placebo-controlled – 18 to 24 months 
follow-up) 
3.1.1 
Safety Objectives 
3.1.1.1 
Primary Safety Objective 
- 
To evaluate the safety and tolerability of repeated doses of ABvac40 in a population of 
patients with a-MCI or vm-AD. 
 
3.1.2 
Efficacy Objectives 
3.1.2.1 
Primary Efficacy (Immunogenicity) Objective 
- 
To assess  the immune response produced during the study by repeated doses of 
ABvac40 in a population of a-MCI or vm-AD. 
 
3.1.2.2 
Secondary (Exploratory) Efficacy Objectives 
- 
To characterize the immune response elicited by repeated doses of ABvac40 in a 
population of a-MCI or vm-AD. 
- 
To assess the changes in the disease biomarkers elicited by ABvac40 in the overall 
study population. 
- 
To assess the changes in cognition and quality of life elicited by ABvac40 in the overall 
study population. 
 
3.2 
Part B (ABvac40 delayed start, open label [Part A assignment will remain 
blinded for investigators and patients] – 18 months follow-up) 
3.2.1 
Exploratory Safety Objective 
- 
To evaluate the safety and tolerability of repeated doses of ABvac40 after delayed start 
in patients receiving placebo during Part A, and the long-term safety and tolerability of 
ABvac40 in patients receiving a booster after their Part A vaccination scheme. 
 

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3.2.2 
Exploratory Efficacy Objectives 
3.2.2.1 
Immunogenicity  
- 
To assess the immune response produced by repeated doses of ABvac40 after delayed 
start in patients receiving placebo during Part A. 
- 
To assess the immune response triggered by a second ABvac40 booster in patients 
receiving ABvac40 during Part A. 
 
3.2.2.2 
Other  
- 
To assess the changes in the disease biomarkers elicited by ABvac40 in the overall 
study population. 
- 
To assess the changes in cognition and quality of life elicited by ABvac40 in the overall 
study population and according to the treatment scheme during Part A and B. 
- 
To assess the immunological memory, characterizing the immune response ex vivo 
elicited by the booster in patients who have received ABvac40 during Part A 
- 
To assess the potential relationship between antibody titration, biomarkers and 
cognitive state. 
- 
To define the optimal ABvac40 treatment scheme. 
 
 
 

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4 
STUDY DESIGN 
A multi-center, prospective, longitudinal, randomized, double-blind, placebo-controlled, two 
parallel treatment groups (verum and placebo), confirmatory phase 2 clinical trial has been 
designed (Part A). 
Additionally, a delayed-start vaccination, open label (Part A assignment will remain blinded 
for investigators and patients) exploratory extension will start after at least 18 months of Part 
A initiation (Part B). 
 
4.1 
Endpoints 
4.1.1 
Part A  
The primary endpoint for safety is the incidence of AEs (overall or grouped as neurological, 
psychiatric or cardiovascular). 
The hypothesis for the primary endpoint for safety is that ABvac40 will be safe for human 
administration, according to the observed pattern of AEs. The trial will be considered 
satisfactory if the pattern of AEs (overall or grouped as neurological, psychiatric or 
cardiovascular) is consistent with a good safety and tolerability profile of ABvac40 for human 
administration at the final visit.  
Additionally, the following secondary safety endpoints will be evaluated including:   
- 
number of withdrawn patients due to adverse events (AEs) 
- 
number of withdrawn patients due to other causes  
- 
number of serious adverse events (SAEs)  
- 
number of clinically significant changes in physical and neurological examination 
- 
number and type of concomitant medications 
- 
number of clinically significant changes in vital signs (blood pressure, heart rate, 
respiratory rate, body temperature), body mass (weight, height). 
- 
number of clinically significant changes in brain MRI  
- 
number of clinically significant changes in electrocardiogram (EKG) 
- 
number of clinically significant changes in analytical haematology, biochemistry, 
coagulation, serology and urine test strip results. 
 
The primary efficacy endpoint is the average maximal increment (MΔ) of anti-Aβ40 antibody 
signal (OD in ELISA) in each subject with regard to the pre-treatment visit (either V0 or V1). 
For the primary efficacy analysis, the trial will be considered successfully confirmatory 
regarding efficacy (immunogenicity) of ABvac40 if the average maximal increment (MΔ) of 
anti-Aβ40 antibody signal (OD in ELISA) in the verum group is >0 OD than the average MΔ 
in the placebo group. For the secondary efficacy analysis, the trial will be considered 
satisfactory if the difference of the average maximal increment (MΔ) of anti-Aβ40 antibody 
signal (OD in ELISA) in the treated group is > 1.778 OD than the average MΔ in the placebo 

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group; the difference that was reached between both groups in the phase I clinical trial of 
ABvac40.  
 
Additionally, the following secondary efficacy endpoints will be evaluated including:   
- 
Characterization of the immune response:   
o Levels of anti-KLH and anti-Aβ42 antibodies in plasma  
o Level of anti-Aβ40 antibodies in CSF  
o Levels of cytokines in plasma including IL-2, IL-4, IL-5, IL-6, IL-10, IL-
13, IL-15, TNF-α and IFN-γ. 
o Analysis of the peripheral blood cell subsets by immunophenotyping. 
o Levels of antibody secreting cells and cytokine-secreting cells (including 
IFN-γ, TNF-α and IL-13)  
- 
Assessment of disease biomarkers: 
o Levels of Aβ peptides in plasma 
o Cortical fibrillary amyloid deposition assessed by PET scans. 
o Levels of CSF biomarkers (Aβ42, Tau, P-tau, neurofilament light and 
neurogranin) and other Aβ peptide species 
o Brain volumetric and atrophy of the hippocampus using magnetic 
resonance imaging 
- 
Assessment of cognition and quality of life: 
o Mini Mental State Examination (MMSE) 
o Clinical Dementia Rating scale (CDR)  
o Repeatable Battery for the Assessment of Neuropsychological Status 
(RBANS) 
o Alzheimer’s Disease Cooperative Study – Activities of Daily Living, Mild 
Cognitive Impairment (ADCS-ADL MCI) 
o Columbia Suicide Severity Rating Scale (C-SSRS) 
o Trail Making Test (TMT) 
o Investigator Global Evaluation (IGE) 
o Euroqol 5 Dimensions (EQ-5D)   
 
4.1.2 
Part B 
All the endpoints of Part B will be explorative. No hypothesis will be tested. 
Both the primary and secondary safety endpoints mentioned in Section 4.1.1 will also be 
evaluated in Part B (only as exploratory safety endpoints). 
Regarding efficacy, the following exploratory endpoints will be evaluated: 
- 
Presence of specific antibodies against Aβ40 in plasma 
- 
Characterization of the immune response:   
o Level of anti-Aβ40 antibodies in CSF  
o Levels of antibody secreting cells  
- 
Assessment of disease biomarkers: 
o Levels of Aβ peptides in plasma  
o Cortical fibrillary amyloid deposition assessed by PET scans. 

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o Brain volumetric and atrophy of the hippocampus using magnetic 
resonance imaging 
- 
Assessment of cognition and quality of life: 
o MMSE 
o CDR scale  
o RBANS 
o ADCS-ADL MCI 
o C-SSRS 
o TMT 
o IGE 
o EQ-5D-5L 
 
4.2 
Study Design and Plan 
The expected duration of the trial will be of 51 months, from February 2018 to May 2022. 
First Patient In: February 2018 
Last Patient In: September 2019 
Last Patient Out (Part B): May 2022 
 
4.2.1 
Part A 
The Part A of the study will last for up to 24 months (from V0 to V25) and at least 18 months 
(up to V23) during which the patients will receive five monthly (every four weeks) 
immunizations plus a booster shot.  
During the study, two interim analyses (Int) will be performed to assess safety, tolerability and 
biological activity of the treatment (including data from the collected disease biomarkers at 
each of them). These analyses will be reviewed by an independent Data Safety Monitoring 
Board (DSMB). Information regarding the DSMB is detailed in Section 9.1.5.1. The first Int 
will be carried out once the first 30 patients have completed the 24-week visit (Int-6m) and the 
second one once all patients have completed the 24-week visit (Int-6m, eight weeks after the 
fifth monthly immunization) or in October 2020, whichever occurs first. The double blinding 
of the study will be maintained throughout these two Int. Additional DSMB reviews may be 
made ad hoc in the event of safety issues. 
Additionally, after all patients complete their 18-months visit (V23), a statistical analysis will 
be performed to determine whether the Part B of the study should be discontinued. 
The study outline for Part A is summarized in the following figure:  
 
 

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Table 2: Overall Study Design (Part A) 
Screening 
 
 
week -8 
0 
4 
8 
12 
16 
 
24 
 
 
 
42 
 
50 
 
 
 
 
 
77 
 
 
 
 
 
104 
Visits 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Verum or 
Placebo 
 
  
MRI 
. 
   
 
 
a-PET 
. 
 
 
CSF 
 . 
 
 
NPB 
 
MRI: Magnetic Resonance Imaging; a-PET: Amyloid PET; NPB: Neuropsychological battery. 
 
Visit Description 
Over the first 50 weeks of the Phase II clinical trial, 21 visits will take place. Additionally, a 
one year long-term follow-up period has been programed. This additional follow-up consists 
of four additional visits (V22-V25) at quarterly intervals.  
The study visits can be grouped as follows: 
 Pre-selection or Screening Visit (V0) 
 Vaccination Visits (V1, V4, V7, V10, V13 and V18*) 
 Safety control visits 
 Phone interview: V2, V5, V8, V11, V14 ,V19, V22 and V24 
 Face-to-face visits: V3, V6, V9, V12, V15, V16 (Int-6m), V17, V20, V21, V23 and 
V25 (Final visit) 
* All patients who will attend their V18 after April 2020 must be tested for COVID-19 by PCR (Polymerase 
chain reaction test) method before receiving the study medication. A specific informed consent form (ICF) must 
be signed by the applicable patients authorizing this test (see Section 6.1.1.1 for further details) 
 
The following table shows the schedule of study procedures and events. 
 

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   Table 3: Schedule of Study Procedures and Events (Part A) 
 
Scree
ning 
Month 
-2 
0 
1 
2 
3 
4 
5 
6 
7 8 
9 
10 
11 
12 
…
15 
…18 …21 …
24 
Week 
-8 
0 
0 
2 
4 
4 
6 
8 
8 
10 12 12 
14 
16 
16 
18 
 
24 
 
 
 
40 
42 
42 
44 
 
50 
 
65 
 77  90  
104 
Day 
-60 
-3 
/0* 
3 
±3 
14 
±3 
28 
±3 
31 
±3 
42 
±3 
56 
±3 
59 
±3 
70 
±3 
84 
±3 
87 
±3 
98 
±3 
112 
±3 
115 
±3 
126 
±3 
 
168 
±7 
 
 
 280 
±7 
294 
±7 
297 
±7 
308 
±7 
 
350 
±15 
 
455 
±15 
 539 
±15 
 630 
±15 
 
728 
±15 
Visit Nº 
(T=by phone) 
0† 
1* 
Vc 
2 
(T) 
3 
Sc 
4 
Vc 
5 
(T) 
6 
Sc 
7 
Vc 
8 
(T) 
9 
Sc 
10 
Vc 
11 
(T) 
12 
Sc 
13 
Vc 
14 
(T) 
15 
Sc 
16 
Int 
6m 
17 
Sc 
18 
Vc 
19 
(T) 
20 
Sc  
21 
Sc 
22 
(T) 
23 
Sc 
24 
(T) 
25- 
FV 
Informed Consent 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vaccination 
ABvac40/placebo 
 
* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
§ 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History, 
Height (only at 
screening) 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight, BP, HR, RR, Tº 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical and 
neurological exam 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neuropsych. Battery 
and IGE (exc. V0/V23) 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Quality of Life EQ-
5D5L 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eletrocardiogram 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
#
 
 
 
 
 
#
 
 
#
 
 
#
 
Urine Analysis (test 
strip) 
2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ApoE Genotyping 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hemogram 
2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biochemistry 
2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biological Activity 
2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRI 
3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a-PET 
4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CSF 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
Medication 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRI: Magnetic Resonance Imaging; a-PET: Amyloid PET; CSF: Cerebrospinal fluid; EKG: Electrocardiogram; exc.: except; IGE: Investigator Global Evaluation; NPB: Neuropsychological battery; FV: 
final visit; Vc: Vaccination; Sc: Safety control; Int: Interim analysis; T: Telephone call; RR: respiratory rate: Tº: body temperature 
 
†The Screening Visit (V0) should be performed in 4 separate days: 

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1Day 1 of V0 (V0a):  
- Signature of informed consent and verification of inclusion and exclusion criteria; medical history, vital signs, physical and neurological exam, 
neuropsychological battery, EKG, concomitant medication for AD and other diseases and delivery of Patient Card and Patient Diary; the scanned EKG 
must be sent to the Medical Advisor and no further assessments can be made to the subject until the approval is received at the center. 
- If the patient meets all neuropsychological criteria, once the EKG has been approved by the Medical Advisor, the Day 2 of V0 (V0b) can be scheduled 
2Day 2 of V0 (V0b): 
- Urine analysis and blood sample extraction (for hemogram, biochemistry and biological activity) 
- If no abnormal findings are found in the blood and urine tests, the Day 3 of V0 (V0c) can be scheduled. 
3Day 3 of V0 (V0c):  
- Magnetic Resonance Imaging 
- Once the MRI has been approved by the MRI Central Reader, the Day 4 of V0 (V0d) can be scheduled 
4Day 4 of V0 (V0d):  
- a-PET 
- Once the a-PET has been approved by the a-PET Central Reader, the patient can be randomized and the first day of V1 can be scheduled (a minimum of 
4 days later, so that the appropriate material for CSF extraction and the IMP can be received at the center). 
* The Inclusion Visit (V1) should be performed in 2 separate days; the vaccination should take place at least 3 days after the CSF extraction, or the time needed 
until resolution of any AE occurring after the CSF extraction, whichever is longer (to avoid interference with the assessment of AEs related to the vaccination), 
with a maximum of 10 days after the urine and blood sample extraction: 
 Day 1 of V1 (V1a):  
- Urine analysis, blood sample extraction (for ApoE genotyping, hemogram, biochemistry and biological activity) and CSF collection  
 Day 2 of V1 (V1b):  
- Physical and neurological exam, neuropsychological battery and IGE, quality of life, vital signs (before vaccination), vaccination, vital signs (after 
vaccination), concomitant medication and AEs. 
 A telephone control interview will take place within the first week (3± 3 days) after each vaccination visit and at V22 and V24.  
 A safety visit will be scheduled two weeks after each vaccination and at V17 and V23. 
 Blood samples will be collected at every safety control visit for safety control and characterization of immune response. 
 Study visits should take place at the Days indicated above, within the following windows: 
- 
During first 6 months: ± 3 days  
- 
Between month 6 and month 12: ± 7 days 
- 
Between month 12 and month 24: ± 15 days 
 If a visit takes place out of window, the patient should be visited as soon as possible; For the five first immunizations the minimum interval between 
vaccinations must be 25 days and the maximum interval must be 31 days; if one vaccination is delayed for any reason, the next dose must be re-scheduled 
to fit this therapeutic window. 
# In this visit the scanned EKG must be sent to the Medical Advisor for review. 
§ All patients who will attend their V18 after April 2020 must be tested for COVID-19 by PCR method before receiving the study medication. A specific ICF 
must be signed by the applicable patients authorizing this test (see Section 6.1.1.1 for further details) 

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4.2.2 
Part B 
The Part B of the study will last for 18 months (from V1B to V22B) during which the patients 
will receive five monthly immunizations plus a booster shot. The first visit of Part B (V1B) 
will take place at least 18 months after the patient started Part A (i.e. he/she should have 
completed V23 of Part A to enter Part B).  
 
The patients randomized to the placebo group during Part A will receive five monthly (every 
four weeks) immunizations with ABvac40 plus a booster shot after 6 months (Delayed start 
group), whereas the patients randomized to the Verum group during Part A will receive placebo 
following this schedule, except in V13B, where they will receive an ABvac40 booster shot 
(Booster group). Given the extended inclusion period of Part A, the V13B booster will take 
place at different timepoints relative to the patient’s last immunization. For the analysis, they 
will be grouped in 2 periods: 12± 3 months and 18± 3 months after last immunization. 
There will not be interim analyses for this Part B, but the DSMB reviews may be made ad hoc 
in the event of safety issues. 
The study outline for Part B is summarized in the following figure: 
 
Table 4: Overall Study Design (Part B) 
Week 
0* 
4 
8 
12 
16 
 
24 
 
 
 
42 
 
50 
 
 
 
 
 
77 
Visits 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Verum  
or placebo 
 
MRI 
. 
   
 
 
a-PET 
. 
 
 
CSF  
 
 
NPB 
 
*At least 18 months after initiating Part A 
† A MRI will be performed before first vaccination of Part B only if the previous MRI was performed more 
than 6 months (±15 days) before V1B 
 
Visit Description 
Over the first 12 months of the Part B, 21 visits will take place. The first visit of Part B (V1B) 
will take place at least 18 months after the patient started Part A (i.e. he/she should have 
completed V23 of Part A to enter Part B).  
The study visits can be grouped as follows: 
 Vaccination Visits*: V1B, V4B, V7B, V10B, V13B and V18B 
 Safety control visits 
† 

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 Phone interview: V2B, V5B, V8B, V11B, V14B and V19B 
 Face-to-face visits: V3B, V6B, V9B, V12B, V15B, V16B, V17B, V20B, V21B and 
V22B 
* All patients must be tested for COVID-19 during the Part B vaccination visits before receiving the study 
medication (see Section 6.1.1.2 for further details). 
The following table shows the schedule of study procedures and events. 

