Conditions: Alzheimer Disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 643
Healthy volunteers: no

Brief summary:
This is a randomized, double-blind, placebo-controlled study that assessed the efficacy, safety, and tolerability of 2 dose levels of COR388 in subjects with a clinical diagnosis of mild to moderate Alzheimer's disease (AD) dementia.

Detailed description:
This was a randomized, double-blind, placebo-controlled study that assessed the efficacy, safety, and tolerability of 2 dose levels of COR388 oral capsules in subjects with probable Alzheimer's disease (AD) dementia according to the National Institute on Aging-Alzheimer's Association (NIA-AA) criteria. The subject did not have other conditions or brain imaging abnormalities that could explain the symptoms of dementia. All subjects were encouraged to have lumbar punctures (LPs) (during screening, week 24 and week 48) in the absence of medical conditions that could increase the risk of the procedure in the opinion of the Investigator. Cerebrospinal fluid (CSF), saliva, and blood were analyzed for measurements of biomarkers of AD and neuroinflammation, and for the presence of bacterial deoxyribonucleic acid (DNA) of Porphyromonas gingivalis (P. gingivalis). A subset of sites monitored subjects for clinical evidence of periodontitis at baseline, 24 and 48 weeks.

The study consisted of 3 phases: a screening phase of up to 6 weeks, a treatment phase of up to 48 weeks, and a safety follow-up phase of 6 weeks.

Arms:
arm 1: COR388 hydrochloric acid (HCl), 80 mg orally administered capsule, BID (twice daily) with water approximately 12 hours apart and no less than 6 hours apart arm 2: COR388 HCl, 40 mg orally administered capsule, BID with water approximately 12 hours apart and no less than 6 hours apart arm 3: Placebo orally administered capsule, BID with water approximately 12 hours apart and no less than 6 hours apart

Interventions: intervention 1: COR388 capsule intervention 2: Placebo capsule
Intervention descriptions: intervention 1: BID (twice daily) intervention 2: BID

Protocol document:
Prot_000.pdf: 
Clinical Study Protocol 
A Randomized, Double-Blind, 
Placebo-Controlled Study of COR388 HCl in 
Subjects with Alzheimer’s Disease 
Protocol Number: COR388-010 
EudraCT Number: 2019-000370-27   
 
 
 
 
NCT03823404 
 
 
Date 17 May 2021  
 


Protocol COR388-010  Version 7.0 
Page 1 
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Cortexyme, Inc.  
Confidential Information 
CORTEXYME, INC. 
Clinical Study Protocol 
A Randomized, Double-Blind, 
Placebo-Controlled Study of COR388 HCl in 
Subjects with Alzheimer’s Disease 
Protocol Number: COR388-010 
EudraCT Number: 2019-000370-27   
Original Protocol Date (Version): 18 January 2019 (Version 1.0) 
Amended Protocol Date (Version): 11 April 2019 (Version 2.0) 
Amended Protocol Date (Version): 25 June 2019 (Version 3.0) 
Amended Protocol Date (Version): 19 December 2019 (Version 4.0) 
Amended Protocol Date (Version): 3 August 2020 (Version 5.0) 
Amended Protocol Date (Version): 15 December 2020 (Version 6.0) 
Amended Protocol Date (Version): 17 May 2021 (Version 7.0) 
Cortexyme, Inc. 
269 East Grand Ave. 
South San Francisco, CA 94080  
CONFIDENTIAL 
This document contains confidential information. Any use, distribution, or disclosure without the prior written 
consent of Cortexyme, Inc., is strictly prohibited except to the extent required under applicable laws or 
regulations. Persons to whom the information is disclosed must be informed that the information is confidential 
and may not be further disclosed by them.


