A Phase Ib Multi-Center, Double-Blind, Randomized, Placebo-Controlled Dose Escalation Study of the Safety, Tolerability and Immunogenicity of ACI-24 in Adults With Down Syndrome
Phase: PHASE1
Conditions: Down Syndrome
Sponsor: AC Immune SA

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CONFIDENTIAL 
ACI-24-1301_Protocol Synopsis_v5.0_Final_20200128 
 
This information is strictly confidential. Clinical personnel solely in connection with a clinical investigation shall 
only use information contained herein. Information contained herein cannot be disclosed, submitted for publication 
or used for any purpose without the Sponsor's prior written authorization. Such information is the property of AC 
Immune and should not be photocopied or distributed to other persons without the Sponsor's prior written 
authorization. Additional copies are to be requested from AC Immune. 
 
 
CLINICAL STUDY PROTOCOL 
Including Amendment 4 
 
 
A Phase Ib Multi-Center, Double-Blind, Randomized, 
Placebo-Controlled Dose Escalation Study of the 
Safety, Tolerability and Immunogenicity of ACI-24 in 
Adults with Down syndrome 
 
 
 
Study Number ACI-24-1301 
 
 
 
IND Number 15342  
 
 
 
 
CONFIDENTIAL 
V5.0 (Final) – 28Jan2020 

  Study Synopsis                                                                                                                                  Page 2 of 8 
 
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  Study Synopsis                                                                                                                                  Page 3 of 8 
 
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1 
STUDY SYNOPSIS 
Study number 
ACI-24-1301 
IND number 
15342 
Study Title 
A Phase Ib multi-center, double-blind, randomized, placebo-controlled dose 
escalation study of the safety, tolerability and immunogenicity of ACI-24 in 
adults with Down syndrome 
Coordinating 
Principal 
Investigators  
Coordinating Center Principal Investigator 
Howard Feldman, MD 
Alzheimer’s Disease Cooperative Study  
University of California, San Diego  
9500 Gilman Drive, MC 0949 
La Jolla, CA 92093-0949 
United States 
 
Overall Coordinating Principal Investigator 
Michael S. Rafii, MD, PhD 
Alzheimer’s Therapeutic Research Institute 
USC Keck School of Medicine of the University of Southern California 
9860 Mesa Rim Road 
San Diego, CA 92121 
United States 
Status, Version 
and Date of 
Protocol 
Final Protocol, version 5.0 dated 28 Jan 2020 
Study Planned 
Dates  
FPFV: Q1 2016 
LPLV: Q2 2020 (Q1 2021 in case of expansion of the optimal dose cohort) 
Number of sites 
Approximately 6 sites in United States 
Name of the 
Finished Product 
ACI-24 
Name 
of 
the 
Active Ingredient 
Palmitoylated peptides from the 1-15 sequence β-amyloid peptide  
(Pal 1-15) 
 
Objectives 
Primary Objectives 
To assess the safety and tolerability of ACI-24 in adults with Down syndrome 
To assess the effect of different doses of ACI-24 on induction of anti-Aβ Ig 
titer in serum 
Secondary Objectives 
To explore the efficacy of ACI-24 on Clinical Global Impression of Change 
(CGIC) in adults with Down syndrome  
To explore the effect of ACI-24 on cognitive and behavioral endpoints in adults 
with Down syndrome  

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To explore the effect of ACI-24 on whole brain, ventricle and hippocampal 
volume 
To explore the effect of ACI-24 on peripheral T cell activation 
To explore the effect of ACI-24 on putative biomarkers of Alzheimer 
pathology in Down syndrome including Aβ levels, total tau, phosphorylated 
tau protein (phospho-tau), NfL, Neurogranin, sAPPα, sAPPß, Orexin-A, 
inflammatory cytokines, angiogenic proteins and vascular injury markers in 
plasma and/or in CSF* (*in subgroup) as applicable 
To assess the effect of different doses of ACI-24 on induction of anti-Aβ Ig 
titer in CSF* (*in subgroup) 
Study Endpoints 
Primary Endpoints 
Safety and tolerability: Adverse events; global assessment of tolerability; 
physical and neurological examination; vital signs; suicidal ideation/behavior; 
MRI imaging; electrocardiogram; routine hematology and biochemistry 
evaluation in blood and urine; inflammatory markers in blood and CSF 
Biological Effect: Antibody titers (serum anti-Aβ Ig) 
 