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   Table 5: Schedule of Study Procedures and Events (Part B) 
 
Part B 
Month 
0† 
1 
2 
3 
4 
5 
6 
7 8 
9 
10 
11 
12 
… 
18 
Week 
0 
0 
2 
4 
4 
6 
8 
8 
10 12 12 
14 
16 
16 
18 
 
24 
 
 
40 
42 
42 
44 
 
50 
 
77 
Day 
-3 
/0* 
3 
±3 
14 
±3 
28 
±3 
31 
±3 
42 
±3 
56 
±3 
59 
±3 
70 
±3 
84 
±3 
87 
±3 
98 
±3 
112 
±3 
115 
±3 
126 
±3 
 
168 
±7 
 
 
280 
±7 
294 
±7 
297 
±7 
308 
±7 
 
350 
±15 
 
539 
±15 
Visit Nº 
(T=by phone) 
1B* 
Vc 
2B 
(T) 
3B 
Sc 
4B 
Vc 
5B 
(T) 
6B 
Sc 
7B 
Vc 
8B 
(T) 
9B 
Sc 
10B 
Vc 
11B 
(T) 
12B 
Sc 
13B 
Vc 
14B 
(T) 
15B 
Sc 
16B 
Sc 
17B 
Sc 
18B 
Vc 
19B 
(T) 
20B 
Sc  
21B 
Sc 
22B 
EOS 
Informed Consent 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vaccination ABvac40/placebo§ 
* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight, BP, HR, RR, Tº 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical and neurological exam 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neuropsych. Battery and IGE  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Quality of Life EQ-5D5L 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eletrocardiogram 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
#
 
 
 
 
 
#
 
 
Urine Analysis (test strip) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hemogram 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biochemistry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biological Activity 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRI 
   ‡
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a-PET 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CSF 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medication 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRI: Magnetic Resonance Imaging; a-PET: Amyloid PET; CSF: Cerebrospinal fluid; EKG: Electrocardiogram; exc.: except; IGE: Investigator Global Evaluation; NPB: Neuropsychological battery; 
EOS: end of study; Vc: Vaccination; Sc: Safety control; T: Telephone call; RR: respiratory rate: Tº: body temperature 
 
† At least 18 months after initiating Part A 
* The First Visit of Part B (V1B) will take place when the results of the last MRI test performed (either at V21 or V25 or before first vaccination of Part B‡) are 
available and support the vaccination.   
‡ A MRI will be performed before first vaccination of Part B only if the previous MRI was performed more than 6 months (±15 days) before V1B. 
 A telephone control interview will take place within the first week (3 ±3 days) after each vaccination visit.  
 A safety visit will be scheduled two weeks after each vaccination and at V17B. 
 Blood samples will be collected at every safety control visit for safety control and characterization of immune response. 

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 Study visits should take place at the Days indicated above, within the following windows: 
- 
During first 6 months: ± 3 days  
- 
Between month 6 and month 12: ± 7 days 
- 
Between month 12 and month 18: ± 15 days 
 If a visit takes place out of window, the patient should be visited as soon as possible; For the five first immunizations the minimum interval between 
vaccinations must be 25 days and the maximum interval must be 31 days; if one vaccination is delayed for any reason, the next dose must be re-scheduled 
to fit this therapeutic window. 
# In this visit the scanned EKG must be sent to the Medical Advisor for review. 
§ All patients must be tested for COVID-19 during the Part B vaccination visits before receiving the study medication (see Section 6.1.1.2 for further details) 

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4.3 
Measures Taken to Minimize/Avoid Bias 
4.3.1 
Subject Numbering 
Within each study site, subjects in the study will receive a consecutive subject number. Subject 
numbers are generated beginning with the study center number (2 digits assigned by the 
sponsor) preceded by “S” followed consecutively with a unique number for each subject (3 
digits, including leading zeros). For example, if the investigator’s center number is 01, subject 
number will be S01-001, S01-002, S01-003, etc. Subject numbers, once assigned, will not be 
reused at any center. 
4.3.2 
Randomization   
Subjects will be randomized into one of two arms, based on a computer-generated 1:1 ratio 
randomization schedule issued to a Randomization Manager not involved in the study. A 
randomization number will be assigned to each subject in addition to the subject number at 
Baseline visit (V1). A stratified randomization will be performed to obtain separate 
randomization schemes for the amyloid-PET positive and amyloid-PET negative subjects 
following a 1:1 verum:placebo ratio. 
A Randomization Manager from the CRO (Clinical Research Organization) not involved in 
the study will prepare two separate randomization lists, one without treatment details (only 
with the treatment code) to be sent to CRO Study Project Manager to proceed with the patients 
randomization  and one with treatment details to be sent to the Independent Representative of 
the Sponsor (IRS) for the packaging and labeling of the study medication, and it will be kept 
secret until the end of the study, or until the database is closed. . This will ensure that the 
statistician involved in the study analysis is blinded until the study is complete or until the 
database is closed. The randomization list will be generated using SAS software version 9.2 or 
equivalent.  
For the DSMB, a randomization list will be sent to the Independent Statistician (IS) in order to 
prepare and confidentially distributing to each member of the DSMB interim reports that 
include data summaries, tables, and listings containing unblinded data. 
The patients will be then numbered by two codes, the Screening number (S01-001 to S0n-00n) 
and the randomization number (R001 to R00n). Randomization numbers will be consecutive, 
with three digits preceded by the letter "R" (for example, R001, R002, R003, etc). The nurse 
or investigator responsible for the study at the center will distribute the IMP blisters following 
the randomization  numeration. 
4.3.3 
Blinding 
Only the IRS and the IS will work without blinding in order to label study medication and to 
prepare all the DSMB documentation, respectively. The IS will be a statistician who does not 
participate in any other activities related to the planning and execution of the study and who 
will be part of the DSMB team (as non-voting member). In this way, the blinding will be assure 
during the Int. 

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For the Part B of the study, both the sites’ PI and the patients will remain blinded. 
Three sets of opaque and blind emergency envelopes will be prepared. The sites’ PI will be 
given a closed envelope bound to each treatment kit (blister) for each subject randomized 
containing information of the treatment that person receives; the PI can open this in a medical 
emergency (see section 8.3). The investigator or person, who opens the envelope, must record 
the date and reasons for opening the sealed envelope in the Case Report Form and in the 
randomization envelope. 
The two remaining sets of emergency envelopes will be given to the global CRO 
 and to 
the pharmacovigilance responsible person.  
Details printed on the emergency envelope: 
 It should be opened only by the Principal Investigator (or assigned delegate in an 
unavoidable situation) in case of emergency. 
 Partial/complete breakage of blinding should be adequately documented. 
 An accidental opening of the envelope should be reported to the sponsor and must be 
documented. 
 Code of the study: 
 Patient No.: R-XXX 
 
Details printed inside the emergency envelope: 
 Patient No.: R-XXX 
 Treatment: verum or placebo 
 
4.4 
Study Treatments 
4.4.1 
Treatments to Be Administered 
The treatments to be administered are verum (ABvac40) and placebo (ABvac40 vehicle 
without its active ingredient). 
The following table shows when the vaccination will occur: 
Table 6:  Treatment Time points 
# 
Treatment visits 
Week # 
Month # 
Part A
1 
V1 
0 
0 
2 
V4 
4 
1 
3 
V7 
8 
2 
4 
V10 
12 
3 
5 
V13 
16 
4 
6 
V18* 
42 
10 

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Part B
1 
V1B†
0
0
2 
V4B†
4
1
3 
V7B†
8
2
4 
V10B†
12
3
5 
V13B†
16
4
6 
V18B†
42
10
* All patients who will attend their V18 after April 2020 must be tested for COVID-19 by PCR method before 
receiving the study medication. A specific ICF must be signed by the applicable patients authorizing this test 
(see Section 6.1.1.1 for further details) 
† All patients must be tested for COVID-19 during the Part B vaccination visits before receiving the study 
medication (see Section 6.1.1.2 for further details) 
 
Verum 
Name: ABvac40  
Active ingredient: Conjugated Aβx-40 to KLH 
Vehicle: Phosphate buffer containing 0.35% aluminium hydroxide (adjuvant)   
Pharmaceutical Form: Injection ready vials 
Posology: Part A: Verum group: Six administrations: the first five administered once every 
4 weeks (28±3 days) and the sixth at week 42 (V18), 26 weeks after the fifth. Each 
administration consists of 1 mL injection of ABvac40 (containing 0.2 mg of Abetax-40). 
Part B: Delayed start group: Six administrations: the first five administered once every 4 
weeks (28±3 days) and the sixth at week 42 (V18B), 26 weeks after the fifth immunization. 
Booster group: One administration at week 16 (V13B).  
Each administration consists of 1mL injection of ABvac40 (containing 0.2 mg of Abetax-
40). 
Method of administration: Subcutaneous injection. 
 
Placebo  
Name: Placebo 
Active ingredient: Nil 
Vehicle: Phosphate buffer containing 0.35% aluminium hydroxide (adjuvant)   
Pharmaceutical Form: Injection ready vials 
Posology: Part A: Placebo group: Six administrations: the first five administered once 
every 4 weeks (28±3 days) and the sixth at week 42 (V18), 26 weeks after the fifth. Each 
administration consists of 1mL injection of ABvac40 vehicle. 

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Part B: Booster group: Five administrations: the first four administered once every 4 weeks 
(28±3 days) and the fifth at week 42 (V18B), 30 weeks after the forth. Each administration 
consists of 1mL injection of ABvac40 vehicle. 
 
4.4.2 
Labeling of Investigational Product(s) 
Investigational products are labeled according to the requirements of local law and legislation.  
Label text (see Label Models document) will be approved according to agreed Araclon-Grifols 
procedures, and a copy of the labels will be made available to the study site. 
 
 
4.4.3 
Packaging of Investigational Product(s) 
The final steps of IMP manufacturing (Fill & Finish) are carried out by 
 
 
 
Thes companies will also be responsible for preparing the vials of the comparator or placebo. 
It shall be carried out in accordance with GMP guidelines. The material will be always sent 
and stored refrigerated at 2-8°C. The investigator is responsible for the proper storage of IMP 
at the center. 
Each patient will be assigned a treatment blister which consists of 8 vials (6 for treatment and 
two as backup) packaged in a labeled cardboard box [Part A]. 
Medication for Part B will consist of 6 vials packaged in a labeled cardboard box. 
 
4.4.4 
Storage of Investigational Product(s) 
The study IMP will be sent to the Pharmacy of each participant center keeping the restrictions 
of temperature during the courier supply (2-8ºC).The investigator is responsible for the proper 
storage of IMP at the center. 
The treatment blisters will be stored separately from the standard practice products, 
refrigerated (2-8°C) in a dark and closed place to which only authorized personnel have access. 
The supplies of medication are exclusively for the purposes indicated in this protocol and 
cannot be used for any other purpose. The researcher will not destroy any label or partially 
used or unused product supply. At the end of the study and, as appropriate during the course 
of the study, the investigator will return all used and unused medication packaging, medication 
labels and a copy of the completed medication-dispensing notebook to the sponsor. All 
supplies will be recounted at the end of the study. 
 will store IMP and placebo spare vials which can be used 
for replacement, if necessary. 
 

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4.5 
Expected Duration of Subject Participation in the Study 
Part A 
The expected duration of a study subject’s participation in Part A will be approximately of 18 
(minimum) to 24 (maximum) months. 
After a Screening Visit (V0), subject randomization will occur at the Baseline Visit (V1) to be 
held within the 60 days after the screening visit. Each participant will receive a maximum of 
six vaccinations, the first five immunizations will be administered at four-week intervals and 
the sixth, a booster shot, will take place 26 weeks after the fifth vaccination (at month 10). 
Part B 
The expected duration of the study subject’s participation in Part B will be of 18 months. Each 
participant will receive a maximum of six vaccinations, the first five immunizations will be 
administered at four-week intervals and the sixth, a booster shot, will take place 26 weeks after 
the fifth vaccination (at month 10). 32 weeks after (at month 18), a long-term safety visit will 
be done.  
4.6 
 Discontinuation Criteria for Individual Subjects and Study 
4.6.1 
Discontinuation Criteria for Individual Subjects 
See Section 5.3 Subject Withdrawal Criteria 
4.6.2 
Premature Termination of Study/Closure of Center 
The sponsor, Institutional Review Board/Ethics Committee (IRB/EC), and/or regulatory 
authorities have the right to close this study or a study center, and the investigator/sponsor has 
the right to close a center, at any time, although this should occur only after consultation 
between involved parties. The IRB/EC and the DSMB must be informed. Should the 
study/center be closed prematurely, all study materials (except documentation that has to 
remain stored at site) must be returned to the sponsor. The site principal investigator will retain 
all other documents until notification given by the sponsor for destruction. 
Completion of the clinical trial is expected when all patients included in the study have finished 
the clinical trial, the database has been closed and the final report is submitted to the health 
authorities. 
The sponsor, Araclon Biotech, S.L. a GRIFOLS company, reserves the right to stop the trial 
prematurely. If the clinical trial is terminated or suspended, the sponsor shall immediately 
inform the investigators and the regulatory authority. The IRB shall be informed immediately, 
noting the sponsor’s reason(s) for terminating or suspending the study. 
If the trial is prematurely terminated, the investigator will inform all patients involved in the 
trial, ensuring that adequate patient monitoring will be continued and all data up to the date of 
termination will be collected and stored. 

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Reasons for premature discontinuation of the trial can be: 
- 
Occurrence of serious unexpected ADR that the Data and Statistics Center (DSC), the 
investigator and Araclon-Grifols, deem cause to prevent the continuation of the trial. 
- 
Incidence of repeated SAEs probably related with the IMP, which constitute a potential 
health risk in the opinion of the Critical Event Committee (CEC). 
- 
The emergence of new scientific data on the investigational product that does not justify 
the continuation of the trial. 
 
A study center can be closed by the sponsor for the following reasons: 
• Lack of enrollment  
• Non-compliance with the requirements of the study protocol 
• Non-compliance with ICH GCP 
• Lack of personnel 
• Serious discrepancies with regard to verification of the original documents  
• Inadequate quality of eCRFs 
• Serious and/or persistent failure to comply with the protocol, GCP of the ICH, and/or 
relevant requirements of the investigator/institution. 
 
In addition, if after analyzing the study data from Part A (up to month 18 – V23) no clinical 
differences have been observed between the Placebo and the Verum group according to the 
following stopping rules, the sponsor could prematurely finalize the study.  A least one of the 
following criteria must have been fulfilled in the Verum group:  
1. For PET negative population: If the lower bound of the 95% exact CI for the proportion 
of negative PET patients treated with vaccine is greater than the proportion in Placebo 
group after 12 months (V21).  
2. For PET positive population: If the lower bound of 95% exact CI for the proportion of 
Reduction of cerebral amyloid plaques of positive PET patients treated with vaccine is 
greater than the proportion in Placebo group after 12 month (V21). 
3. For PET positive population: If the lower bound of the 95% exact CI for the mean of 
decline in Clinical Dementia Rating-Sum of Boxes (CDR-SB) in the positive PET 
patients treated with vaccine is greater than the mean in Placebo group after 18 months 
(V23). 
 
4.7 
Accountability Procedures for Investigational Product(s)  
Investigational product is to be used only for the study in accordance with the directions given 
in this protocol. The Investigator, or designee such as the study pharmacist, is responsible for 
the distribution of the investigational product in accordance with directions given in the 
protocol and pharmacy manual. 

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The IMP and its comparator or placebo, packaged in individual blisters containing 8 vials, will 
be supplied by 
 to a central 
depot.  
Upon requested by the study sites, once the baseline visit (V1 or V1B) for a new subject has 
been set up, central depot will send the treatment kits and their corresponding emergency 
envelopes with an acknowledgment form. The Pharmacist must sign the form and send it to 
the person responsible for managing the study at central depot to confirm receipt of the IMP 
kits.  
The investigator is responsible for maintaining accurate records of the investigational product 
for his/her site. Investigational product inventory/dispensing documentation verifying the 
receipt, dispensing, destruction, or return must be maintained and kept current by the 
investigator, or designee. The inventory must be made available for inspection by the monitor.  
Investigational product supplies (including placebo) must be accounted for by the monitor and 
inventory/dispensing logs must be verified by the monitor prior to IMP return or destruction. 
Written documentation of any used and unused inventory is required. At the end of the study, 
a copy of the inventory/dispensing log(s) will be retrieved by the monitor and returned to 
Araclon-Grifols. 
4.8 
Maintenance of Treatment Randomization Codes  
For a randomized and blinded study, access to the actual randomization schedules or codes 
must be strictly controlled during the course of the study. Unveiling the blinding of treatment 
assignment during the study should only occur if it is absolutely necessary to identify treatment 
assignment in an emergency situation (eg, due to a serious adverse event). The date and reason 
for the unblinding must be recorded in the subject’s medical record and on the subject’s eCRF. 
(See section 8.3). 
4.9 
Data to Be Recorded on the eCRFs 
This section identifies the data to be recorded on the eCRF (and corresponding source 
documents) at the different visits unless elsewhere specified (laboratory manuals and/or data 
management guidelines). Other data which are initially recorded in written or electronic files 
from efficacy or safety assessments will be subsequently uploaded to the subjects’ eCRF (see 
section 7.2 and 8.2, respectively)  
4.9.1 
Part A 
4.9.1.1 
Screening phase: visit V0 (weeks -8 to 0) 
During this period, a pre-selection visit (V0) will be carried out up to a maximum of 60 days 
before the start of treatment (V1). In the pre-selection (V0) visit the investigator will assess the 
patient's suitability for inclusion in the clinical trial. 
Before any assessment or intervention for the study is completed, the investigator will inform 
the patient and caregiver, about the trial. Both will receive a written detailed description of all 

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activities and requirements involved of the trial (Patient’s Information and caregiver Leaflet), 
and the investigator will ensure that they completely understand the clinical trial. 
Once understood and accepted, they will proceed to sign the informed consent. 
The investigator will keep a selection record in which suitability of each patient as deduced at 
the screening visit will be reported, independent of whether or not the patient ends up 
participating in the clinical trial. This selection record will be saved along with the original 
documents of the clinical trial. 
After signing the informed consent and to verify the suitability of patients, the following 
assessments will be carried out preferably in four separate days: 
 Day 1 of V0 (V0a):  
- Signature of informed consent and verification of inclusion and exclusion criteria; 
medical history, vital signs, physical and neurological exam, neuropsychological 
battery, EKG, concomitant medication for AD and other diseases (all relevant 
treatments at the Investigator’s opinion administered during the 6 months prior to the 
screening visit) and delivery of Patient Card and Patient Diary; the scanned EKG must 
be sent to the Medical Advisor and no further assessments can be made to the subject 
until the approval is received at the center. 
- If the patient meets all neuropsychological criteria, once the EKG has been approved 
by the Medical Advisor, the Day 2 of V0 (V0b) can be scheduled 
 Day 2 of V0 (V0b): 
- Urine analysis and blood sample extraction (for hemogram, biochemistry and 
biological activity) 
- If no abnormal findings are found in the blood and urine tests, the Day 3 of V0 (V0c) 
can be scheduled. 
 Day 3 of V0 (V0c):  
- Magnetic Resonance Imaging 
- Once the MRI has been approved by the MRI Central Reader, the Day 4 of V0 (V0d) 
can be scheduled 
 Day 4 of V0 (V0d):  
- a-PET 
- Once the a-PET has been approved by the a-PET Central Reader, the patient can be 
randomized and the first day of V1 can be scheduled (a minimum of 4 days later, so 
that the appropriate material for CSF extraction and the IMP can be received at the 
center). 
 