Protocol COR388-010  Version 7.0 
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Contact Information 
Sponsor Michael J. Detke, MD, PhD 
Cortexyme, Inc. 
269 East Grand Ave. 
South San Francisco, CA 94080 
mdetke@cortexyme.com 
+1 (317) 902-2002 
  
Medical Monitor Stephen Kirzinger, MD 
Sr. Medical Director 
Worldwide Clinical Trials 
1106 Colonel Anderson Parkway 
Louisville, KY 40222 
Phone: +1 (502) 419-4732  
Email: stephen.kirzinger@worldwide.com 
 
 
 


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Investigator’s Agreement 
 
I have read Protocol COR388-010 and agree to conduct the study according 
to its terms. I understand that all information supplied to me by 
Cortexyme, Inc., is confidential.   
 
 
 
                      
Principal Investigator Signature                                       Date 
 
 
 
 
 
 
 
 
 
 


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1 
PROTOCOL SYNOPSIS 
Title A Randomized, Double-Blind, Placebo-Controlled Study of COR388 HCl in 
Subjects with Alzheimer’s Disease 
Objectives 
The objectives of the study are to:  

Assess the efficacy of 2 dose levels of COR388 HCl in Alzheimer’s
disease (AD) subjects; and

Assess the safety and tolerability of 2 dose levels of COR388 HCl in
AD subjects.
Study Phase 
Phase 2/3 
Study Design 
This is a randomized, double-blind, placebo-controlled study that will 
assess the efficacy, safety, and tolerability of 2 dose levels of 
COR388 HCl in subjects with probable AD dementia according to the 
National Institute on Aging-Alzheimer’s Association (NIA-AA) criteria 
(McKhann 2011). The study will enroll approximately 573 generally healthy 
male and female subjects 55 and 80 years of age. Enrolled subjects 
must have a documented diagnosis of probable AD dementia with clinical 
evidence of progressive cognitive decline in the last year. Clinical decline 
will be defined as the evidence of progressive cognitive decline on 
sequential evaluations based on information from informants and/or 
cognitive testing in the context of either formal neuropsychological 
evaluation or standardized mental status examinations for probable AD 
dementia (McKhann 2011). The subject should not have other conditions 
or brain imaging abnormalities that can explain the symptoms of dementia. 
All subjects will have lumbar punctures (LPs) performed at baseline 
(Visit 2) and at end of treatment Week 48 (Visit 10) or early termination 
visit (ET). Cerebrospinal fluid (CSF) will be tested for measurement of 
bacterial DNA (Pg) using quantitative polymerase chain reaction (qPCR), 
biomarkers of AD, and gingipain activity. Saliva, and blood will be 
analyzed for biomarkers of AD and neuroinflammation, and for the 
presence of bacterial deoxyribonucleic acid (DNA) of Porphyromonas 
gingivalis (P. gingivalis [Pg]) using qPCR.  
A subset of sites will be selected to monitor subjects for clinical evidence 
of periodontitis in addition to AD. An oral examination will be conducted by 
a study dentist/hygienist at these sites to assess for the presence of 
clinical evidence of periodontitis at screening, 24 and 48 weeks. 
Subgingival plaque (SGP) and buccal cell swabs will be collected at these 
sites and analyzed for measurements of biomarkers associated with 
P. gingivalis DNA, proteins, and inflammation.