Secondary Endpoints 
Efficacy: Change from baseline in clinical global impression of change; 
Cognitive function [change from baseline in CANTAB motor control, reaction 
time, paired associative learning; Brief Praxis Test] and behavior (change from 
baseline in Vineland Adaptive behavior scale; Neuropsychiatric Inventory) 
Biological Effects: T-cell activation; Biomarkers including Aβ levels, total tau, 
phospho-tau, NfL, Neurogranin, sAPPα, sAPPß, Orexin-A, inflammatory 
cytokines, angiogenic proteins and vascular injury markers in plasma and/or in 
CSF as applicable; Antibody titer (CSF anti-Aβ Ig);  
Brain Imaging Effect: Whole brain, ventricle and hippocampal volume 
assessed by MRI 
Design 
This is a prospective placebo controlled, double-blind and randomized dose 
escalation study of 2 doses of ACI-24 treatment versus placebo over 24 months 
(12 months treatment phase and 12 months safety follow up period). 
Treatment 
2 dose-cohorts of 8 subjects each (6 subjects on ACI-24 300 µg, 6 subjects on 
ACI-24 1,000 µg and 2 subjects on placebo in each dose-cohort) will be treated 
with subcutaneous (s.c.) injections at month 0,1,2,3,6,9 and 12 with 12 months 
follow-up.  
The dose-cohorts will be studied sequentially in ascending dose order. Safety 
and tolerability will be reviewed prior to dose escalation. The 2nd dose-cohort 
is expected to start once safety and tolerability data up through Visit 8 [week 
14] of the last subject of the preceding cohort have been reviewed by the 
DSMB.  
The number of participants in the optimal dose cohort may optionally be 
expanded by an additional 8 subjects,  leading to a total of 16 subjects in that 

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cohort (i.e. 12 subjects on active, 4 subjects on placebo), in order to collect 
further safety and tolerability data at the corresponding dose.  
The decision to expand either cohort 1 or cohort 2 will be based on safety, 
tolerability and immunogenicity or target engagement data after Visit 8 [week 
14] of the last subject of cohort 2 - following review of safety and tolerability 
data by a DSMB. If, based on the interim analysis results at week 14, it is felt 
more appropriate to collect additional long-term data before deciding whether 
to expand one of the two cohorts, the decision may be postponed until the time 
of the interim analysis of data from cohort 2 which is planned at Visit 12 (week 
28).  
Follow-up 
All subjects will be followed up for 12 months after their last dose with a final 
safety and efficacy assessment.  
Number of 
subjects 
Two dose-cohorts of 8 subjects each (6 active, 2 placebo). Total of 16 
randomized subjects and an optional expansion of the number of participants 
in the optimal dose cohort by an additional 8 subjects, totaling 24 randomized 
subjects (if applicable).  
Subject 
Population 
Adults with Down syndrome 25-45 years of age (male and female). 
Inclusion/ 
Exclusion Criteria 
Inclusion criteria 
1. Males or females with Down syndrome aged ≥25 to ≤45 years, with a 
cytogenetic diagnosis being either Trisomy 21 or Complete 
Unbalanced Translocation of the Chromosome 21. 
2. Subjects and their study partner/legal representative in the opinion of 
the investigator able to understand and to provide written informed 
consent. 
3. Written informed consent obtained from subjects and their study 
partner/legal representative before any trial-related activities. 
4. In the opinion of the investigator able to fully participate in the trial 
and sufficiently proficient in English to be capable of reliably 
completing study assessments. 
5. Subjects have a study partner/legal representative who have direct 
contact with the subjects at least 10 hours per week and who can be 
asked questions about the subjects. 
Exclusion criteria 
1. Subjects weighing less than 40 kg. 
2. IQ less than 40 (as assessed by Kaufman Brief Intelligence Test, 
Second Edition (KBIT-2). 
3. In the investigators opinion, any clinically significant current 
psychiatric or neurologic illness, including a past illness with a risk of 
recurrence, other than Down syndrome. 
4. Any medical condition likely to significantly hamper the evaluation 
of safety of the study drug. 
5. DSM-IV criteria for drug or alcohol abuse or dependence currently 
met within the past five years. 

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6. History or presence of uncontrolled seizures. If history of seizures, 
they must be well controlled with no occurrence of seizures in the 
past 2 years prior to study screening.  The use of anti-epileptic 
medications is permitted. 
7. History of meningitis or meningoencephalitis. 
8. History of malignant neoplasms within 3 years prior to study 
screening or where there is current evidence of recurrent or metastatic 
disease. 
9. History of persistent cognitive deficits immediately following head 
trauma. 
10. History of inflammatory neurology disorders. 
11. History of autoimmune disease with potential for CNS involvement. 
12. MRI scan at screening showing a single area of cerebral vasogenic 
edema, superficial siderosis, or evidence of a prior macro-
hemorrhage, or showing more than four cerebral microhemorrhages 
(regardless of their anatomical location or diagnostic characterization 
as “possible” or “definite”). 
13. MRI examination cannot be done for any reason, including metal 
implants contraindicated for MRI studies and/or severe 
claustrophobia. 
14. Significant hearing or visual impairment or other issues judged 
relevant by the investigator preventing to comply with the protocol 
and to perform the outcome measures. 
15. Severe infections or a major surgical operation within 3 months prior 
to screening. 
16. History of chronic or recurrent infections judged to be clinically 
significant by the investigator. 
17. History or presence of immunological or inflammatory conditions 
which are judged to be clinically significant by the investigator. 
18. Celiac disease not on a gluten free diet for at least 3 months prior to 
study screening. 
19. Chronic benign skin pathologies, unless viewed as clinically 
insignificant in the investigator’s opinion. 
20. Any vaccine received within the past 2 months before baseline, 
except influenza vaccine which if indicated must be given at least 2 
weeks prior to baseline. 
21. Clinically significant arrhythmias or other abnormalities on ECG at 
screening. (Minor abnormalities documented as clinically 
insignificant by the investigator will be allowed.) 
22. Clinically significant abnormal vital signs including sustained sitting 
blood pressure greater than 160/90 mmHg.     
23. In the opinion of the site investigator, deviations from normal values 
for hematologic parameters, liver function tests, and other 
biochemical measures, that are judged to be clinically significant. 
24. Subjects with treated hypothyroidism not on a stable dose of 
medication for at least 3 months prior to screening and having 
clinically significant abnormal serum T-4 and TSH at screening. 
25. Subjects with diabetes mellitus with an HbA1c of ≥ 8.0%. 
26. Subjects who have been receiving any experimental drug for Down 
syndrome with a washout less than 30 days or less than five half-lives 
of the drug, whichever is longer. 
27. Female subjects being pregnant as confirmed by serum testing at 
screening or planning to be pregnant or lactating. 