Data to be recorded in the eCRF (and corresponding source documents) at the Pre-selection 
visit (V0): 
- 
Diagnosis of AD. 
- 
Check inclusion and exclusion criteria. 
- 
Demographic information (age, sex, smoking status, ethnicity, education level). 
- 
Vital signs (blood pressure, heart rate, respiratory rate, body temperature). 

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- 
Body mass (height and weight). 
- 
Medical and surgical history. 
- 
History of illness. 
- 
General treatment for AD. 
- 
Physical examination. 
- 
Neurological examination. 
- 
Record concomitant medication. 
- 
Mini-Mental Status Examination (MMSE). 
- 
Clinical Dementia Rating Scale score (CDR). 
- 
RBANS score. 
- 
Sheikh & Yesavage Geriatric Depression Scale score. 
- 
Electrocardiogram (EKG). 
- 
MRI and verify: Hachinski Ischemic Scale, Scheltten Scale concordant with the 
diagnosis of a-MCI or vm-AD. 
- 
Laboratory tests blood analysis. 
- 
Urine test strip 
- 
a-PET (only after MRI results) 
- 
"Patient card" given to the patient and the caregiver. 
- 
Decision on eligibility. 
- 
Columbia Suicide Severity Rating Scale (C-SSRS) 
 
In addition, the investigator will document, in the patient's medical record, the participation in 
this clinical trial. 
 
 
4.9.1.2 
Selection and Active Phase: visits V1-V21 (weeks 0-50) 
Eligible patients will be randomized at baseline visit (V1). 
 
The Inclusion Visit (V1) should be performed in 2 separate days; the vaccination should take 
place at least 3 days after the CSF extraction, or the time needed until resolution of any AE 
occurring after the CSF extraction, whichever is longer (to avoid interference with the 
assessment of AEs related to the vaccination), with a maximum of 10 days after the urine 
and blood sample extraction: 
 
 Day 1 of V1 (V1a):  
- Urine analysis, blood sample extraction (for ApoE genotyping, hemogram, 
biochemistry and biological activity) and CSF collection 
  
 Day 2 of V1 (V1b):  
- Physical and neurological exam, neuropsychological battery and IGE, quality of life, 
vital signs (before vaccination), vaccination, vital signs (after vaccination), 
concomitant medication and AEs. 
 

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The Active Phase period consist in two different types of visits: vaccination visits (V1, V4, 
V7, V10, V13 and V18) and safety visits (phone interview: V2, V5, V8, V11, V14, V19 and 
face-to-face visits: V3, V6, V9, V12, V15, V16, V17, V20 and V21). 
 
Data to be recorded in the eCRF (and corresponding source documents), at the Vaccination 
Visits (V1, V4, V7, V10, V13 and V18): 
- 
Medical Evaluation 
o Physical and neurological examination 
o Vital signs (blood pressure, heart rate, respiratory rate, body temperature) 
before and after the Vaccination 
o Corporal biometry (weight) 
- 
Medical History: 
o Record relevant past and concomitant diseases 
o Record concomitant medication. 
o Record any adverse events. 
- 
Randomization at Visit 1.  
- 
Lumbar puncture to obtain CSF, only at V1. 
- 
Treatment:  
o Administer the study treatment  
o Assess vaccine reaction, local and systemic. 
o 2 hour after vaccination vital signs and a thorough examination of the patient to 
assess any reaction to the vaccine will be carried out and any adverse events 
(AEs) recorded. 
- 
Neuropsychological Battery (V1; only ADS-ADL MCI and TMT) 
- 
Quality of Life EQ-5D-5L (V1) 
- 
Laboratory tests (hemogram, biochemistry and biological), and ApoE genotyping (only 
at V1). 
- 
COVID-19 PCR test result (only at V16) 
 
Data to be recorded in the eCRF (and corresponding source documents) at the safety phone 
interview (V2, V5, V8, V11, V14 and V19): 
- 
Medical History: 
o Local or systemic reactions to the vaccine 
o Concomitant Medication 
o Adverse events 
 
Data to be recorded in the eCRF (and corresponding source documents) at the safety face-to-
face visits [V3, V6, V9, V12, V15, V16 (Int-6m), V17, V20 and V21]: 
- 
Medical History: 
o Local or systemic reactions to the vaccine 
o Adverse Events, Assess vaccine reaction 
o Concomitant Medication information update 
- 
Medical Evaluation 
o Physical and neurological examination 
o Vital signs (blood pressure, heart rate, respiratory rate, body temperature). 
o Corporal biometry (weight) 

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o Decision on subject’s continuity 
- 
Laboratory tests (hemogram, biochemistry and biological) 
- 
Urine test strip 
- 
MRI (V9) 
 
 
In V16 (Int-6m), the following data will be additionally recorded in the eCRF (and 
corresponding source documents): 
o Electrocardiogram 
o Overall assessment carried out by the investigator 
o Neuropsychological Battery and IGE 
o MRI 
 
 
In V21, it will be additionally recorded in the eCRF (and corresponding source documents): 
o Electrocardiogram 
o Overall assessment carried out by the investigator 
o Neuropsychological Battery and IGE  
o QoL EQ-5D-5L  
o MRI 
o a-PET (only after MRI results) 
o Lumbar puncture to obtain CSF. 
 
4.9.1.3 
Follow-up Period: Visits V22 - V25 (weeks 51 to 104) 
This period consist in two phone interviews (V22 and V24), two face-to-face visits [V23 and 
V25 (Final visit)]. Data to be recorded in the eCRF (and corresponding source documents) at 
these visits are the same than those of the phone interview visits and face-to-face visits, 
respectively described above, in addition to Neuropsychological Battery and EKG (V23 and 
V25) and IGE and QoL (V25 only). V25 also includes MRI, a-PET (only after MRI results) 
and lumbar puncture to obtain CSF. 
 
4.9.2 
Part B 
Before any assessment or intervention for the study is completed, the investigator will inform 
the patient and caregiver, about the Part B of the trial. Both will receive a written detailed 
description of all activities and requirements involved of the Part B (Patient’s Information and 
caregiver Leaflet), and the investigator will ensure that they completely understand the clinical 
trial. 
Once understood and accepted, they will proceed to sign the informed consent. This will take 
place between Last Visit of Part A and First Visit of Part B (V1B). 
The V1B should take place when the results of the last MRI test performed (either at V21 or 
V25 or within 6 months (±15 days) of V1B) are available and support the vaccination. 

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The Part B consist in two different types of visits: vaccination visits (V1B, V4B, V7B, V10B, 
V13B and V18B) and safety visits (phone interview: V2B, V5B, V8B, V11B, V14B, V19B 
and face-to-face visits: V3B, V6B, V9B, V12B, V15B, V16B, V17B, V20B, V21B and V22B). 
 
Data to be recorded in the eCRF (and corresponding source documents), at the Vaccination 
Visits (V1B, V4B, V7B, V10B, V13B and V18B): 
- 
Medical Evaluation 
o Physical and neurological examination (except at V1B) 
o Vital signs (blood pressure, heart rate, respiratory rate, body temperature) 
before and after the Vaccination 
o Corporal biometry (weight) 
- 
Medical History: 
o Record relevant past and concomitant diseases 
o Record concomitant medication. 
o Record any adverse events. 
- 
Treatment:  
o Administer the study treatment  
o Assess vaccine reaction, local and systemic. 
o 2 hour after vaccination vital signs and a thorough examination of the patient to 
assess any reaction to the vaccine will be carried out and any adverse events 
(AEs) recorded. 
- 
Laboratory tests (hemogram, biochemistry and biological; at V1B: only biological) 
- 
COVID-19 related information  
 
Data to be recorded in the eCRF (and corresponding source documents) at the safety phone 
interview (V2B, V5B, V8B, V11B, V14B and V19B): 
- 
Medical History: 
o Local or systemic reactions to the vaccine 
o Concomitant Medication 
o Adverse events 
 
Data to be recorded in the eCRF (and corresponding source documents) at the safety face-to-
face visits [V3B, V6B, V9B, V12B, V15B, V16B, V17B, V20B, V21B and V22B]: 
- 
Medical History: 
o Local or systemic reactions to the vaccine 
o Adverse Events, Assess vaccine reaction 
o Concomitant Medication information update 
- 
Medical Evaluation 
o Physical and neurological examination 
o Vital signs (blood pressure, heart rate, respiratory rate, body temperature). 
o Corporal biometry (weight) 
o Decision on subject’s continuity (except in V22B) 
- 
Laboratory tests (hemogram, biochemistry and biological) 
- 
Urine test strip 
- 
MRI (V9B, V16B, V17B, V21B and V22B only) 
 

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In V16B, the following data will be additionally recorded in the eCRF (and corresponding 
source documents): 
o Electrocardiogram 
o Overall assessment carried out by the investigator 
o Neuropsychological Battery and IGE 
 
In V21B, it will be additionally recorded in the eCRF (and corresponding source documents): 
o Electrocardiogram 
o Overall assessment carried out by the investigator 
o Neuropsychological Battery and IGE  
o QoL EQ-5D-5L  
o a-PET 
o Lumbar puncture to obtain CSF 
Finally, in V22B, it will be additionally recorded in the eCRF (and corresponding source 
documents): 
o Electrocardiogram 
o Overall assessment carried out by the investigator 
o Neuropsychological Battery and IGE  
 
4.9.3 
Premature discontinuation visit (PDV) 
In the event that a patient prematurely discontinues completely the study for any reason, a final 
assessment of the clinical trial (premature discontinuation visit) must be carried out as soon as 
possible after discontinuing the study, indicating the reason for discontinuation. 
All patient documents should be as complete as possible. 
For patients who prematurely discontinue the clinical trial the same assessments as the 
50-weeks visit (V21, see 4.9.1) should be performed. However, if a randomized patient 
withdraws the study before receiving the first IMP administration the following assessments 
will not be needed: electrocardiogram; urine analysis (test strip); hemogram, biochemistry, 
biological activity, MRI, a-PET, CSF. 
If a patient discontinues early from the study treatment, he/she should continue with the 
remaining safety assessment visits (without any more treatment administration nor related 
phone interviews) (see 5.3.4 for more details). 
 
4.9.4 
Information collected on selection failures 
Subjects who have signed informed consent but were not randomized for any reason shall be 
recorded in the selection record and complete V0 in the eCRF. No further information will be 
collected on these subjects. 
 
 

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5 
SELECTION AND WITHDRAWAL OF SUBJECTS  
Study Population: 
The study population will consist of a representative group of patients of both sexes with a-
MCI or vm-AD, who meet all the selection criteria and give their informed consent to 
collaborate in the study, after being informed. The a-MCI will meet the clinical criteria defined 
by the National Institute on Aging–Alzheimer’s Association. The vm-AD will meet the criteria 
for probable AD defined by National Institute of Neurological and Communicative Diseases 
and Stroke/Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA). 
The patients’ recruitment will be competitive until the required number of patients is 
completed. Approximately 22 international centres will be involved: Spain (17 sites), France 
(3 sites), Sweden (1 site) and Italy (1 site). 
 
5.1 
Inclusion Criteria 
A subject must meet all the following inclusion criteria: 
1. Male or female between 55 and 80 years of age, both inclusive, at the time of signing 
informed consent. 
2. The patient (or legal representative, if applicable) and a close relative/caregiver must read 
the subject information sheet, agree to participate in the clinical trial and sign the informed 
consent form (the patient and a close relative/caregiver). 
3. Presence of a stable caregiver to attend the patient study visits. 
4. Mini-Mental Status Examination (MMSE) score between 24 and 30 points (inclusive), 
according to age and education level.  
5. Clinical Dementia Rating (CDR) scale scoring 0.5.  
6. Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Score on 
the Delayed Memory Index (DMI) of 85 or lower.  
7. The results of the patient’s MRI brain scan must be concordant with the diagnosis of 
clinical a-MCI or vm-AD according to the following criteria: Scheltens scale, and 
measurement of white matter and past haemorrhages. 
8. If the patient is receiving treatment for AD, must have been stable during the two months 
before the selection visit.  
9. Treatment for concomitant diseases must be stable during the previous month before the 
treatment of the study. 
10. Positive assessment of the candidate by the investigator for complying with the 
requirements and procedures of the study.  

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5.2 
Exclusion Criteria:  
A subject meeting any of the following exclusion criteria is NOT eligible for participation in 
the study. 
1. Known allergy to components of the vaccine or prior history of anaphylaxis, a severe 
allergic reaction or a history of hypersensitivity to any component of the formulation. Allergy 
to fish or shellfish. 
2. Active infectious disease (i.e. hepatitis B, C). Positive syphilis serology. 
3. History or presence of autoimmune disease, except mild eczema, rhinitis or psoriasis.  
4. Presence or history of immunodeficiency (i.e. HIV). 
5. Significant kidney and/or liver disease, as defined by plasma creatinine  2.5 mg/dL (221 
mol/l) and/or total bilirubin > 3 mg/dL (51.3 mol/l) measured at the local site laboratory.  
6. History of asthma or reactive airway disease with bronchospasm in the last 6 months, or 
currently on regular treatment. 
7. Major uncontrolled systemic condition (e.g. diabetes, congestive heart failure, 
hypertension). 
8. History of cancer (≤5 years since the last specific treatment). Exceptions: basocellular 
carcinoma. 
9. Significant alterations in hematological, biochemical or urine analytical parameters, 
particularly those relating to levels of vitamin B12, folic acid or thyroid tests.  
10. History of any other central nervous system disorder, degenerative or non-degenerative 
neurological or psychiatric condition that, in the investigator's opinion could be the cause of 
the dementia, or could explain the cognitive impairment, or that might interfere with cognitive 
function directly or by its treatment. 
11. Geriatric Depression Scale (GDS; abbreviated version), score >5. 
12. Has a “yes” answer to C-SSRS suicidal ideation items 4 or 5, or any suicidal behavior 
within 6 months before Screening, or has been hospitalized or treated for suicidal behavior in 
the past 5 years before Screening. 
13. History or signs of cerebrovascular disease (ischemic or haemorrhagic stroke, transient 
ischemic attack), or diagnosis of possible, probable or clear vascular dementia according to 
NINDS-AIREN criteria.      
14. Presence on MRI of a relevant pattern of microvascular disease (Leukoaraiosis, Fazekas 
score ≥2 in the deep white matter scale or ≥4 in the global score) or more than one lacunar or 
territorial infarcts. Any other MRI finding that, in the opinion of the investigator, might be a 
relevant contributing cause of subject´s cognitive impairment. Presence of up to 3 
microhemorrhages will be acceptable. 
15. History of bleeding disorder or predisposing conditions, blood clotting or clinically 
significant abnormal results on coagulation profile at Screening, as determined by the 
Investigator.  
16. Patients being treated with anticoagulants or antiaggregant therapy (aspirin at a 
prophylactic dose ≤ 325 mg daily or clopidogrel at a dose ≤75 mg daily are allowed) should 
not be recruited in the study. 
17. Modified Hachinski Ischemic Scale, score higher than 4. 

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18. Surgery (with general anaesthetic) within the previous three months to be included in the 
trial, or programed during the study period.  
19. Treatment within 30 days prior to visit 0 with systemic corticosteroids or other 
immunosuppressant’s. 
20. Vaccination against influenza or any other vaccination within 2 months before first IMP 
dose. 
21. Patients, who have previously been randomized in this trial. 
22. Participation in another clinical trial within the previous 1 month to screening visit, or 
within the previous 12 months after the last dose to the screening visit in the case of subjects 
who participated in trials with a study drug whose intention was to modify the progression AD 
unless documentation of receipt of placebo is available. The patient cannot be included in the 
study if the experimental drug was an immunotherapeutic drug, including IVIG or a vaccine 
against Alzheimer's disease unless documentation of receipt of placebo is available.   
23. Patients with alcohol or drug abuse or dependence. 
24. Absolute (having a pacemaker or implantable defibrillator) or relative (bare metal stent or 
stent implanted in the last six months) contraindications to MRI examination. Feeling of 
claustrophobic do not let perform MRI or PET scan.  
25. Patients unlikely to comply with the protocol (e.g., unable to return for follow-up visits) 
26. Women of childbearing potential, pregnant or nursing. 
Note: All women will be considered to be of childbearing potential unless they are postmenopausal 
(amenorrheic for at least 12 consecutive months, in the appropriate age group, and without other 
known or suspected cause) or have been sterilized surgically (i.e. bilateral tubal ligation, total 
hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing) 
27. Significant alterations in the EKG that are associated with an added risk for the patient 
 
5.3 
Subject Withdrawal Criteria 
5.3.1 
Screen Failures  
Screening evaluations, those performed at pre-selection or screening visit (V0) will be used to 
determine the eligibility of each subject for enrollment.  Subjects who fail to meet eligibility 
criteria during screening evaluations will be considered screen failures and will not participate 
in the study. 
5.3.2 
Removal of Subjects   
Subjects may withdraw or be withdrawn from the study for the following reasons: 
1. At their own request or at the request of their legally acceptable representative. 
2. If, in the site’s principal investigator's opinion, after consulting to the Medical Advisor, 
continuation in the study would be detrimental to the subject's well-being. 
3. At the specific request of the sponsor if, in the Medical Advisor’s opinion, continuation 
in the study could be detrimental to the subject´s well-being or in case that the subject 
have incurred in a major violation of the protocol. 