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Due to the nature of AD, subjects must identify a primary caregiver prior to 
enrollment in the study who will assist the subject with study participation. 
The primary caregiver must sign a caregiver informed consent.  
The safety of study participants will be evaluated throughout the study by 
repeated physical examinations, vital signs, safety laboratory tests,12-lead 
electrocardiograms (ECGs), Columbia-Suicide Severity Rating Scale 
(C-SSRS), magnetic resonance imaging (MRI), and assessments of 
treatment-emergent adverse events (TEAEs). Periodic safety reviews will 
be conducted during the study.  
Following the Data Monitoring Committee (DMC) recommendation after 
the November 16, 2020 meeting, increased frequency of liver safety 
monitoring has been implemented, which increased the frequency of 
safety laboratory analyte collections (see Table 1 and Table 2, Schedule 
of Evaluations).    
The study will consist of 3 periods: a screening period of up to 6 weeks, a 
treatment period of up to 48 weeks, and a safety follow-up period of 
6 weeks. An interim analysis may be conducted to reassess the sample 
size and evaluate for efficacy after 24 weeks of treatment on key outcome 
measures. 
Screening 
During the screening period, the eligibility of subjects will be confirmed 
according to the Schedule of Evaluations in this protocol. The Mini-Mental 
State Examination (MMSE) will be administered by a trained rater to 
assess the level of cognitive impairment. MMSE will be assessed as early 
in the screening period as possible. Subjects with MMSE score of 12-24, 
inclusive, will have the rest of their screening procedures performed or 
scheduled. Magnetic resonance imaging (MRI) of the brain will be 
performed in all subjects at screening, except subjects with an absolute 
contraindication for MRI, who can have a Computed Tomography (CT) 
scan of the brain instead. Screening procedures can be done on multiple 
days if needed, with more invasive procedures done after less invasive 
screening procedures are completed. A screen failure is any subject who 
signs the informed consent but does not qualify for the study or 
discontinues the study prior to randomization. A subject can be rescreened 
if the Principal Investigator thinks the subject may qualify for the study 
upon rescreening, and if the Medical Monitor agrees.  
Treatment Period 
Subjects who meet all eligibility criteria will enter the treatment period and 
will be randomized 1:1:1 to receive 40 mg COR388 HCl, 80 mg COR388 
HCl, or placebo twice a day. Randomization will be stratified by baseline 
MMSE (MMSE 12 and 18, and MMSE 19 and 24) and 
Apolipoprotein E (ApoE4 positive either homozygous or heterozygous vs. 
all others) genotype to assure balanced distribution of mild and moderate 
AD and a balanced distribution of ApoE4 subjects, across treatment arms. 
Subjects will receive their assigned blinded study treatment orally twice a 
day for up to 48 weeks and will come back to the investigative site 
periodically for scheduled efficacy and safety evaluations. Blood samples 
for pharmacokinetics levels and biomarkers will be collected during 
selected visits. Baseline LP will be performed prior to the first dose of 
study drug, and follow-up LP will be done at the end of the treatment 
period. Subjects will continue to receive the study drug for 48 weeks, 
unless the Investigator determines that treatment of a given subject should 


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be stopped or interrupted for safety or tolerability reasons, the subject 
withdraws consent, or the Sponsor decides to stop the study.  
Safety Follow-up Period 
After completion of study treatment, subjects will continue to be monitored 
on the study for 6 weeks and will have a phone call to assess safety at 
Weeks 49 and 51 and will return for the Safety Follow-up Visit (Week 54). 
For subjects with early termination, end of study procedures (Week 48) will 
be performed, and subjects will be encouraged to return to the clinic for 
the Safety Follow-up Visit after 6 weeks. Phone calls will be performed to 
assess safety at Week 1 and Week 3 after end of study procedures are 
performed. 
Open Label Extension 
The open label extension (OLE), as described below, was implemented in 
protocol versions 4.0 through 6.0. On 16 February 2021, the Sponsor 
terminated the OLE portion of the study following notification from the 
Food and Drug Administration (FDA) of a partial clinical hold. Per this 
notification, no new patients were enrolled into OLE, and all active 
participants were discontinued from study treatment with a requirement 
that a follow-up visit occur 4 weeks after the last dose of COR388. 
Open Label Extension Period 
Subjects who choose to participate in the OLE portion of the study and 
meet all eligibility criteria will begin the treatment period after completing 
the Week 48 Visit. Subjects will receive COR388 HCl 40 mg or 80 mg 
treatment orally twice a day for up to 48 weeks and will come back to the 
investigative site periodically for scheduled efficacy and safety evaluations. 
Subjects will continue to receive the study drug for 48 weeks, unless the 
Investigator determines that treatment of a given subject should be 
stopped or interrupted for safety or tolerability reasons, the subject 
withdraws consent, or the Sponsor decides to stop the study. 
Open Label Extension Safety Follow-up Period 
After completion of study treatment for the OLE, subjects will continue to 
be monitored on the study for 6 weeks and will have 2 phone calls to 
assess safety at Week 97 and Week 98 and will return for the Safety 
Follow-up Visit at Week 102. 
For subjects with early termination, end of study procedures (Week 96) will 
be performed, and subjects will be encouraged to participate in the Safety 
Follow-up phone calls and return to the clinic for Safety Follow-up Visit.  
Study Population 
The study will enroll approximately 573 generally healthy male and female 
subjects, 55 and 80 years of age, with mild to moderate probable AD 
dementia according to the NIA-AA criteria, who experienced clinical 
decline in the last year as defined in the study protocol. 
Criteria for Inclusion 
& Exclusion 
Investigators should contact the Medical Monitor if they have questions 
about eligibility of specific subjects. 
Inclusion Criteria: 