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28. Female subjects not using a reliable method of contraception (unless 
abstaining). 
29. Patient receiving any anticoagulant drug, or aspirin at doses greater 
than 100 mg daily in the 7 days prior to lumbar puncture (in order to 
avoid risk of bleeding during scheduled or unscheduled lumbar 
puncture)   
30. Use of antidepressants other than SSRI/SNRIs at stable dose, 
antipsychotics (typical or atypical), GABA agonists (e.g. gabapentin), 
or stimulants (e.g. methylphenidate, modafinil). In exceptional cases, 
low doses of atypical antipsychotics (e.g. risperidone up to 0.5 
mg/day or quetiapine up to 50 mg/day) or benzodiazepines are only 
allowed after review by the site principal investigator, in consultation 
with the project director and/or medical monitors. 
31. Current use of immunosuppressant or immunomodulating drugs or 
their use within the past 6 months prior to study screening. Current 
use of steroids or their use within the past 3 months prior to study 
screening. 
32. Use of Cholinesterase Inhibitor or use of Glutamatergic drugs 
(Topiramate, Memantine, Lamotrigine) if not on stable dose for at 
least 3 months prior to screening.  
33. Subjects who have donated blood or blood products during the 30 
days prior to screening who plan to donate blood while participating 
in the study or within four weeks after completion of the study. 
Study drug 
ACI-24 or placebo to be administered subcutaneously  
Dosage, duration 
of treatment 
Dose-cohort 1: 300 µg antigen or placebo, dose-cohort 2: 1,000 µg antigen or 
placebo. 
In both cohorts, ACI-24 will be administered 7 times: 4 times with 1 month 
interval, and then 3 times with 3 months interval. The treatment period will last 
12 months with the final double-blind evaluation after 24 months (see study 
plan).  
 
 
 
 
 

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2 
STUDY PLAN – INVESTIGATIONAL EVENTS 
Study Plan 
Treatment Period 
Follow-up Period 
  
  
Visit Number 
Vs 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16 
V17 
V18 
V19 
Phone  
call 
V20 
Phone  
call 
V21 
Time (weeks ± days) 
-4w 
0 
w2 
w4 
w6 
w8 
w10 
w12 
w14 
w16 
w24 
w26 
w28 
w36 
w38 
w40 
w48 
w50 
w52 
w60 
w66 
w72 
w84 
w96 
  
+3d 
±3d 
±3d 
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±10d 
±10d 
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±10d 
±10d 
Treatment (Immunization) 
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Subject Information / Consent 
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Medical History, Concomitant 
Illnesses,  
Demographic Data 
 
Inclusion / Exclusion Criteria  
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(incl. KBIT-2 at Vs only) 
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Withdrawal Criteria 
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Adverse Events 
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Vital signs 
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Global Assessment of 
Tolerability 
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Physical and neurological 
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CANTAB and BPT 
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Vineland and NPI 
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CGIC (≠ baseline interview) 
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Suicidal ideation / behavior 
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Lumbar Puncture (CSF) (in 
subgroup) 
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MRI 
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ECG 
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Blood 
- Hematology & biochemistry 
(incl. CRP & ESR) 
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- PT (INR)/PTT (only subgroup) 
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- Anti Aβ Ig 
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- Biomarkers 
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- T cell profile 
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- TLR4 expression** 
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- ApoE genotyping 
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- Screening tests (see Section 
11.1) 
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Urine 
- Routine evaluation 
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- Pregnancy test 
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* Any results obtained during Screening Visit will be reviewed at Visit 1 [week 0] to ensure that the subject still fulfills Inclusion / Exclusion Criteria. ** TLR4 blood samplings have been collected on site as per the previous versions of the 
protocol (v1.0 to v4.0) however the TLR4 laboratory testing will not be performed according to clinical study protocol v5.0.