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4.  In case of AEs related to the IMP, particularly allergic reactions or micro- or macro-
hemorrhages detected by MRI in the safety control visits (see sections 8.2.6 and 8.3.10). 
 
Subjects who withdraw after being randomized will remain in the study database and their data 
until the date of discontinuation will be analyzed.  
In all cases, the reason for withdrawal must be recorded in the eCRF and in the subject's 
records.  
5.3.3 
Subject Replacement  
It is expected that 120 patients (60 in verum and 60 in placebo) with a-MCI or vm-AD will be 
included in the clinical trial as per protocol, from whom ̴ 40% will prematurely withdraw. 
However, since all enrolled patients who receive any amount of study drug will be valid for 
the primary safety analysis and the number of patients expected to complete the clinical trial 
taking into account a 40% of premature discontinuations (approximately 70) will have more 
than 85% power to evaluate the primary efficacy endpoint, there will be no need to replace 
withdrawn patients who have received at least one dose of the IMP or placebo, as correspond. 
Therefore, patients who have been randomized and did not received any dose of IMP or 
placebo will be replaced. 
5.3.4 
Follow-up of Subjects Withdrawn from Study Treatment 
Subjects who receive any amount of investigational product and discontinue early from the 
study treatment will be requested to continue with the remaining safety assessment visits 
(without any more treatment administration nor related phone interviews). The following visits 
are those considered minimum “safety assessment visits” to be performed in subjects 
withdrawn from study treatment (as applicable according to the time of withdrawal):  
 Safety control visits 
 Face-to-face visits: V3, V6, V9, V12, V15, V16 (Int-6m), V17, V20, V21, V23 and 
V25 (Final visit) [Part A]; V3B, V6B, V9B, V12B, V15B, V16B, V17B, V20B, 
V21B and V22B [Part B] 
There is no need to perform any additional Vaccination Visit nor phone interviews. 
Withdrawn subjects should receive at least a premature discontinuation visit within the 15 days 
after their last treatment’s administration (PDV; see section 4.9.3). If a randomized subject 
withdraws the study before receiving the first IMP administration, the following assessments 
of the PDV will not be needed: electrocardiogram; urine analysis (test strip); hemogram, 
biochemistry, biological activity, MRI, a-PET, CSF. 
In accordance with good clinical practice (GCP), patients that discontinue the trial prematurely 
due to adverse events will be followed-up until resolution of the AE, properly documenting 
both the cause of premature withdrawal as well as management of data collected and the 
subsequent treatment received by the patients. 
 

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6 
TREATMENT OF SUBJECTS 
See Section 4.4 for the treatment(s) to be administered, including the name(s) of all the 
product(s), the dose(s), the dosing schedule(s), the route/mode(s) of administration. 
6.1 
Administration and Timing of Investigational Products for Each 
 
Subject 
Treatment will consist of the administration of six 1 mL doses of verum (the IMP; ABvac40 
vaccine) or placebo (comparator; the vaccine vehicle without the API) along a “treatment 
period” spanning for 42 weeks (10 months) for both Part A and Part B (see Figure 1). The first 
five doses will be administered at four-week intervals on visits V1, V4, V7, V10 and V13 [Part 
A] and V1B, V4B, V7B, V10B and V13B [Part B]. The sixth dose, a delayed booster shot, will 
be administered at V18 [Part A] or V18B [Part B], 26 weeks after the fifth dose. 
Figure 1 Treatment administration schedule scheme 
 
 
ABvac40 dose (or placebo) is dispensed in 1 mL vials, ready for direct injection. Each patient 
will be assigned a treatment kit (blister) containing 8 vials (verum or placebo as corresponds) 
including 2 spare vial. For Part B treatment kits will contain 6 vials of verum or placebo. 
All treatments will take place at the trial center and will be administer by trained staff from 
each site.  
Injections will be administered subcutaneously (sc) proceeding with special care to avoid 
intravenous administration, gently aspirating with the syringe before injecting. As a first option 
the lateral aspect of the arm will be used, about 8-10 cm above the elbow. As a prerequisite the 
regional lymph node group must be intact, if neither arm has intact lymphatic drainage, the 
injection will be administered to an anterior thigh, roughly half way between the groin and 
knee. 
After each treatment the patient will remain under observation for 2 hours in the center. At the 
end of this time, vital signs will be assessed and a thorough examination carried out including 
inspection of the injection site to assess any reaction to the vaccine.  
R
0
4
8
12
16
42
V1B
V4B
V7B
V10B
V13B
V18B
V1
V4
V7
V10
V13
V18
Placebo group
Verum group
Delayed start group
Booster group
Week
Visit
0
4
8
12
16
42
Week (Part B)
Visit
Part A
Part B
Placebo administration
ABvac40 administration
ABvac40 booster

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6.1.1 
COVID-19 Testing 
6.1.1.1 
Part A 
All patients who will attend their V18 after April 2020 must be tested for COVID-19 by PCR 
method before receiving the study medication (Urgent safety notification has been send to 
Competent Authorities). 
The aforementioned patients must sign a specific ICF authorizing this test. In case they refuse, 
they will continue participating in the study but they will not receive the study treatment. 
After authorization, the required samples will be taken by a trained study staff or delegate and 
sent to the central laboratory (
) where a standard PCR test for 
COVID-19 detection will be performed.  
After 24-48h, the patient will be communicated with the results. In case the patient test negative 
for COVID-19, he or she will continue with the study procedures (including receiving the study 
treatment) normally. 
In case the patient test positive for COVID-19, the PCR test will be repeated until the patient 
test negative and is asymptomatic. During this time, the patient will not receive the study 
treatment. Under any delay scenario, the subsequent visits will be re-scheduled accordingly. 
 
6.1.1.2 
Part B 
All patients must be tested for COVID-19 during the Part B vaccination visits before receiving 
their study medication, unless the patient has already overcome the disease (it has to be 
documented) and remains asymptomatic.  
At each vaccination visit, the patients will perform a rapid serological test at the study site to 
detect SARS-CoV-2 antibodies in serum. 
In case the patient test positive and he or she is completely asymptomatic for COVID-19, he 
will continue with the study normally. 
In case the patient test negative, a PCR test for COVID-19 detection will be performed. The 
required samples will be taken by a trained study staff or delegate and sent to the central 
laboratory (
) where a standard PCR test for COVID-19 detection will 
be performed.  
After 24-48h, the patient will be communicated with the results. In case the patient test negative 
and remains completely asymptomatic for COVID-19, he or she will continue with the study 
procedures (including receiving the study treatment) normally. 
In case the patient test positive for COVID-19, the PCR test will be repeated until the patient 
test negative and is asymptomatic. During this time, the patient will not receive the study 
treatment. The administration of the study treatment can be delayed for up to one month. In 
case it should be delayed beyond one month, the vaccination will be skipped. Under any delay 
scenario, the subsequent visits will be re-scheduled accordingly. 
 
 

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6.2 
Prior and Concomitant Therapy 
Patients are allowed to continue their usual treatment for Alzheimer's disease during the trial; 
it should remain stable throughout the study duration. 
For subjects receiving at least one dose of the IMP, all relevant treatments (at the Investigator’s 
opinion) administered during the 6 months prior to the screening visit for any indication and 
for Alzheimer’s disease will be recorded in the eCRF, including the trade and generic names 
of the medication, the dose, the route of administration, and the duration of the medication 
(frequency). For subjects who do not receive at least one dose of the IMP (e.g. screening failure 
subjects), only the concomitant medication used to resolve SAEs reported during the screening 
period, will be collected in the eCRF. 
6.2.1 
Prohibited Medications Prior to Study Participation 
 As described in the Exclusion Criteria: 
• 
Treatment within 30 days prior to visit 0 with systemic corticosteroids or other 
immunosuppressant’s. 
• 
Vaccination against influenza or any other vaccination, within 2 months before first IMP 
dose. 
• 
Participation in another clinical trial within the previous 1 month to screening visit, or 
within the previous 12 months after the last dose to the screening visit in the case of subjects 
who participated in trials with a study drug whose intention was to modify the progression AD. 
The patient cannot be included in the study if the experimental drug was an immunotherapeutic 
drug, including IVIG or a vaccine against Alzheimer's disease. 
• 
Patients with alcohol or drug abuse or dependence. 
6.2.2 
Prohibited Concomitant Medications during the Study 
Administration of any of the following drugs interferes with the assessment and interpretation 
of clinical trial results and, therefore, any patient taking these drugs is not eligible for 
participation in the trial. These drugs are also prohibited during the whole study follow-up: 
- 
Treatment with immunosuppressive drugs 
- 
Treatment with experimental immunotherapeutics including IVIG or vaccines for 
Alzheimer's disease 
6.2.3 
Restricted Concomitant Medications during the Study 
This section describes medications that are restricted but not prohibited during the study 
participation: 

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- 
Sedatives will not be permitted the night before the neuropsychological tests, 
particularly neuroleptics.  
- 
Avoid administration of the influenza vaccine or any other vaccination during the 1 
month prior and 15 days after each vaccination or until next Safety visit, whatever 
occurs earlier. 
- 
If a patient with MCI needs to start a dementia treatment or a patient with AD needs 
modification of their dementia treatment before Int-6m visit (or V16B) or between Int-
6m and V21visits (or between V16B and V21B), the investigator should discuss with 
him/her the benefit/risk balance in order to evaluate if the change can wait until after 
the Int-6m (or V16B) or V21 visit (or V21B), respectively. If the modification needs 
to be done before Int-6m (or V16B) visit or between Int-6m and V21 visit (or between 
V16B and V22B), respectively, the subject must be discontinued from the study 
treatment, but not from the study follow-up (see Section 5.3.4).  
- 
Treatment with benzodiazepines and nootropics is authorized only at regular and stable 
doses in steady state (chronic use). Any dose change or treatment modification during 
the study will be reported both as an Adverse Event and as a change in the Concomitant 
medication section of the eCRF. If a patient needs to modify the dose before Int-6m (or 
V16B) visit or between Int-6m and V21 visits (or between V16B and V22B), the 
decision for the patient to continue with the study treatment will depend on clinical 
judgment and will be assessed on a case-by-case basis by the Medical Advisor. 
6.3 
Treatment Compliance 
Treatment compliance is ensured because all treatments will take place at the trial center and 
will be administered by trained staff from each site. 
Nevertheless, the reasons for any deviation from the administration of less than 100% of the 
investigational product dose as prepared must be recorded in the case report form (eCRF) and 
in the subject’s medical records. 
 
 

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7 
ASSESSMENT OF EFFICACY 
7.1 
Efficacy Variables  
 
7.1.1 
Part A 
7.1.1.1 
Primary Efficacy Variable 
- 
Maximal increment of specific anti-Aβ40 antibody signal (antibody titers estimated 
by ELISA [signal optical density (OD) values]) in each subject with regard to the pre-
treatment visit (either V0 or V1)  
7.1.1.2 
Secondary Efficacy Variables 
- 
Characterization of the immune response:     
o Levels of anti-KLH and anti-Aβ42 antibodies in plasma  
o Level of anti-Aβ40 antibodies in CSF  
o Levels of cytokines in plasma including IL-2, IL-4, IL-5, IL-6, IL-10, IL-13, IL-15, 
TNF-α and IFN-γ (Sandwich ELISA) 
o Analysis of the peripheral blood cell subsets by immunophenotyping 
o Levels of antibody-secreting cells and cytokine-secreting cells (including IFN-γ, 
TNF-α and IL-13) 
- 
Assessment of disease biomarkers: 
o Levels of Aβ peptides in plasma 
o Levels of cortical fibrillary amyloid deposition; as standardized uptake value ratio 
(SUVR) in amyloid-PET scans. 
o Levels of CSF biomarkers (Aβ42, Tau, P-tau, neurofilament light and neurogranin) 
and other Aβ peptide species 
o Brain volumetric and atrophy of the hippocampus assessed by magnetic resonance 
imaging. 
- 
Assessment of cognition, suicide risk and quality of life: 
o Mini Mental State Examination (MMSE) 
o Clinical Dementia Rating scale (CDR) 
o Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) 
o Columbia Suicide Severity Rating Scale (C-SSRS). 
o ADCS-ADL MCI  
o Trail Making Test (TMT) 
o Investigator Global Evaluation (IGE) 
o Euroqol 5 Dimensions (EQ-5D) 
 

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7.1.2 
Part B 
7.1.2.1 
Exploratory Efficacy Variables 
- 
Maximal increment of specific anti-Aβ40 antibody signal (antibody titers estimated by 
ELISA (signal OD values) in each patient with regard to the pre-treatment visit (either 
V0/V1 [Booster group] or V1B [Delayed start group]). 
- 
Characterization of the immune response:   
o Level of anti-Aβ40 antibodies in CSF  
o Levels of antibody secreting cells  
- 
Assessment of disease biomarkers: 
o Levels of Aβ peptides in plasma  
o Cortical fibrillary amyloid deposition assessed by PET scans. 
o Levels of CSF biomarkers (Aβ42, Tau, P-tau, neurofilament light and 
neurogranin) and other Aβ peptide species  
o Brain volumetric and atrophy of the hippocampus using magnetic resonance 
imaging 
- 
Assessment of cognition and quality of life: 
o MMSE 
o CDR scale  
o RBANS 
o ADCS-ADL MCI 
o C-SSRS 
o TMT 
o IGE 
o EQ-5D-5L 
 
7.2 
Methods and Timing for Assessing, Recording, and Analyzing Efficacy 
Parameters 
7.2.1 
Observations and Measurements 
The following is a description of the procedures/assessments to take place at each study visit.  
See the Section 4.2 Study Design and Plan (Schedules of Study Procedures and Events in Table 
3 and Table 5). 
The primary efficacy variable is average maximal increment (MΔ) of specific anti-Aβ40 
antibody signal (antibody titers estimated by ELISA [signal optical density (OD) values]) in 
each subject with regard to the pre-treatment visit (either V0 or V1). Additionally, the other 
efficacy assessments will be exploratory analyzed to enrich the ABvac40 proof of concept. In 
particular, the efficacy analysis will consist i) in the assessment and characterization of the 
immune response elicited by ABvac40, ii) assessment of the AD biomarkers and iii) 
assessment of the cognition and quality of life of the subjects along the study. 
For a summary of the procedures/assessments to take place at each study visit see table 3 and 
table 5 in section 4.2.  
 

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7.2.1.1 
Assessment and characterization of the immune response 
For the assessment and characterization of the immune response blood samples will be 
collected at visits V0, V1, V3, V6, V9, V12, V15, V16, V17, V20, V21, V23 and V25 (Part 
A), and at visits V1B, V3B, V6B, V9B, V12B, V15B, V16B, V17B, V20B, V21B and V22B 
(Part B). All these analysis, together with the levels of Aβ peptides in plasma, will be 
centralized at the Araclon-Grifols. 
The laboratory tests to be performed with these samples are listed below. (Detailed descriptions 
of the laboratory test procedures are located in the study Laboratory Manual document): 
- 
Characterization of the antibodies generated by vaccination with ABvac40: it will proceed 
to the titration of antibodies generated against the immunogenic peptide (Aβx-40), other 
vaccine components (KLH) and Aβ-42 peptide. The specificity and isotype of these 
antibodies will also be characterized. These analyzes will be carried out in plasma samples 
by Enzyme-Linked ImmunoSorbent Assay (ELISA). 
For the Part A, patients in the verum group will be classified as “Positive Responders” 
when their maximal increment (MΔ) of anti-Aβ40 specific antibody signal (OD in ELISA) 
from the pre-treatment visit (either V0 or V1) is equal or greater than 3 times the standard 
deviation of the titration ELISA. The antibody titers (defined as the inverse of the maximal 
plasma sample dilution which showed an OD increase ≥ 3 SD with regard to the preimmune 
sample) of Positive Responder patients will be reported. 
- 
Analysis of cytokines in plasma: quantitation of a panel of cytokines in order to 
characterize the type of immune response (Th1 or Th2) by sandwich ELISA [Part A]. 
- 
Analysis of antibody-secreting cells: quantitation of B-lymphocytes secreting antibodies 
against Aβ or other components of the vaccine. This analysis will be performed by 
Enzyme-Linked ImmunoSpot (ELISpot) assay. 
- 
Analysis of cytokine-secreting cells: quantitation of cells secreting cytokines in order to 
characterize the potency and type of immune response (Th1 or Th2). This analysis will be 
performed by ELISpot assay [Part A].  
- 
Immunophenotyping of circulating blood cells: Quantitation of the relative number of 
peripheral blood mononuclear cells (cluster of differentiations; CD) to monitor the effect 
of the vaccine at cellular level. This analysis will be performed by multicolor flow 
cytometry [Part A]. 
Analysis for antibody titration and determination of Aβ peptide and cytokine levels will be 
carried out at Int-6m (V16) and Final visit (V25/V23) [Part A] and at V22B (Part B), once the 
samples from all the subjects are available. Analysis of antibody-secreting cells [Part A and 
Part B], cytokine-secreting cells [Part A] and the immunophenotyping [Part A] will be 
performed subject by subject, immediately after each visit upon receiving the sample in the 
laboratory. 
 
7.2.1.2 
Assessment of the AD biomarkers 
- 
Quantification of Aβ peptide species: levels of Aβ peptides in plasma, including Aβ40 
Aβ42 and Aβ17 will be analyzed with ABtest sandwich ELISA and/or liquid 
chromatography-mass spectrometry (LC-MS).  