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Subjects will be eligible to participate in this study if they meet all of the 
following criteria: 

Subject has provided full written informed consent prior to the
performance of any protocol-specified procedure; or if unable to
provide informed consent due to cognitive status, subject has
provided assent and a legally authorized representative has
provided full written informed consent on behalf of the subject.

Caregiver has provided full written informed consent, on a
separate informed consent form (ICF), on his/her own behalf prior
to the performance of any protocol-specified procedure.

Male and female subjects must be 55 years to 80 years of age, at
the time of consent.

Subject has probable AD dementia according to the NIA-AA
criteria (McKhann 2011) with clinical evidence of progressive
cognitive decline in the last year. Clinical decline will be
determined based on serial cognitive test scores, if available, or
subject/caregiver report as documented by the Investigator.

Subject has an MMSE score between 12 and 24 inclusive at both
screening and Visit 2 and a 3-point difference between these
visits.

Subject has a Modified Hachinski score ≤4 at screening.

Subject has brain MRI scan consistent with the diagnosis of AD
performed during the screening period. Computed Tomography
scan can be used only if the subject has an absolute
contraindication for MRI.

Subject has a primary caregiver willing to accept responsibility for
supervising the treatment (e.g., administering study drug),
accompanying the study subject to clinic visits and assessing the
condition of the subject throughout the study in accordance with all
protocol requirements.

Subject is not likely to experience a change in living conditions
(e.g., institutionalization, moving to a different city, etc.), or change
in primary caregiver, during participation in the trial.
 Subjects with background symptomatic therapy with
acetylcholinesterase inhibitors, and/or memantine, are allowed as
long as the dose has been stable for 90 days prior to screening
and no changes are planned during the study.
 Subjects who have occasional use of sedative agents are
acceptable, but these agents should not be given within 48 hours
prior to cognitive assessments.
 Subjects who have background medications used for stable
chronic illnesses that are not prohibited by the protocol are
allowed. The dose of psychoactive drugs must be stable for
30 days prior to screening, and no changes must be planned
during the study unless for safety reasons.
 Subject has body mass index <38 kg/m2 at Screening.
 Subject must be able to ingest oral medications and can swallow
the study drug without breaking or crushing.


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15. Subject must be willing to undergo Apolipoprotein E genotype
(ApoE) genetic testing (ApoE results may be disclosed after trial
completion).
16. Subjects participating in the study must meet one of the following
criteria:
a.
Females: Surgically sterilized (e.g., hysterectomy, bilateral
oophorectomy or tubal ligation) for at least 6 months or
postmenopausal (postmenopausal females must have no
menstrual bleeding for at least 1 year). If not
postmenopausal, agree to use a highly effective method of
contraception that can achieve a failure rate of less than
1% per year when used consistently and correctly, such
as hormonal contraception or a double barrier method
(e.g., intrauterine device plus condom or true abstinence
defined as in line with the preferred and usual lifestyle of
the subject. Periodic abstinence e.g. calendar, ovulation,
symptothermal, post-ovulation methods are not
acceptable. Declaration of abstinence for the duration of a
trial, and withdrawal are not acceptable methods of
contraception) from 30 days prior to dosing until 30 days
after last dose and have negative human chorionic
gonadotropin (ȕ-hCG) test for pregnancy at screening.
b.
Males who have not had a vasectomy must use
appropriate contraception methods (barrier or true
abstinence defined as in line with the preferred and usual
lifestyle of the subject. Periodic abstinence e.g. calendar,
ovulation, symptothermal, post-ovulation methods are not
acceptable. Declaration of abstinence for the duration of a
trial, and withdrawal are not acceptable methods of
contraception) from 30 days prior to dosing until 90 days
after last dose.
Open Label Extension: Subjects will be eligible to participate in the open 
label extension portion of the study if they meet inclusion criteria # 8, 9, 10, 
11, 12, 14, and 16 above. Subjects with any change in their medical 
history that in the Investigator’s opinion will increase the subject’s risk of 
participating in the study or confounding study assessment should not 
continue in the open label extension portion of the study. The Investigator 
should contact the Sponsor with questions of eligibility for participation. 
NOTE: Effective 16 February 2021, the OLE portion of the study was 
terminated by the Sponsor.  
Exclusion Criteria: 
Subjects will not be eligible to participate in this study if they meet any of 
the following exclusion criteria: 
1.
Subject has imaging consistent with other differential dementia
diagnoses other than the diagnosis of AD. For example, any
suggestion of vascular disease including multiple infarction
involving large blood vessels or localized single infarction (angular
gyrus, thalamus, anterior cerebral artery and posterior cerebral
artery region), multiple lacunae of the basal nuclei or white matter
or extensive lesions of the periventricular white matter or
combination of several lesions are considered exclusionary.


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Additionally, any single lacune in an area known to impact 
cognition such as the hippocampus will also be exclusionary. 
Finally, Probable CAA with/without supporting pathological 
evidence according to the modified Boston criteria, if in the opinion 
of the investigator this may be contributing to symptoms 
overlapping with those of AD or confound neuropsychological 
assessments, would be exclusionary.  Importantly, should there be 
any evidence of neurologic symptoms between scanning and 
baseline visits, rescanning is necessary to ensure proper patient 
selection. 
2.
Subject has had an increase or restoration of cognition based on
medical history.
3.
Subjects who meet the following imaging exclusion criteria will not
be included in this study:
a.
Claustrophobia that will result in significant anxiety and
difficulty lying still for brain imaging (MRI or CT scan).
b.
Severe motor problems or chronic pain indication that
prevents the subject from lying still for brain imaging.
4.
Subject with history of cancer requiring systemic therapy in the last
5 years; except for localized cancer of the skin and in-situ cervical
cancer successfully treated with surgical excision.  Stable (for at
least 90 days) prostate cancer is allowed.
5.
Subject has a contraindication for LP, such as infected skin over
the needle entry site, possible increased intracranial pressure,
severe thrombocytopenia or coagulopathy, suspected spinal
epidural abscess, or spinal structural abnormalities that would
interfere with LP procedures.
6.
Subject has evidence of clinically significant unstable
cardiovascular, pulmonary, renal, hepatic, gastrointestinal,
neurologic or metabolic disease within 6 months prior to
Screening.
7.
Subject has any of the following cardiovascular conditions:
a.
Unstable angina, uncompensated and/or symptomatic
congestive heart failure (Grade 2 or higher on the New
York Heart Association scale) or myocardial infarction
within 6 months.
b.
Acute or poorly controlled blood pressure >180 mmHg
systolic or >100 mmHg diastolic.
c.
Current, or recent history of, any of the following that are
clinically significant in the investigator's judgment:
arrhythmia, hypotension, heart block (1st, 2nd or 3rd degree
AV block), ANY bundle branch block, ventricular pacing,
symptomatic ectopy, unstable arrhythmias including atrial
fibrillation; stable atrial fibrillation is allowed.
d.
History of prolonged QT or prolonged QT on screening
ECG (QTcF 480 msec).
e.
History of prolonged PR interval or prolonged PR interval
on screening ECG (PR >210 msec).