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- 
The level of cortical fibrillary amyloid deposition will be assessed at the pre-immune stage 
(V0), V21 and Final visit (V25) [Part A], and at V21B [Part B] by amyloid-PET scans, 
which will be assessed centrally by the a-PET Central Reader. The Aβ-PET standardized 
uptake value ratio (SUVR) is a surrogate marker of cortical Aβ pathology and will be 
assessed to explore the effect of ABvac40 on the cerebral Aβ load. An additional perfusion 
PET scan study will be performed within the first 5 min after tracer injection in order to 
adequately adjust the assessment of Aβ burden (SUVRs) for possible changes in patients 
brain perfusion caused by treatment or any other factor occurring along the study period. 
Detailed procedures for acquiring, recording and assessing Aβ-PET are described in the 
PET Site Operations Guide) 
- 
The levels of CSF biomarkers (Aβ40, Aβ42, tau, P-tau, neurofilament light  and total 
protein and albumin) together with levels of other Aβ peptide will be assessed at the pre-
immune stage (V1), V21 and at the Final visit (V25) [Part A] and at V21B [Part B] by 
ELISA sandwich and/or LC-MS. 
Additionally, CSF levels of anti-Aβ40 antibodies will be determined by titration ELISA to 
deepen in the knowledge of ABVac40 mechanism of action. 
Detailed procedures for acquiring, recording and assessing CSF biomarkers are described 
in the Laboratory Manual document). 
- 
Brain volumetric and atrophy will be assessed at visits V0, V16, V21 and V25 by MRI as 
an exploratory indication of ABvac40 efficacy. An additional MRI will be performed 
before first vaccination of Part B only if the previous MRI was performed more than 6 
months (±15 days) before V1B to identify any safety findings. During Part B, they will be 
assessed at V16B, V21B and V22B by MRI. Additional MRI will be performed at V9 and 
V17 to control for safety (V9B and V17B in Part B) (see section 8.2.6). 
Detailed procedures for acquiring, recording and assessing MRI are described in the 
Neuroimaging Management document). 
 
7.2.1.3 
Assessment of cognition and quality of life 
Assessment of cognition and quality of life will be carried out at visits V0, V1, V16, V21 
during the active phase of the study and at V23 and V25 during the follow-up. The tests to be 
used are summarized in the following table. 
 
 

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Table 7 Neuropsychological tests: 
 
 
Detailed procedures for acquiring, recording and assessing cognition and quality of life are 
described in the Assessment Management document. 
The answers of the patients to these tests will be registered in paper/electronic form in the study 
records; In addition and only for CDR and RBANS and as long as the patient specifically 
consent to it, the answers will be also registered through audio recording to ensure that if 
necessary a diagnosis verification could be carried out posteriorly. These audio recording will 
be destroyed at the end of the study. 
 
At V16B, V21B and V22B visits of Part B, the complete Neuropsychological battery will be 
performed. In addition, the test for quality of life will be performed in V21B.  
 
7.2.2 
Description of Laboratory Tests and Procedures 
Detailed procedures for acquiring, recording and assessing laboratory tests are described in the 
Laboratory Manual document. The following table summarizes the name, description and 
location of Laboratory tests and procedures for blood, CSF and urine analysis (see Table 8). 
 
 
 
Neuropsychological Battery
V0 
Screening   
Week -8
V1           
Baseline      
Week 0
V16             
Int-6m
Week 24 
V21       
Int-12m
Week 52
V23       
Week 77
V25         
Final visit 
Week 104
MMSE (24-30 at inclusion)
X
-  
X
X
X
X
CDR (global score of 0.5 at inclusion)
X
-  
X
X
X
X
RBANS (score ≤ 85 at inclusion)
X
-  
X
X
X
X
COLUMBIA-SSRS (no answer "YES" in item 
4 or 5 at inclusion)
X
-  
X
X
X
X
ADCS-ADL MCI
-  
X
X
X
X
X
TMT-B
-  
X
X
X
X
X
GDS abbreviated (score≤ 85 at inclusion)
X
-  
-  
-  
-  
-  
IGE
-  
X
X
X
-  
X
Quality of Life Tests
EQ-5D-5L
-  
X
-  
X
-  
X
Neuropsychological tests

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Table 8. Name, description and location of Laboratory tests 
 
Description
Location
Blood 
Analysis
Hematology
Hematocrit, hemoglobin, erythrocytes, VCM, MCHC, 
leukocytes, neutrophils, lymphocytes, monocytes. eosinophils, 
basophils, thrombocytes
 
Biochemistry
Sustrates:
Glucose, Total cholesterol, triglycerides, creatinine, Total 
bilirubin, Total proteins, Albumin, Uric acid, BUN, C-reactive 
protein, apolipoprotein E, Homoscysteine, Ferritin    
Enzymes:
SGOT (AST), SGPT (ALT), Alkaline phosphatase, GGT, LDH, 
CPK
Electroliters:
Sodium, Potassium, Calcium, Chloride, inorganic phosphorus      
 
Coagulation
APTT, fibrinogen, INR (prothrombin time)
 
Vitamin
B12 vitamin, Folic acid
 
Hormones
Free T4, TSH
 
Others
HbA1c
 
Serology
Syphilis (VDRL, TPHA), HIV, Hepatitis B, Hepatitis C
 
Reumatology Factors
RF, ANA
 
ANTIBODIES : Visits V0 
and V21
Anti-nuclear antibodies (ANA), native anti-DNA antibodies, 
anti-thyroglobulin antibodies, Anti-TPO antibodies
 
Additional Special Tests, 
Visit V1
ApoE gen
Araclon Biotech
Biological Activity: 
Antibody Titration, 
Measure of ABetas, 
Inflammation Factors
Concentration of specific antibodies to Aβ40, KLH and 
Aβ42 peptides in plasma                                                              
Levels of antibody-secreting cells and cytokine-secreting 
cells (including IFN-γ, TNF-α and IL-13).                                    
Levels of Aβ peptides in plasma.                                                
Levels of citoquines in plasma: IL-2, IL-4, IL-5, IL-6, IL-10, 
IL-13, IL-15, TNF-α and IFN-γ.
Number of peripheral blood mononuclear cells (cluster of 
differentiations; CD) including CD3, CD4, CD8, CD19, CD25, 
CD27 and CD69.
Araclon Biotech 
Urinalysis
Microscopic evaluation is 
done only with cause.
Analyzes will be performed with test strips at the trial center. If 
clinically relevant abnormalities are detected, a urine sample 
will be sent to the laboratory to analyze sediment.
 
CSF 
Analysis
Cells
Total Proteins
Glucose
Levels of Aβ1-40, Aβ1-42; Total tau and Phosphorylated tau
Special Lab
Name, Description, and Location of Laboratory Tests and Procedures

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If sample collected for laboratory analyses are non-analyzable or non-reportable due to various 
factors, they will need to be recollected by contacting the subject for unscheduled visit(s) so 
that additional samples (blood, urine) can be collected from subjects and assayed for critical 
analytes at any study time point. In this case, the data from the last sample analyzed at the 
corresponding study time point will be recorded in the eCRF.  
 Backup sample of blood will be collected at screening visit (V0). This sample will be used 
together with sample from baseline visit (V1) to assess pre-treatment levels of critical analytes. 
Samples will be stored/retained in the Araclon-Grifols facilities for additional or repeated 
analysis until Araclon-Grifols deems that all analysis in support of the study have been 
completed. After his period, the samples will be destroyed. If an additional, not related with 
the initially programed analysis is intended subjects will be requested to extend their informed 
consent.  
Biological samples will be managed according to local regulations of each participating 
country. Araclon-Grifols will comply with all pertinent legislation to maintain the 
confidentiality of all health-related information obtained in the study. 
 
 
 
 

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8 
ASSESSMENT OF SAFETY  
8.1 
Safety Parameters 
The primary safety variable is the rate (%) of Adverse Events (AEs). The trial will be 
considered satisfactory if the pattern of AEs (overall or grouped as neurological, psychiatric or 
cardiovascular) is consistent with a good safety and tolerability profile of ABvac40 for human 
administration at the final visit (V25/V22B). 
Additionally the following secondary safety variables will be evaluated:     
- 
withdrawal criteria (continuation decision) 
- 
number of withdrawn patients due to adverse events (AEs); cause of withdrawal  
- 
serious adverse events (SAEs)  
- 
physical  and neurological examination 
- 
concomitant medication 
- 
vital signs (blood pressure, heart rate, respiratory rate, body temperature), body 
mass index (weight, height). 
- 
brain MRI  
- 
electrocardiogram (EKG) 
- 
analytical haematology, toxicology (reactive protein), biochemistry, coagulation, 
serology and urine test strip results. 
 
8.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters 
The above mentioned safety parameters, except MRI and EKG, will be assessed at pre-
screening visit, treatment visits, face to face safety visits, Int visit and final visit during Part A, 
and at treatment visits, face to face safety visits and final visit during Part B.  
Brain MRI will be performed only at visits V0, V9, V16, V17, V21 and V25 [Part A] and at 
V1B (only in the absence of a MRI performed within 6 months (±15 days)), V9B, V16B, 
V17B, V21B and V22B [Part B]; EKG will be performed only at visits V0, V16, V21, V23 
and V25 during Part A and at visits V16B, V21B and V22B during Part B, and will be assessed 
centrally by the Medical Advisor (except at V22B); and urine test strip will be performed  at 
visits V0, V1, V3, V6, V9, V12, V15, V16, V17, V20, V21, V23 and V25 during Part A and 
at  V3B, V6B, V9B, V12B, V15B, V16B, V17B, V20B, V21B and V22B during Part B. 
All these parameters will be available in the eCRF. The parameters will be either entered in 
the eCRF (and corresponding source documents) by the site staff or electronic records from 
vendors will be uploaded to the subject’s eCRF, as specified in the corresponding manuals and 
guidelines 
 

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8.2.1 
Adverse Events  
Adverse events, including adverse reactions (AR) occurring at any time between signing of the 
subject’s ICF and the last day of the subject’s participation in the clinical trial will be recorded 
on the appropriate subject’s eCRF entry. The recording of adverse events will be elicited by 
spontaneous reporting by the study individual or by a non-leading inquiry or direct observation 
by the study staff. It is Investigator’s responsibility to ensure that all AEs are appropriately 
recorded.  
 
8.2.2 
Clinical Laboratory Evaluations 
Blood tests for hematology, toxicology (reactive protein), biochemistry and coagulation will 
be carried out at visits V0, V1, V3, V6, V9, V12, V15, V16, V17, V20, V21, V23 and V25 
[Part A] and at visits V3B, V6B, V9B, V12B, V15B, V16B, V17B, V20B, V21B and V22B 
[Part B] or at the time of an early discontinuation (PDV) (see Table 3 and Table 5). Serology, 
analysis of rheumatology factors and anti-nuclear antibodies will be carried at V0 and V25. 
Urine test strip will be performed at visits V0, V1, V3, V6, V9, V12, V15, V16, V17, V20, 
V21, V23 and V25 [Part A] and at visits V3B, V6B, V9B, V12B, V15B, V16B, V17B, 
V20B,V21B and V22B [Part B] or at the time of an early discontinuation (PDV). Additionally, 
at baseline visit (V1) the ApoE genotyping. All these clinical laboratory analysis will be 
centralized at 
 and at Araclon-Grifols. For detailed information on 
clinical laboratory tests see the Laboratory Manual. 
Analytical and urine test strip results will be registered in the eCRF. Data will be either entered 
in the eCRF (and corresponding source documents) by site staff or uploaded from electronical 
records afterwards to the corresponding section of the subject’s eCRF as detailed in laboratory 
manual and data management guidelines.  
The investigator must review the results of laboratory analyses when received, and sign and 
date them. The Investigator will be required to classify laboratory results out of the normal 
range reported by the laboratory as clinically significant or not according to his/her criteria. 
Laboratory results out of the normal range judged by the Investigator as clinically significant 
will be flagged and recorded in the subject’s eCRF as an AE. 
All patients with clinically significant abnormal laboratory values should be regularly 
monitored until these values return to the normal range or until another valid reason other than 
an adverse event related to the drug is identified. 
The results of these clinical laboratory analysis carried out at the screening visit (V0), will 
determine the inclusion of the patient into the clinical trial. The Medical Advisor’s approval is 
needed in V0, V16 and V16B in order to accept the continuation of the patient in the study. 
At Screening Visit (V0), V21, V25 and V21B the presence of several auto-antibodies will be 
determined within assessment of eligibility and safety. 
 

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8.2.3 
Vital Signs and body mass index 
Vital signs will be measured by a medically certified individual or a nurse according to his/her 
standard clinical practice. Vital signs will be measured at the following visits: (V0, V1, V3, 
V4, V6, V7, V9, V10, V12, V13, V15, V16, V17, V18, V20, V21, V23 and V25 [Part A], and 
V1B, V3B, V4B, V6B, V7B, V9B, V10B, V12B, V13B, V15B, V16B, V17B, V18B, V20B, 
V21B and V22B [Part B] and PDV, if applicable)  The following vital signs will be assessed: 
- 
Temperature 
- 
Blood Pressure (systolic blood pressure [SBP]) and diastolic blood pressure [DBP]), 
- 
Heart Rate 
- 
Respiratory Rate 
 
Body temperature will be measured orally or at the axilla. Measurements of systolic and 
diastolic blood pressure, heart rate and respiratory rate will be recorded after at least five 
minutes of lying at rest. The blood pressure measurements will always be taken from the same 
arm. If there is any suspicion that the measurement is unreliable, blood pressure will be 
measured again. The value obtained on this second occasion will be deemed final and shall be 
recorded in the relevant section of the eCRF. 
To calculate the body mass index (BMI), height will only be measured during visit 1 (day 0). 
Body weight (patient in light clothing without shoes) will be recorded at all visits (and PDV, 
if applicable). The results will be used to calculate body mass index. 
Vital signs will be routinely monitored. Results will be recorded in source documents and on 
the subject eCRF. The Investigator will be required to classify vital signs abnormalities as 
clinically significant or not according to his/her criteria. Vital signs abnormalities judged by 
the Investigator as clinically significant will be recorded in the subject’s eCRF as AEs. 
 
8.2.4 
Physical and Neurological Examinations 
A complete physical examination of patients will be carried out at all face to face visits (V0, 
V1, V3, V4, V6, V7, V9, V10, V12, V13, V15, V16, V17, V18, V20, V21, V23 and V25 [Part 
A] and V1B, V3B, V4B, V6B, V7B, V9B, V10B, V12B, V13B, V15B, V16B, V17B, V18B, 
V20B, V21B and V22B [Part B]; and PDV, if applicable). The general patient status will be 
assessed including examination of neck (including thyroid), eyes, ears, throat, abdomen, 
skin/mucous membranes, and cardiovascular, respiratory, genito-urinary and musculoskeletal 
systems. 
At each visit, a conventional neurological examination will be carried out, consisting in a brief 
inspection of cortical functions, cranial nerves, motor function, reflexes, sensory function, gait 
and posture. A medically certified individual will conduct the physical and neurological 
examination at all of the face-to-face visits. Results will be recorded in the physical and 
neurological examination sections of the subject’s eCRF. 
 

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After the baseline visit (V1), any new finding or worsening of a previous finding from physical 
and neurological examination will be recorded in the subject’s eCRF as an AE. 
 
8.2.5 
EKG 
An electrocardiogram (EKG) will be performed at visits V0, V16, V21, V23 and V25 during 
Part A and at visits V16B, V21B and V22B during Part B (and PDV, if applicable). All EKGs, 
will be assessed centrally by the Medical Advisor. Any new finding or worsening of a previous 
finding will be recorded in the subject’s eCRF as an AE. 
 
 
8.2.6 
Brain MRI 
The brain MRI in the AB1601 study is fundamentally a safety protocol designed to identify 
the occurrence of cerebral complications secondary to the administration of ABvac40. It will 
be performed at visits V0, V9, V16, V17, V21 and V25 during Part A and at visits V1B (only 
in the absence of a MRI performed within 6 months (±15 days)), V9B, V16B, V17B, V21B 
and V22B during Part B, and will be assessed centrally by the MRI Central Reader. 
Additionally, data from MRI at visits V0, V16, V21, V25, V16B, V21B and V22B will be used 
for exploratory efficacy analysis (see section 7.2.1). The MRI at the pre-selection visit (V0) 
will also be used to see if patients who want to enter the study meet the criteria for inclusion 
and none of the exclusion criteria.  
Electronic MRI results will be uploaded to the subject’s eCRF. Detailed procedures for 
acquiring, recording and assessing MRI results are described in the Neuroimaging 
Management document. 
Any new finding or worsening of a previous finding will be recorded in the subject’s eCRF as 
an AE. Particular attention will be paid to the so called Amyloid Imaging Related 
Abnormalities (ARIA). The spectrum of ARIA includes signal hyperintensities on fluid 
attenuation inversion recovery sequences thought to represent "vasogenic edema" and/or sulcal 
effusion (ARIA-E), as well as signal hypointensities on GRE/T2* thought to represent 
hemosiderin deposits (ARIA-H), including microhemorrhage and superficial siderosis. 
A decision tree is set in place for the management of these SAE in case of occurrence (see 
section 8.3.10). 
 
8.2.7 
 Patient’s Diary and Patient emergency card 
Study subjects will be provided with a “Patient Diary” (PD). This will be used to record body 
temperature, local reactions to the treatment or any other AE. Furthermore, the subject will be 
required to record in the PD any concomitant medication including changes in the conventional 
treatment of AD. 
The patient/caregiver will be told to come to subsequent visits with the patient diary completed. 
The researcher will transcribe information recorded by the patient/caregiver in the relevant 
pages of the eCRF. The patient's original diary will be kept at the trial center along with the 
original documents. 

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Upon inclusion in the study, each patient and their caregiver will receive a "patient card" stating 
that they are participating in a clinical trial, identified by its code, title, and name of the study 
drug. The name, address and emergency telephone number (available 24 hours) of the 
responsible investigator will be printed on the card along with a request to contact the 
investigator in case of emergency. If a patient suffers a serious adverse event and needs to go 
to hospital, they should go to the nearest hospital possible; the patient and caregiver will be 
advised to carry the "patient card" with them at all times during the study, as a safety measure. 
 
8.3 
Procedures for Eliciting Reports of and for Recording and Reporting 
Adverse Event and Intercurrent Illnesses 
8.3.1 
Warnings/Precautions 
For complete information on ABvac40 refer to the IB document. 
 
8.3.2 
Adverse Event Monitoring 
Subjects must be carefully monitored for AEs. This monitoring includes clinical and laboratory 
tests and physical signs. Adverse events should be assessed in terms of their seriousness, 
severity, and causal relationship to the IP.  
Adverse events will be elicited by spontaneous reporting by the study individual or by a non-
leading inquiry or direct observation by the study staff.  
8.3.3 
Adverse Event Definitions 
8.3.3.1 
Adverse Events  
An AE is defined as any untoward medical occurrence in a subject or clinical investigation 
subject administered a medicinal product or study treatment and which does not necessarily 
have a causal relationship with this administration. An AE can therefore be any unfavorable 
and unintended sign (including any abnormal laboratory finding, for example), symptom, or 
disease temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product.  
The frequency of adverse events should be investigated using indirect questions at each study 
visit (e.g., How are you today? How do you feel?). Adverse events can also be detected when 
the patient directly and spontaneously reports them during a visit or between visits or by 
physical examination, blood test and other assessments. Abnormal laboratory parameters are 
only considered as an adverse event if the researcher classifies them as "clinically significant". 
Alzheimer’s Disease clinical signs or symptoms and pathological laboratory parameters are 
not considered adverse events if already present in the first assessment, except when 
deterioration or increase in frequency is observed. 
All adverse events will be documented in a specific form for adverse events. The 
documentation includes the following information: 

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- 
Duration (start and end date), 
- 
Intensity (mild, moderate, severe), 
- 
Possible causal relationship with study treatment (related or not), 
- 
Action taken (no measure taken, adjust dose/temporarily stop study drug, permanently 
discontinue 
study 
drug, 
administer 
concomitant 
medication, 
provided 
a 
nonpharmacological therapy, brief or prolonged hospitalization) 
- 
Assessment of outcome (full recovery, improvement, unchanged, deterioration), 
- 
Meet any of the severity criteria. 
 
8.3.3.2 
Suspected Adverse Drug Reactions/Adverse Reactions 
A Suspected Adverse Drug Reactions (ADR) includes any noxious and unintended reaction to 
an investigational medicinal product, regardless of dose administered. Unlike AEs, in the case 
of an adverse reaction a causal relationship between a medicinal product or study treatment 
and an AE is at least a reasonable possibility. 
8.3.4 
Assessment of Causality of Adverse Event 
The Investigator is required to provide a causality assessment for each AE reported to the 
Sponsor. The Sponsor will consider the Investigator’s causality assessment and also provide 
its own assessment.  
Causal relationship to the study drug will be established according to medical judgment on 
whether there is a reasonable possibility of a causal relationship between the AE and the 
IMP administration: 
The Investigator must determine and classify the AE causality according to the following 
categories: 
 Not related: There is not a reasonable possibility of causal relationship between the 
AE and the study drug. 
 Related: There is evidence to suggest a causal relationship between the study drug and 
the AE. 
 
Criteria to assess the causal relationship should take into account of the following conditions: 
1) a plausible temporal sequence from the study drug administration to the AE onset; 2) 
whether the event follows a known response pattern to the suspected treatment; 3) whether the 
AE could be reasonably explained by the subject’s clinical state, comorbidities, or concomitant 
medications, as well as 4) the occurrence of improvement on stopping/reducing the treatment 
(positive dechallenge) and/or reappearance of the event on repeated exposure (positive 
rechallenge). 
8.3.5 
Severity of Adverse Event or Suspected Adverse Drug Reaction 
AEs and suspected ADRs will be classified depending on their severity according to the 
following definitions: 

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Mild: an AE which is well tolerated by the subject, causing minimum degree of malaise and 
without affecting normal activities. 
Moderate: an AE that interferes with the subject’s normal activities. 
Severe: an AE that prevents the subject from performing their normal activities. 
AE and suspected ADR severity gradation must be distinguished from AE and suspected ADR 
seriousness gradation, which is defined according to event consequence. For example, 
headache can be mild, moderate or severe but not necessarily serious in all these cases. 
The Investigator will be responsible for assessing the AE and suspected ADR intensity during 
the clinical trial, taking into account current criteria included in this section. 
8.3.6 
Expectedness of Adverse Event or Suspected Adverse Drug Reaction 
An AE or suspected ADR is considered “unexpected” if the nature, seriousness, severity or 
outcome of the reaction(s) is not consistent with the reference information. The expectedness 
shall be determined by the Sponsor according to the reference document for any serious ADRs 
(potentially related SAEs) for expedited safety reporting purposes. 
8.3.7 
Seriousness of Adverse Event or Suspected Adverse Drug Reaction   
An AE or suspected ADR is considered “serious” if, in the view of either the Investigator or 
Sponsor, it results in any of the following outcomes:  
• Death 
• Life-threatening AE (life-threatening in the definition of “serious” refers to an event in 
which the subject was at risk of death at the time of the event; it does not refer to an event 
which hypothetically might have caused death if it were more severe) 
• In-patient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions  
• A congenital anomaly/birth defect 
• An important medical event (important medical event in the definition of “serious” refers 
to those events which may not be immediately life-threatening, or result in death, or 
hospitalization, but from medical and scientific judgment may jeopardize the subject or/and 
may require medical or surgical intervention to prevent one of the other outcomes listed 
above). 
*Hospitalization is to be considered only hospital stay for equal or more than 24 hours. The 
following hospitalizations should not be reported as SAEs: 
- 
Hospitalization or prolongation of hospitalization needed for procedures required by 
the clinical trial protocol. 

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- 
Hospitalization or prolongation of hospitalization as part of a routine procedure 
followed by the center. 
- 
Hospitalization for a survey visit, annual physicals, or social reasons. 
- 
Elective or pre-planned hospitalizations for a pre-existing condition that had not 
worsened from Baseline (e.g. elective or scheduled surgery arranged prior to start of 
the study). 
- 
Admissions not associated with an AE (e.g. social hospitalization for purposes of 
respite care). 
This definition permits either the Sponsor or the Investigator to decide whether an event is 
“serious”. If either the Sponsor or the Investigator believes that the event is serious, the event 
must be considered “serious” and evaluated by the Sponsor for expedited reporting.  
8.3.8 
Adverse Event Documentation 
For subjects receiving at least one dose of the IMP, all AEs and SAEs occurring after the 
subject has signed the ICF through the Final Visit (i.e., end of study) must be fully recorded 
in the subject’s eCRF, and SAE form (if serious) as well as in the medical record. For subjects 
who do not receive at least one dose of the IMP (e.g. screening failure subjects), all SAEs 
occurring after the subject has signed the ICF through the until subject withdrawal must 
be fully recorded in the subject’s eCRF, and SAE form as well as in the medical record. If no 
AE has occurred during the study period, this should also be indicated in the eCRF. 
It is the responsibility of the Investigator to ensure that AEs are appropriately recorded. 
At each visit, AEs will be elicited by asking the individual a non-leading question such as “Do 
you feel different in any way since the last visit?”  Moreover, AEs will also be collected 
through directly observed events or spontaneously volunteered by the subject. Clearly related 
signs, symptoms and abnormal diagnostic procedures should preferably be grouped together 
and recorded as a single diagnosis or syndrome wherever possible. 
The following variables must be recorded in the AE eCRF: 
• The verbatim term (a diagnosis is preferred) 
• Date/time of onset 
• Date/time of resolution 
• Severity (mild, moderate, severe) 
• Causality (unrelated, possibly related, definitely related)* 
• Seriousness (yes, no) 
• Action taken (with regard to IMP) 
• Other action (to treat the event) 
• Outcome and sequel (follow-up on AE) 
 

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*Causality assessment will be made only when the AE occurs after the subject has received at 
least one dose of the IMP. An AE occurring before subject's exposure to IMP will be always 
labeled as "unrelated". 
In addition to the Investigator’s own description of the AEs, each AE will be encoded 
according to the Medical Dictionary for Regulatory Activities (MedDRA). 
For example, a laboratory test abnormality considered clinically significant, eg, causing the 
subject to withdraw from the study, requiring treatment or causing apparent clinical 
manifestations, or judged clinically significant in the context of the subject’s medical history 
by the Investigator, should be reported as an AE. Each event must be described in detail along 
with start and stop dates, severity, relationship to IMP, action taken and outcome. Each event 
must be adequately supported by documentation as it appears in the subject’s medical or case 
file. 
8.3.9 
Reporting of Serious Adverse Events  
Any SAE that occurs after signing the study ICF through the Final Visit (ie, end of study) 
must be expeditiously reported whether or not considered attributable to the study drug. Each 
SAE must be fully recorded in the subject’s eCRF and SAE Report Form. In addition, any SAE 
that occurs greater than 14 months after the last dose of the investigational product should be 
reported if the Investigator feels that the event is related to the use of investigational product. 
SAEs will be reported using the designated SAE Report Form. When the Investigator becomes 
aware of a SAE, she/he must submit a completed, signed and dated SAE Report Form (in 
English) within 24 hours to the 
 by email/fax. The date of this SAE discovery by the site 
staff should be documented in the source documents (i.e. medical records).  
Each SAE must be followed up until resolution or stabilization. After the initial report, all 
relevant information for SAE follow-up, and for the outcome, must also be supplied to the 
Sponsor in a timely manner (within 3 days from its identification or within 24 hours for relevant 
new information) by means of the SAE Report Form. In addition, the Sponsor or contract 
research organization (CRO) may request additional information and/or reports. 
All SAE Report Forms must be reported to 
 by email or fax to: 
 
 
Fax: 
 
e-mail:  
 
When required, and according to local law and regulations, SAEs must be reported to the 
IRB/EC and regulatory authorities. 

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8.3.10 
Special safety procedures 
8.3.10.1 
Serious adverse events of special interest 
Amyloid Imaging Related Abnormalities (either ARIA-E or ARIA-H) and Aseptic Meningo-
Encephalo-Myelitis have occurred in clinical trial of anti-β-amyloid immunotherapies and are 
considered as Serious Adverse Events. They should be reported as previously described. 
In addition, a specific Decision Tree is set in place for the management of these SAEs, in case 
of occurrence see below:  
 
Process for positive ARIA (ARIA-H and ARIA-E) findings 
The results of the central MRI safety read will be made available to the Site and Sponsor prior 
to the next scheduled dose. The dose cannot be administered until the MRI results are received 
and approval is received from the MRI Central Reader. In the event of a positive ARIA (ARIA-
H or/and ARIA-E) finding, the MRI Safety Review Committee, composed by i) the site IP, ii) 
the MRI central reader and iii) the study Medical Advisor (who will have access to the MRI 
data and central radiology reports) will review the Central Radiology read together with all 
other safety data available to the Sponsor determine the appropriate course of action. If there 
is a positive ARIA finding, then the subject will be asked to attend a follow-up scans at 2, 4, 6 
and 12 months after the event in order to consider the ARIA finding resolved or clearly 
decreased and stabilized (as per the central read). Those scans are classified as “unscheduled” 
scans. 
 
ARIA-H reporting 
Any new micro-hemorrhage (1 or more) found in an MRI is an ARIA-H and needs to be 
informed to 
Drug Safety either as a new SAE or Follow up SAE (Section 8.3.9), taking 
account of the following:  
 
 If the total number of new micro-hemorrhage is greater than 3 (at any time during the 
study) in relation to V0, patients will stop the study medication regardless of number 
of events presented at screening visit.  
 
 If the total number of new micro-hemorrhage is less than 3 (at any time during the 
study) in relation to V0, patients will NOT stop the study medication regardless of 
number of events presented at screening visit.  
 
In addition and in order to consider an ARIA-H as a new event or progression of previous one, 
we will take in consideration the following: 
 
- Any new micro-hemorrhage (1 or more) showed in the follow up MRIs and/or Protocol 
MRIs in a subject with previous ARIA-H will be consider a progression of previous 
ARIA-H if the patient DID NOT TAKE the study medication in between of MRI 
examinations. In such cases, a Follow up SAE will be completed with all information 

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(Follow up SAE will be completed, regardless of new findings, after a Follow Up MRI 
in order to keep 
 Drug Safety informed on the progression of patients). 
 
- Any new micro-hemorrhage (1 or more) showed in the follow up MRIs and/or Protocol 
MRIs will be consider a NEW ARIA-H if the patient took the study medication in 
between of MRI examinations and in such case, a new SAE Report Form will be 
completed with all information required. 
 
ARIA Thresholds and ARIA Decision 
We propose this to be based in the guidelines published by the Alzheimer Association Research 
Roundtable Working Group (Sperling et al. 2011) as follow. 
1. Patients developing mild ARIA-E or mild ARIA-H (≤3 incident micro-haemorrhages) 
without clinical symptoms could continue in the study. 
2. Patients developing moderate or severe ARIA-E (as assessed by the MRI central reader) 
without clinical symptoms, or those with ARIA-E accompanied by mild clinical symptoms, 
will suspend treatment and resume once ARIA (and symptoms, if any) resolved. 
For these patients, if ARIA appears at the MRI after the third shot and resolve within two 
months, they resume for the remaining two shots and booster; if ARIA does not resolve within 
two months then, they resume at the booster shot (m10) if resolved; otherwise, they 
permanently discontinue treatment. 
3. Patients who develop ARIA-E or ARIA-H (≤3 incident micro-haemorrhages) 
accompanied by moderate, severe, or serious clinical symptoms, >3 incident micro-
haemorrhages, any incident macro-haemorrhage, or >1 incident haemosiderosis at any 
time during the study will permanently discontinue treatment. 
 
8.3.10.2 
Reactions to the vaccine 
Reactions to the vaccine may vary from mild to severe reactions (shock or anaphylaxis) that 
can cause death. If such a severe reaction is suspected, patients will be observed for 24 hours 
in the study center after administration of the vaccine (overnight hospitalization) and before 
being discharged vital signs and a thorough examination will be recorded to assess any reaction 
to the vaccine (see Appendix 1). 
8.3.11 
Reference safety information 
8.3.11.1 
Expected Serious Adverse Drug Reactions 
 Expected serious Adverse Drug Reactions (ADR) to ABvac40 are Amyloid Imaging Related 
Abnormalities (ARIA) either ARIA-edema (ARIA-E) or ARIA-hemorrhagic (ARIA-H). 
ARIA-E is the most frequent SAE occurring in clinical trial involving passive 
immunotherapies with monoclonal antibodies targeting Aβ peptides. Incidence of ARIAs 
appeared to depend, among other factors, on the drug product characteristics and dosing but 
can affect a relevant proportion of the participants (up to 50% in some cases). Although ARIAs 
have been much less frequently reported after active immunization of patients with vaccines 
against Aβ peptides (in particular, not cases of ARIA-E or ARIA-H occurred during ABvac40 

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phase I clinical trial), their occurrence in this phase II is deemed as expected and a specific 
protocol is set in place to managing this serious Adverse Drug Reaction. 
 
All Expected serious ADRs must  be submitted to expedited safety reporting using the 
designated SAE Report Form and the procedure described in the Clinical Trial Protocol (see 
section 8.3.9), and msut be accompanied with the corresponding MRI report available. 
 
8.3.11.2 
Unexpected Serious Adverse Drug Reactions 
All other SAEs considered as potentially related with the investigational medicinal product 
(IMP), including Aseptic Meningo-Encephalo-Myelitis and systemic reactions to the vaccine 
(see appendix 1) should be considered as unexpected and submitted to expedited safety 
reporting using the designated SAE Report Form and the procedure described in the Clinical 
Trial Protocol (see section 8.3.9). 
 
8.4 
Type and Duration of the Follow-Up of Subjects after Adverse Events  
In so far as is possible, all individuals will be followed up until the AE or suspected ADR has 
been resolved. If an AE/suspected ADR/SAE is present when the subject has completed the 
study, the course of the event must be followed until the final outcome is known, or the event 
has been stabilized and no further change is expected and the Investigator decides that no 
further follow-up is necessary. 
 
 

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9 
STATISTICS 
9.1 
Statistical Methods 
Unless otherwise specified, descriptive statistics will include the number of observations, 
number of missing values, mean (95% CI), standard deviation (SD), median, minimum, Q1, 
Q3 and maximum values for the continuous/quantitative data or absolute and relative 
frequency counts and percentages for categorical/qualitative data. 
Individual patient data will be listed. 
Data handling and evaluation procedures will be described in the Statistical Analysis Plan. 
 