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f.
History of prolonged QRS interval or prolonged QRS
interval on screening ECG (QRS >120 msec).
g.
Supraventricular or ventricular ectopy on the screening
ECG or Brugada pattern on the ECG.
8.
Subject with major stroke, uncontrolled seizure disorder, or other
medical illnesses that in the Investigator’s opinion will increase the
subject’s risk of participation in the study or confound study
assessments.
9.
Subject with history or current evidence of major neurological or
psychiatric illness such as schizophrenia, bipolar disorder,
Parkinson’s Disease, etc. Subjects with major depressive
disorder that may interfere with the patient’s ability to perform the
study and all assessments. NOTE: Mild depression or depressive
mood arising in the context of AD are not criteria for exclusion.
The use of anti-depressants or the use of anti-epileptic medication
for non-seizure-related treatment is allowed if the dose has
remained stable for at least 60 days prior to enrollment.
10. Subject with history of violent or aggressive behavior that requires
medication to control.
11. Subjects with active suicidal thoughts (Type 4 or 5 on the
C-SSRS) in the 6 months preceding screening or at baseline; or
have a history of a suicide attempt in the previous 2 years, or more
than 1 lifetime suicide attempt; or are at serious suicide risk in the
Investigator’s clinical judgment.
12. Subject with history of alcohol or drug use disorder within
12 months of screening as defined by the Diagnostic and
Statistical Manual of Mental Disorders-5.
13. Subject with previous treatment with investigational vaccine
therapy for AD.
14. Subject has participated in another Investigational New Drug (IND)
research study involving small molecule drugs within 60 days or
biological drugs within 90 days prior to the first dose of study drug
or 5 half-lives of the investigational drug, whichever is longer.
15. Subject has a history of epilepsy or seizure disorder requiring
ongoing treatment, or any seizure or loss of consciousness within
6 months prior to enrollment.
16. Subject has any of the following laboratory findings at screening:
a.
Alanine aminotransferase >3 x upper limit of normal
(ULN), aspartate aminotransferase >3 x ULN, or history of
clinically significant liver disease in the Investigator’s
judgment.
NOTE: Subjects with ALT or AST >2 x ULN at Visit
9/Week 40 will not be eligible to participate in OLE.
NOTE: Effective 16 February 2021, the OLE portion of the
study was terminated by the Sponsor.
b.
Hemoglobin 10 g/dl.


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c. International Normalized Ratio (INR) >1.5 or total bilirubin 
>1.5 x ULN (unless subject has evidence of Gilbert’s 
disease). 
d. Creatinine clearance (CL) of <45 ml/min. 
e. Poorly controlled diabetes as defined by hemoglobin A1C 
(HbA1C) >8.  
f. 
Positive blood screen for Human Immunodeficiency Virus 
(HIV 1 and 2), Hepatitis B surface antigen (HBsAg), or 
Hepatitis C virus antibodies (HCV-Ab) at Screening. 
g. Positive urine screen for drugs of abuse that include 
opiates, cocaine, amphetamines, or barbiturates.  
17. Subject has abnormal laboratory tests that suggest an alternate 
etiology for dementia, such as serum vitamin B12 deficiency, 
thyroid function abnormality, severe anemia, electrolyte 
abnormality, or positive syphilis serology. In these cases, the 
patient should be re-evaluated to determine if these potential 
causes of dementia have been addressed. Only if these causes 
have been ruled out as the cause of the dementia can the patient 
be enrolled. 
18. Use of systemic (i.e., oral, intravenous, etc., but not topical) 
antibiotics in the last 60 days or history of recurrent infection that 
requires chronic or repeated courses of antibiotics.  
 