9.1.1 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized by treatment in the overall group 
and according to a-PET status (a-PET+ and a-PET-). For quantitative variables the number of 
observations, number of missing values, mean (95% CI), SD, median, Q1/Q3 and 
minimum/maximum will be provided. For qualitative variables, the frequency and percentage 
will be provided. Demographic variables will be compared between treated and placebo groups 
as correspond (Mann-Whitney or Chi square). 
9.1.2 
Efficacy Analysis (Part A) 
9.1.2.1 
Primary Efficacy Analysis (immunogenicity) 
The primary variable for immunogenicity is the average maximal increment (MΔ) of anti-Aβ40 
antibody signal (OD in ELISA). 
For the comparison of the response to treatment between the verum and placebo group the 
maximal increment (MΔ) of anti-Aβ40 antibody signal (OD in ELISA) with regard to the pre-
treatment visit (either V0 or V1) in each subject will be used as a summary measure. The 
treatment comparisons will be carried out by one-sided t test or Mann–Whitney U test if 
variable has non-normal distribution. 
The trial will be considered successfully confirmatory regarding efficacy (immunogenicity) of 
ABvac40 if the average maximal increment (MΔ) of anti-Aβ40 antibody signal (OD in ELISA) 
in the verum group is >0 OD than the average MΔ in the placebo group. This primary efficacy 
analysis will be conducted in the overall study population. 
 Null hypothesis: The  average maximal increment (MΔ) of anti-Aβ40 antibody signal 
(OD in ELISA) for the treated group is equal to that for placebo. 
 Alternative hypothesis: The  average maximal increment (MΔ) of anti-Aβ40 antibody 
signal (OD in ELISA) for the treated group is >0  OD than the average MΔ in the 
placebo group. 
The MΔ of anti-Aβ40 antibody signal between the two treatment groups will be compared 
using an Analysis of Covariance (ANCOVA) model, using the MΔ as the dependent variable, 
baseline anti-Aβ40 antibody signal (OD in ELISA) as covariate and the treatment group and 

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amyloid positivity as fixed effects. In addition, the number and percentage of patients in each 
visit reaching a value greater or equal than the MΔ will be tabulated by groups for each 
variable. 
Patients in the verum group will be classified as “Positive Responders” when: i) their MΔ of 
anti-Aβ40 antibody signal is equal or greater than 3 times the standard deviation of the titration 
ELISA and ii) more than the 50% of the signal in the visit reaching the MΔ is eliminated by 
pre-adsorption of the sample. The antibody titers, defined as the inverse of the maximal plasma 
sample dilution which showed an OD increase ≥ 3 SD with regard to the pre-immune sample 
(either V0 or V1), of “Positive Responder” will be reported. 
9.1.2.2 
Secondary Efficacy Analysis 
The trial will be considered satisfactory if the difference of the average maximal increment 
(MΔ) of anti-Aβ40 antibody signal (OD in ELISA) in the treated group is > 1.778 OD than the 
average MΔ in the placebo group; the difference that was reached between both groups in the 
phase I clinical trial of ABvac40. 
The secondary efficacy variables regarding assessment of disease biomarkers and cognition 
(see section 7.1) will be analyzed descriptively in the overall group and separately in the 
amyloid-PET negative (verum and placebo) and the amyloid-PET positive (verum and 
placebo) subjects pertaining to the ITT and PP populations 
For the exploratory comparison of the secondary efficacy variables for the characterization of 
the immune response (section 7.1.2) between the verum and placebo group, the maximal 
increment (MΔ) with regard to the pre-treatment visit (either V0 or V1) in each subject will be 
used as a summary measure for each of the following variables: i) the OD signal for plasma 
peptides and cytokines levels, or Aβ plasma levels as determined by LC-MS, ii) the relative 
number of cells subsets from peripheral blood mononuclear cells; and iii) the number of 
cytokine and antibody producing cells. Statistical comparison between groups of treatment will 
be done for the variable MΔ by means of ANCOVA models, using the MΔ as the dependent 
variable, baseline as covariate and the treatment group and amyloid positivity as fixed effects. 
In addition, the number and percentage of patients in each visit reaching a value greater or 
equal than the MΔ will be tabulated by groups for each variable. 
Mixed-model repeated-measures (MMRM) analyses will be performed for all the primary and 
secondary efficacy variables (section 7.1) to assess between-group differences in change scores 
from baseline (V0/V1) to Int-6m (V16), V21 and to the final visit (V25). The dependent 
variable in each MMRM analysis will be “change from baseline”. Fixed effects will include 
baseline scores on outcome measures, age at baseline, group assignment, amyloid positivity, 
study visit, and treatment-by-visit interaction. Additionally, covariates that are significantly 
associated with the response measure (p < 0.15) and are out of balance at baseline (p < 0.2) 
will be included as fixed effects. Variables considered as potential covariates in each model 
will be demographic variables, baseline characteristics, general treatment for AD and 
concomitant medication. 
9.1.3 
Safety Analysis (Part A) 
All the safety variables will be evaluated in the Safety population. 
 

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9.1.3.1 
 Primary Safety Analysis 
The primary safety variable is the frequency (%) of Adverse Events (AEs). The primary safety 
endpoint will be analyzed descriptively in the Safety population. For this primary safety 
analysis, the amyloid-PET negative and the amyloid-PET positive subjects within each 
treatment group will be pooled together.  
The trial will be considered satisfactory if the pattern of AEs (overall or grouped as 
neurological, psychiatric or cardiovascular) is consistent with a good safety and tolerability 
profile of ABvac40 for human administration. 
All AEs will be coded using the last version of the MedDRA dictionary where neurological 
AEs corresponds with the System Organ Class (SOC) Nervous system disorders, psychiatric 
AEs corresponds with the SOC Psychiatric disorders, and cardiovascular SOC corresponds 
with Vascular Disorders and Cardiac disorders. 
The number and percentage of patients in each treatment group reporting at least 1 occurrence 
of an AE for each unique SOC and PT will be tabulated. AEs will be also tabulated by severity 
and by the relationship to study medication in each treatment group as assessed by the 
investigator. Patients who experienced multiple adverse events with the same PT will be 
counted once for the summaries, using the worst severity. Specific tables will be provided for 
AEs of special interest such as neurological, psychiatric and cardiovascular AEs. 
As an exploratory analysis, the incidence of AEs (overall or grouped as neurological, 
psychiatric or cardiovascular) will be compared between the group receiving the active 
treatment (ABvac40) and the control group receiving placebo. Fisher's exact test will be used 
for these analyses. 
9.1.3.2 
Secondary Safety Analysis  
The safety and tolerability analysis will be based on the safety population, comprising all 
subjects who took at least one dose of study medication. 
Withdrawal criteria (discontinuation decision): 
Withdrawal criteria will be summarized using descriptive statistics. 
Number of withdrawn patients due to adverse events (AEs); reason for withdrawal: 
The number and percentage of patients (in each treatment group) prematurely discontinuing 
study treatment due to an AE will be tabulated by SOC and PT. Listings of patients with AEs 
leading to discontinuation and individual narrative summaries for these cases will be provided. 
Serious adverse events (SAEs) 
The number and percentage of patients in each treatment group reporting at least 1 occurrence 
of a SAE for each unique SOC and PT will be tabulated. SAEs will be also tabulated by the 
relationship to study medication in treatment groups as assessed by the investigator. Listings 
of patients with SAEs (and deaths) and individual narrative summaries for these cases will be 
provided. 
Physical and neurological examination 

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Physical findings (normal and abnormal) will be listed for each clinical trial subject. Any 
clinically significant abnormality developed by individual during the clinical trial and not 
already present at baseline will be reported as an AE. 
Physical and neurological examination data will be summarized in tables. 
Concomitant medication 
Concomitant medication and concomitant therapy will be summarized as number of patients 
being treated with each type of medication/therapy classified according to ATC level 3 and 
World Health Organization (WHO) Drug Dictionary preferred term.  
Vital signs and anthropometric data 
Vital signs (blood pressure, heart rate, respiratory rate and body temperature) and 
anthropometric data (body mass index, weight and height) will be summarized together with 
changes from baseline. 
Brain MRI 
Brain MRI findings will be listed for each clinical trial subject and summarized in tables. 
ECG 
Overall interpretation of ECG results (i.e. normal or abnormal and clinical significance) as well 
as ECG findings will be summarized in tables.  
Laboratory safety assessments 
For laboratory data, summary statistics will be produced for observed values and for changes 
from baseline to each visit. In addition, the number of abnormal and clinically significant 
observations will be tabulated for each treatment group by visit. Abnormal values will be 
flagged in listings.  
Shift tables will show the number of patients who changed from below, within or above the 
reference range at baseline to below, within or above the reference range at each time of 
assessment.  
For laboratory values which are below the limit of quantification, the value corresponding to 
the limit of quantification will be used when summarizing data (e.g. if the result is <x.xx then 
the value x.xx will be used in the statistical analysis). “Overflow” readings in OD signal will 
be replaced by the maximal signal measurable by the Microplate reader. 
 
9.1.4 
Efficacy and Safety Analysis (Part B) 
The analyses for Part B will mirror the analyses of Part A, without testing any hypothesis. The 
detailed statistical analyses will be described in the Statistical Analysis Plan. 
 
9.1.5 
Interim Analysis (Int)  
During the study, two Int will be performed to assess safety, tolerability and biological activity 
of the treatment (including data from the collected disease biomarkers at each of them). These 
analyses will be reviewed by an independent DSMB. The first Int will be carried out once the 

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first 30 patients have completed the 24-week visit (Int-6m) and the second one once all patients 
have completed the 24-week visit (Int-6m, eight weeks after the fifth monthly immunization), 
or in October 2020, whichever occurs first.  The double blinding of the study will be maintained 
throughout these two Int. Additional DSMB reviews may be made ad hoc in the event of safety 
issues. 
The DSMB statistical analysis plan (SAP) will provide the technical details of the Int. 
. To assure blinding, all Int will be performed by an IS, who is not involved in any other tasks 
in this study. 
 
9.1.5.1 
Data Safety Monitoring Board (DSMB) 
In order to assess safety and critical efficacy endpoints during the conduct of the trial, an 
independent DSMB has been appointed. The DSMB is an independent group consisting of 
three physicians who are not investigators in the study or other IMP development studies who 
have collective experience in the conduct and safety monitoring of clinical studies as well as 
monitoring and evaluation of clinical study safety data in randomized clinical studies in early 
phase. In addition, an IS will be also part of the DSMB.  
The membership of the DSMB and the responsibilities of the DSMB are defined in the DSMB 
Charter. The Charter, signed by all DSMB members, includes detailed information about 
DSMB members’ responsibilities, timing and purpose of DSMB meetings and Safety/Efficacy 
endpoints reviews of DSMB meetings, with their final recommendations.  
The aims of the DSMB are to safeguard the interest of trial participants, assess the safety and 
efficacy of the interventions during the trial, and monitor the overall conduct of the clinical 
trial. Thus, the DSMB will provide recommendations and advice to the Sponsor. The Sponsor 
has overall executive responsibility over the Study. Any recommendation and/or decision will 
be taken in the best interest of the participants of this study, in order to safeguard their welfare 
and safety, and in accordance with CGP (ICH E6) and the latest version of the Declaration of 
Helsinki. 
Schedules meetings of the DSMB will be face-to-face or by teleconference. These meetings 
will be classified as organizational meeting (kick-off) or formal data evaluation meetings. 
At least two formal data evaluation meetings will be scheduled at: 
1. Once the first 30 patients have completed the 24-week visit (Visit 16) 
2. Once all patients have completed the 24-week visit (Visit 16), or in October 2020, 
whichever occurs first. 
All two formal data evaluation meetings will be closed sessions and will include the safety 
endpoints as well as the main efficacy endpoints. At the three meetings, the DSMB will review 
the blinded/unblinded safety and efficacy data. 
For the formal data evaluation meetings the IS will produce listings and summaries tables, 
including, but not limited to: 
 Recruitment figures and losses to follow-up (all meetings) 
 Demography and ApoE genotyping (all meetings) 
 Safety parameters (all meetings):  

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- Number of withdrawn patients, number of patients who discontinued from treatment and 
reasons for withdrawal and discontinuation, respectively 
- SAEs and AEs 
- Rate (%) AEs 
- Expected serious adverse drug reactions like Amyloid Related Imaging Abnormalities 
- Physical and neurological examination significant abnormal findings 
- Concomitant medication 
- Vital signs (blood pressure, heart rate, respiratory rate, body temperature) and body mass 
index (weight, height) values. 
- Safety Brain MRI 
- Key EKG parameters 
- Analytical haematology, toxicology (reactive protein), biochemistry, coagulation, 
serology and urine test strip results (all data regardless if they are abnormal). 
 Average maximal increment (MΔ) of anti-Aβ40 antibody signal (OD in ELISA) (all 
meetings) 
 Aβ40 & Aβ42 in plasma (all meetings) 
 RBANS total score (all meetings) 
 Results of futility analysis and sample size re-estimation (all meetings)  
After each formal data evaluation meetings, the DSMB will provide recommendations to the 
Sponsor mainly in the following areas:  
 Suspension of recruitment pending further safety review, if data received suggest significant 
adverse effect of the investigational medicinal product.  
 Stop the study due to efficacy concerns (futility)*:  
- If, given the data up to the meeting’s cut-off date, the futility analysis, based on the 
primary efficacy analysis (confirmatory) of superiority (meaning that the average 
maximal increment [MΔ] of specific anti-Aβ40 antibody signal [OD in ELISA] for the 
treated group is >0 OD to that of placebo group), yields a conditional power of less than 
20% the DSMB will recommend to stop the study. Details on the futility analysis will be 
given in the DSMB SAP. 
*A safety and efficacy reviews will be taken into account in order to make a recommendation 
 Increase the sample size based: 
- If pooled SD for the average maximal increment (MΔ) of anti-Aβ40 antibody signal (OD 
in ELISA) is higher than the estimated 1.6 (according to the results of the Phase I study), 
the DSMB will recommend to the sponsor to increase the sample size according to the 
observed pooled SD, to ensure at least 80% power to detect a treatment superiority with 
margin of 1.778 in average maximal increment (as considered in the secondary efficacy 
analysis [satisfactory])  
Despite the statistical stopping rules indicated above, these are not formal rules; the 
recommendation to stop rests on the wise judgment of the DSMB on the basis of the totality 
of evidence at their disposal, both within the trial and externally. However, the ultimate 
decision rests with the Sponsor. 

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Details of the formal data evaluation meetings are included in the DSMB SAP and DSMB 
Charter. 
 
9.2 
Determination of Sample Size 
This trial is intended as a confirmatory assay for the primary safety and primary efficacy 
variables. 
For the safety primary endpoint, the sample size may be calculated to ensure ≥95% probability 
of detecting an adverse event that occurs with a rate of at least 5% within the ABvac40 treated 
dose cohort. Under these assumptions, using the Hanley´s simple approximation [32], a 
minimum of 60 patients in the active dose arm will be needed (and 60 in the placebo group). 
This sample size (60 patients in the active group and 60 in the placebo group), considering 
~40% dropouts along the clinical trial, will imply that approximately 70 patients will complete 
the study. These 70 patients will have greater than 85% power to detect a treatment increment 
of 1.778 (the one found in ABvac40 Phase I trial) in maximum change from baseline in anti-
Aβ40 antibody signal (OD in ELISA without preadsorption) between the active group and 
placebo group, using a one-sided T test at a significance level of 0.025 (and considering 
standard deviations of 2.0 and 1.0 in the active and placebo groups, respectively). The study 
will not be powered to demonstrate efficacy in clinical or other biomarker outcomes. 
Thus, the screening will be continued until 120 individuals diagnosed with a-MCI or vm-AD 
with amnestic syndrome of the hippocampal type had been recruited into the trial and have 
received at least one dose of the Verum or placebo, as correspond. A minimum of 70 subjects 
are expected to complete the study per protocol (35 in each treatment group).  
 
9.3 
Level of Significance to Be Used 
The statistical tests will be performed with a 2.5% significance level for the primary efficacy 
(immunogenicity) variable and 5% for the and will be one-sided for the primary variable of 
biological activity and two-sided for the secondary biological activity/efficacy variables. In 
addition to the tests, 95% CI will be reported. 
 
9.4 
Criteria for Termination of the Study  
The Investigator or the Sponsor may terminate this study prematurely for any reasonable cause. 
The Independent Ethics Committee(s) (IECs) and Competent Authorities (CAs) should be 
informed promptly.  
Conditions that may warrant termination include, but are not limited to: 
 The discovery of an unexpected, significant, or unacceptable risk to the subjects 
enrolled in the study, or potential study subjects 
 A decision on the part of the Sponsor to suspend or discontinue development of the 
IMP 

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 If after analyzing the study data from Part A (up to month 18 – V23), no clinical 
differences have been observed between the Placebo and the Verum group according 
to the following stopping rules, the sponsor could prematurely finalize the study.  A 
least one of the following criteria must have been fulfilled:  
1. For PET negative population: If the lower bound of the 95% exact CI for 
the proportion of negative PET patients treated with vaccine is greater than 
the proportion in Placebo group after 12 months (V21).  
2. For PET positive population: If the lower bound of 95% exact CI for the 
proportion of Reduction of cerebral amyloid plaques of positive PET 
patients treated with vaccine is greater than the proportion in Placebo group 
after 12 month (V21). 
3. For PET positive population: If the lower bound of the 95% exact CI for 
the mean of decline in Clinical Dementia Rating-Sum of Boxes (CDR-SB) 
in the positive PET patients treated with vaccine is greater than the mean in 
Placebo group after 18 months (V23). 
If the CAs obtains information that raises doubts about the safety or scientific validity of the 
clinical study, the CAs can suspend or prohibit the study. Before the CAs reaches its decision 
it shall, except where there is imminent risk, ask the Sponsor and/or the Investigator for their 
opinion, to be delivered within one week (Directive 2001/20/EC, Article 12, Section 1).  
If the study is prematurely terminated or suspended for any reason, the Investigator/institution 
should promptly inform the study subjects and should assure appropriate therapy and follow-
up for the subjects. 
 
9.5 
Procedure for Accounting for Missing, Unused, and Spurious Data  (if 
applicable) 
In the ITT population, to perform the statistical analyses that uses the end point (the last time-
point of each variable), if a subject prematurely withdraws from the study, missing data with 
respect to each variable will be replaced by the mean value of the corresponding treatment 
group at the corresponding visit. 
 
9.6 
Reporting Deviation(s) from the Statistical Analysis Plan 
The detailed statistical analysis methodologies will be documented in the Statistical Analysis 
Plan.  If there are any deviations from the originally planned analyses in the Statistical Analysis 
Plan, they will be fully described and justified in the protocol amendment(s) and/or final 
Clinical Study Report. 
 
9.7 
Subject Population(s) for Analysis 
The Safety population consists of all subjects who received any amount of study drug. 

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The Intent-to-treat (ITT) population consists of all subjects randomized who received at least 
one dose of study medication for whom at least one post-baseline anti-Aβ40 antibody signal 
assessment is available. 
There will be two per-protocol (PP) populations: 
 Part A: consists of all subjects who have received all doses of study medication (on 
V1, V4, V7, V10, V13 and V18), have attended the safety visit after booster (V20) and 
have no major protocol deviations. 
 Part B: consist of all subjects who have received all doses of study medication (on 
V1B, V4B, V7B, V10B, V13B and V18B), have attended the safety visit after booster 
(V20B) and have no major protocol deviations. 
 

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10 DIRECT ACCESS TO SOURCE DATA/DOCUMENTS  
The data will be recorded and kept current in eCRFs (and corresponding source documents) 
by the study site personnel directly responsible for the information and reviewed for 
completeness by the monitor. Araclon-Grifols personnel or designee can review the records. 
In accordance with ICH GCP guidelines, the monitor must have direct access to the 
investigator’s source documentation in order to verify the data recorded in the eCRFs for 
consistency and to verify adherence to the protocol, and the completeness, consistency, and 
accuracy of data entered. “Source documentation” includes individual subject files, separate 
from the eCRFs, which should be maintained and include visit dates, laboratory results, 
concomitant treatment, vital signs, medical history, examinations, AEs, investigational product 
dispensing logs, and other notes as appropriate.  The investigator agrees to cooperate with the 
monitor to ensure that any problems noted during the course of these monitoring visits are 
resolved. 
The investigator agrees to allow an auditor appointed by the sponsor as well as representatives 
of the relevant authorities and the ethics committees to verify, through an audit at the study 
center, that the study is implemented and documented according to the study protocol, good 
clinical practice and applicable regulations. The auditor/inspector will have to examine all 
essential documents and verify from a random sample of data entered into the clinical report 
forms is correct according to the original data found in clinical records. Therefore, the 
researcher will provide direct access to the data/documents and locations where trial activities 
are carried out (e.g., Laboratories, rooms and hospital pharmacy). 
 
 
 

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11 QUALITY CONTROL AND QUALITY ASSURANCE 
Monitoring and auditing procedures defined/agreed by the sponsor will be followed, in order 
to comply with ICH GCP guidelines. Each center will be visited at regular intervals by a 
monitor to ensure compliance with the study protocol, ICH GCP and legal aspects. The on-site 
verification of the eCRF for completeness and clarity will include cross checking with source 
documents, and clarification of administrative matters. Query verification of data will be 
described in the Data Management Plan. 
Representatives of regulatory authorities or of Araclon-Grifols may conduct audits or 
inspections or audits of the investigator study site. If the investigator is notified of an audit or 
inspection by a regulatory authority, the investigator agrees to notify the Araclon-Grifols 
Representative (eg, CAM, PM, PL) immediately. The investigator agrees to provide to 
representatives of a Regulatory Agency or Araclon-Grifols access to records, facilities, and 
personnel for the effective conduct of an audit or inspection. 
11.1 Monitoring 
This study will be monitored regularly by a clinical monitor according to the GCP guidelines 
of the ICH and appropriate standard operating procedures (SOPs). 
Before the study begins, the monitor will review the protocol and eCRFs with the researcher 
and his team. 
It is the investigator’s responsibility to ensure that the study is carried out according to the 
agreed study protocol and that data sent to the sponsor in the eCRF and in all required reports 
are accurate, complete, legible and on time. Furthermore, it is the investigator’s responsibility 
to ensure that all relevant data such as the patient’s medical history, concomitant diseases and 
medication, date of inclusion in the study, dates of study visits, results of examinations and 
development if adverse events are documented correctly in the subject’s original files. 
The investigator will be responsible for making sure that all persons involved in the trial 
receive training regarding their duties. 
The investigator agrees to allow the monitor to personally verify the correct execution and 
documentation of the study during scheduled visits. The purpose of trial monitoring is to verify 
that: 
- 
The human rights and welfare are protected. 
- 
The data reported are accurate, complete, and verifiable from original documents. 
- 
The conduct of the trial is consistent with the up-to-date approved protocol and any 
possible amendments, with GCP and with applicable legal requirements. 
 
To this end, data entered in the eCRF will be compared with data from medical records, etc. In 
particular, the availability of signed and dated informed consent will be checked. No 
information from the medical records regarding the identity of the subjects in the study will 
leave the study center. 

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For the verification of the original data, as a minimum the following information from patient 
files will be included: 
- 
Date of patient written informed consent, selection number of, 
- 
Dates of patient visits, adverse events (mild and severe), 
- 
Confirmation of the diagnosis of the indication that is being treated (mild or moderate 
AD in this case), 
- 
IMP and administration regimen (e.g., Initiation of treatment, dose), concomitant 
medication, 
- 
Primary variables of biological activity, secondary variables of biological activity. 
Print outs of the analytic data, EKGs and MRI data are considered original data. 
The investigator and their team will cooperate with the clinical monitor, providing any missing 
information whenever possible. The investigator will be available to answer any questions that 
arise during monitoring of the study. 
 
11.2 
Audit and inspection 
The investigator agrees to allow an auditor appointed by the sponsor as well as representatives 
of the relevant authorities and the ethics committees to verify, through an audit at the study 
center, that the study is implemented and documented according to the study protocol, good 
clinical practice and applicable regulations. The auditor/inspector will have to examine all 
essential documents and verify from a random sample of data entered into the clinical report 
forms is correct according to the original data found in clinical records. Therefore, the 
researcher will provide direct access to the data/documents and locations where trial activities 
are carried out (e.g., Laboratories, rooms and hospital pharmacy). 
 
11.3 
Data Management 
11.3.1 
Data Documentation 
The clinical report forms are designed for recording assessments by different investigators and 
they provide accurate advice on definitions of terms. The sponsor or designee will explain in 
detail how to complete the eCRFs to people involved in data entry. 
The data recorded in the eCRFs during the study will be documented under a subject number 
and the subject will only be identifiable by their subject number. If, as an exception, it is 
necessary to identify a subject for legal or safety reasons, both the sponsor (including CRO 
staff) and the investigator are required to maintain the confidentiality of this information. 
As a general rule, all information in the eCRF should be traceable to the subject’s original 
documents on file. As a minimum the following information must be available as original data 
in the patient's medical record kept by the researcher: 
- 
Compliance of the patient to participate in this study (study identified by study number, 
product under investigation, randomization number), history 
- 
Records of diseases/treatments and concomitant medication, dates of visits, 
- 
Use of study medication, records of adverse events, 

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- 
Reasons for premature discontinuation, as appropriate, 
All data entered in the eCRF requires that an electronic or written record be defined as original 
data. 
eCRFs are to be filled in immediately after each examination. The investigator will give a 
reasonable explanation for any missing data. The investigator will sign completed eCRFs to 
confirm reliability and truthfulness of data. 
If the investigator authorizes other people to enter data into the eCRF, this delegation must be 
documented with the names, positions, signatures and initials of these people. 
11.3.2 
Data processing 
All data will be entered in the eCRF (and corresponding source documents) by investigator or 
designee according to pre-defined instructions in the Data Entry Manual. Data entry will be 
performed on an ongoing basis as subjects perform their visits.  
 Electronic Data Capture system (Trial Master) will be used in this study. The EDC 
system will maintain an audit trail that will document changes together with date and user in 
the database after the data entry has started. 
Laboratories and vendors data will be entered by study staff in the eCRF unless elsewhere 
specified, in which case electronic files will be uploaded into patients eCRF, as explained in 
the relevant manuals and detailed in the Data Transfer Specification.  
11.3.3 
Coding 
The following dictionaries should be used for coding: 
- Medical history: MedDRA 
- Adverse events: MedDRA 
- Concomitant medication: WHO-DD (ATC) 
 
11.3.4 
 Data cleaning 
During the initiation phase of the study, a Data Management Plan (DMP) will be developed 
which will describe in detail how data will be managed.  
Automatic checks defined in the Data Validation Plan (DVP) will be generated by the system. 
Manual queries will also be created, if needed. Investigator or designated site staff will be 
required to respond to the checks and queries and confirm or correct the data. Query 
Management will be detailed in the DMP.  
 
11.3.5 
Missing and false data 
All missing or false data will be investigated. If the investigator cannot provide a reasonable 
explanation, then the data shall be treated as unresolved queries. All data from the eCRF will 
be exported into SAS datasets and will be considered for analysis as specified in the statistical 
analysis plan. 
 

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11.3.6 
Closing the database 
After the study has been completed, the occurrence of any emergency decryption of the code 
and any violation of the protocol will be determined. Once these actions are completed and the 
database is declared complete and accurate, it will be closed. Any subsequent changes to the 
database can only be done through a joint agreement in writing between the Sponsor and 
. 
 
 
 

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12 ETHICS 
12.1 Institutional Review Board/Ethics Committee   
Documented approval from appropriate IRBs/ECs will be obtained for all participating 
centers/countries prior to study start, according to ICH GCP guidelines, local laws, regulations 
and organizations. When necessary, an extension, amendment or renewal of the IRBs/ECs 
approval must be obtained and also forwarded to the sponsor.  The IRBs/ECs must supply to 
the sponsor, upon request, a list of the IRBs/ECs members involved in the vote and a statement 
to confirm that the IRBs/ECs is organized and operates according to ICH GCP guidelines and 
applicable laws and regulations. 
12.2 Ethical Conduct of the Study 
The procedures set out in this protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the sponsor and investigator abide by 
ICH GCP guidelines.  The study will also be carried out in keeping with applicable local law(s) 
and regulation(s).  This may include an audit by the sponsor representatives and/or an 
inspection by Regulatory Authority representatives at any time.  The investigator must agree 
to the audit or inspection of study-related records by the sponsor representatives and/or 
Regulatory Authority representatives, and must allow direct access to source documents to the 
sponsor and/or Regulatory Authority representatives.   
Modifications to the study protocol will not be implemented by either the sponsor or the 
investigator without agreement by both parties. However, the investigator may implement a 
deviation from, or a change to, the protocol to eliminate an immediate hazard(s) to the study 
subjects without prior IRB/EC/Sponsor approval/favorable opinion. As soon as possible, the 
implemented deviation or change, the reasons for it and if appropriate the proposed protocol 
amendment should be submitted to the IRB/EC/Sponsor. Any deviations from the protocol 
must be fully explained and documented by the investigator. 
No medical waivers for protocol inclusion/exclusion criteria will be allowed by the sponsor, 
and that in case the need for a change to the protocol is identified, it will be submitted as a 
protocol amendment to the competent regulatory authority and/or ethics committee as 
applicable per regulations. 
Direct advertising will be used in this study in order to solicit subject participation. Direct 
advertising includes, but is not necessarily limited to: newspaper, radio, TV, bulletin boards, 
posters that are intended for candidate subjects. Any advertisement will be submitted for 
review and approval to the IRB/EC charged with this responsibility to ensure that the 
information contained in the advertisement is not misleading and that the procedure for 
recruiting subjects gives adequate protection for the rights and welfare of the subjects. 
12.3 Regulatory Authority Approvals/Authorizations 
Regulatory Authority approvals/authorizations/ notifications, where required, must be in place 
and fully documented prior to study start. Study information including contact information for 

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investigator sites responsible for conducting the study will be posted on a publicly accessible 
clinical registry (ies) as required by local law. 
12.4 Subject Information and Consent 
Subject information and ICF will be provided to investigator sites. Prior to the beginning of 
the study, the investigator must have the IRB/EC written approval/favorable opinion of the 
written ICF and any other written information to be provided to subjects.  The written approval 
of the IRB/EC together with the approved subject information/ICF must be filed in the study 
files and a copy of the documents must also be provided to Sponsor by the investigator site.  
Written ICF must be obtained from the patient (or legal representative, if applicable) and from 
a close relative/caregiver before any study specific procedure takes place.  Participation in the 
study and date of ICF given by the subject and by the close relative/caregiver should be 
documented appropriately in the subject’s files. A signed copy of the subject and close 
relative/caregiver ICFs will be provided to the subject (or subject’s authorized representative) 
and to the close relative/caregiver, respectively. 
12.5 Confidentiality 
All records identifying the subject will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available. 
Subject names will not be supplied to the sponsor. Only the subject code number and subject 
initials will be recorded in the eCRF, and if the subject’s name appears on any other document 
(i.e., pathologist report), it must be removed before a copy of the document is supplied to the 
sponsor.  Study findings stored on a computer will be stored in accordance with local data 
protection laws.  Subjects will be informed in writing that representatives of the sponsor, 
IRB/EC, or Regulatory Authorities may inspect their medical records and personal health 
information to verify the information collected, and that all personal information made 
available for an audit or inspection will be handled in strictest confidence and in accordance 
with local data protection laws and with the European General Data Protection Regulation 
(2016/679) (GDPR). 
If the results of the study are published, the subject’s identity will remain confidential.  
The investigator will maintain a list to enable subjects’ records to be identified. 
12.6 Patient health insurance 
During their participation in the study, each subject will be covered by an insurance policy in 
accordance with the Spanish Medicines Act, which covers any possible risks arising from their 
participation in the study. 
Patients will be informed of the existence of the contract and the obligations that come with it:  
 The insured person can only receive other medical treatment during the clinical trial, if 
the clinical investigator consents to such treatment. Emergency treatment is exempt 
from this rule. 

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 The insurer must be informed immediately of any health deterioration that may result 
from the clinical trial. In case of damages, the subject’s signed informed consent form 
will be presented.  
If it is necessary to make an insurance claim, the medical investigator will notify the monitor 
and sponsor immediately so they can submit the claim to the insurance company. 
 
12.7 
Compensation for the subject 
By participating in this clinical trial, no additional costs will be incurred. A taxi services and a 
meal voucher will be available for all participants and caregiver throughout the study. In 
addition, travel by private car, public transport or taxi will be reimbursed. For private car travel, 
the amount of fuel used shall be reimbursed; for public transport or taxi, the refund can only 
be made on presentation of the original receipt. Any additional costs related to participation in 
this study may be refunded upon presentation of the original receipt. For this, patients should 
contact the staff responsible for the study during visits.  
 
 
 
 

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13 DATA HANDLING AND RECORD KEEPING 
13.1 Data Handling 
The study data will be recorded and kept current in the eCRF by the site study personnel 
directly responsible for the information. Entries made in the eCRF must be verifiable against 
source documents. The data in the eCRF will be monitored at the site by Araclon-Grifols 
representatives at regular intervals and reviewed for completeness and compared with the 
source documents. Examples of acceptable source documents include individual subject 
medical records, prospective information gathered on source documentation worksheets, lab 
reports and other diagnostics pertinent to this study which are separate from the eCRFs.  The 
listing of types of source documents which will be defined in the source data agreement will 
be filed in TMF. 
All adverse events (AEs) and serious adverse events (SAEs) must be recorded. All SAEs must 
be recorded on the SAE form. The SAE form must be kept in site records with a copy provided 
to the designated person as detailed in the study file.   
13.2 Record Retention 
At study completion, all study data will be transferred to Araclon-Grifols according to ICH 
GCP guidelines, local laws, regulations, and Araclon-Grifols requirements.  The study file and 
all source data should be retained until notification is given by the sponsor for destruction. 
An investigator is required by ICH GCP guidelines to retain the study files.  If an investigator 
moves, withdraws from an investigation or retires, the responsibility for maintaining the 
records may be transferred to another person (i.e., other investigator). Araclon-Grifols must be 
notified in writing of the person responsible for record retention and the notification will be 
retained in the sponsor study file and the investigator site file. 
 
 
 

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14 FINANCING AND INSURANCE 
In the event of subject injury as a direct result of either administration of investigational 
product or any non-standard of care study procedure, Sponsor will pay for the costs of 
treatment, provided the subject has followed the instructions given by the study doctor and the 
illness or injury is not due to the natural progression of any conditions existing before the 
subject participated in the study.  Financial compensation for such things as lost wages, 
disability, or discomfort due to any research-related injury is not available. 
Sponsor shall maintain comprehensive general liability insurance or self-insurance in amounts 
adequate to cover any damage, demand, claim, loss or liability caused or incurred by Sponsor, 
or as otherwise required by applicable laws and/or regulations. 
 
 
 

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15 PUBLICATION POLICY 
Institution and the Investigator agree that the first publication shall be made in conjunction 
with the presentation of a joint, multi-center publication of the study results from all 
appropriates sites.  If such a multi-center publication is not submitted within twelve (12) 
months after conclusion of the study at all sites or after Araclon-Grifols confirms there will be 
no joint, multi-center publication, then institution and/or Investigator shall have the right, at 
their discretion, to publish, either in writing or orally, the results of the study performed under 
the protocol, subject to the conditions outlined below: 
• The results of the study will be reported in the publicly accessible registry(ies). 
• Institution and/or Investigator shall furnish Araclon-Grifols with a copy of any proposed 
publication at least thirty (30) days in advance of the date of submission for publication.   
• Within said thirty (30) day period, Araclon-Grifols shall:   
- 
Review such proposed publication for Confidential Information (other than Study 
results) and for subject information subject to the Health Insurance Portability and 
Accountability Act of 1996 (“HIPAA”) and other applicable privacy laws; 
- 
Review such proposed publication for the unauthorized use of the name, symbols 
and/or trademarks of Araclon; 
- 
By written notice to the Investigator, identify with specificity the text or graphics in 
such proposed publication that Araclon-Grifols contends contains Confidential 
Information, protected subject information, or the unauthorized use of Araclon or 
Grifols’ name, symbols and/or trademarks so that the proposed publication may be 
edited appropriately to remove such text or graphics before publication; and  
- 
By written request, Araclon-Grifols may delay proposed publications up to sixty (60) 
days to allow Araclon-Grifols to protect its interests in Araclon-Grifols Inventions 
described in such publications.   
• Institution and/or Investigator shall give Araclon-Grifols the option of receiving an 
acknowledgment for its sponsorship of the study in all such publications or presentation. 
  
 
 
 

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17 APPENDICES

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Appendix 1 
Definition of adverse reactions 
Local reactions: 
They are those that occur in the injection area. The appearance of erythema, pruritus and 
hyperemia in that area is considered as an effect that may be associated with the administration 
thereof but it’s not considered as an adverse reaction. We will consider such case when an 
induration (wheal) occurs at the site of inoculation of the extract and it has a diameter which 
is referred below. Regarding to the moment of occurrence of local adverse reaction, we 
differentiate between: 
• Immediate: local adverse reaction that occurs within 30 minutes after extract administration. 
It is considered that it happens when the largest diameter of the wheal is larger than 5 cm in 
adult subjects and 3 cm in pediatric subjects. 
• Delayed: local adverse reaction that begins 30 minutes after extract administration. It is 
considered that it happens when the largest diameter of the wheal exceeds 10cm in adult 
subjects and 7cm in pediatric subjects. 
Systemic reactions: 
They are those that occur away from the injection site. As in the case of local reactions, we 
differentiate between immediate or delayed response considering the occurrence within or after 
the first 30 minutes following extract administration, respectively. The severity of systemic 
adverse reaction is usually associated with the speed of beginning of the first symptoms of it. 
Currently, systemic adverse reactions are ranked in five grades (1-5), depending on their 
severity, where grade 1 is the least severe and grade 5 is the most sever. Classification in these 
grades is based on the affected organ and the intensity of the registered clinical manifestations: 
• Grade 1: exclusive implication of one of the following systems/organs: skin, conjunctiva, 
upper respiratory tract, or other (non-specific). 
• Grade 2/3: Involvement of more than one of the systems/organs described above or 
presence of asthma, gastrointestinal involvement or lower respiratory tract (grade 2 with 
reduced FEV1 baseline of 40% with good response to rescue bronchodilators; grade 3 with a 
reduction less than 40% without adequate response to the rescue bronchodilators). 
• Grade 4: respiratory failure and/or cardiovascular with hypotension (no need to be 
associated with loss of consciousness). 
• Grade 5: death of the subject.