Open Label Extension: Subjects will not be eligible to participate in open 
label extension portion of the study if they meet any of the following 
exclusion criteria # 1, 4, 6, 7, 8-12, 15, 16 a, b, c, d and e. Laboratory 
testing and ECG results from Visit 9 will be used to evaluate eligibility. 
Subjects with any change in their medical history that in the Investigator’s 
opinion will increase the subject’s risk of participating in the study or 
confounding study assessment should not continue in the open label 
extension portion of the study. The Investigator should contact the 
Sponsor with questions of eligibility for participation.  
NOTE: Effective 16 February 2021, the OLE portion of the study was 
terminated by the Sponsor. 
 
Study Treatments Eligible subjects will be randomized 1:1:1 to receive one of the following 
treatments: 
 
80 mg COR388 HCl, twice daily (bid); 
 
40 mg COR388 HCl, bid; or 
 
Placebo, bid 
 
Open Label Extension: Subjects will receive 40 mg or 80 mg COR388 HCl, 
bid. 
NOTE: Effective 16 February 2021, the OLE portion of the study was 
terminated by the Sponsor. 
 
Drug Supplies The study drug will be provided in capsule form for oral administration. All 
capsules will be identical in appearance. 
 
 


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Duration of Subject 
Participation 
Double-blind: 48 weeks of treatment + up to 6 weeks for screening + 6 
weeks Safety follow up for subjects who don’t participate in open label 
extension 
Open Label Extension: 48 weeks of treatment + 6 weeks for Safety 
follow-up 
NOTE: Effective 16 February 2021, the OLE portion of the study was 
terminated by the Sponsor. 
Total Duration of Participation: up to 108 weeks  
Efficacy Evaluations 
The two co-primary endpoints are: 
 
Mean change in Alzheimer’s Disease Assessment Scale-Cognitive 
Subscale 11 (ADAS-Cog 11) from baseline to the end of treatment 
period. 
 
Mean change in Alzheimer’s Disease Cooperative Study Group-
Activities of Daily Living (ADCS-ADL) from baseline to the end of 
treatment period. 
Secondary endpoints in all subjects include: 
 
Change in Clinical Dementia Rating-Sum of Boxes (CDR-SB). 
 
Change in Mini-Mental State Examination (MMSE) 
 
Change in Neuropsychiatric Inventory (NPI)  
Exploratory endpoints in all participating subjects include change from 
screening/baseline and/or Visit 2 to the end of treatment period in the 
following measures: 
 
 
 
Blood-based biomarkers in serum and peripheral blood 
mononuclear cells (PBMCs); and 
 
Saliva biomarkers of P. gingivalis infection and inflammation. 
 
Cerebrospinal fluid: 
o 
CSF Aȕ42, total Tau, and phosphorylated Tau; 
o 
Bacterial DNA in the CSF based on quantitative 
polymerase chain reaction (qPCR) and sequencing; and 
o 
CSF biomarkers. 
 
 
Exploratory endpoints in subjects participating in sub-studies include 
change from screening/baseline to the end of treatment period in the 
following measures: 
 
Winterlight Speech Assessment (only in English speaking (primary 
language) subjects and only in the US and UK); 
 
Magnetic resonance imaging sub-study (subjects who have MRIs 
done in conjunction with the study): 
o 
Hippocampal volume; and 
o 
Cortical thickness. 
 


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 
Clinical periodontitis sub-study (subjects enrolled at selected 
sites):  
o 
Pocket Depth (PD); 
o 
Clinical Attachment Level (CAL) at 6 sites per tooth 
(distobuccal [DB], buccal [B], mesiobuccal [MB], 
distolingual [DL], lingual [L], and mesiolingual [ML]); 
o 
The percentage of sites with Bleeding on Probing (BOP); 
and 
o 
Biomarkers of P. gingivalis infection and inflammation in 
subgingival plaque (SGP) and buccal cell swabs. 
 
 
Safety Endpoints 
Safety endpoints include: 
 
The incidence and severity of TEAEs; 
 
Vital signs and physical examinations; 
 
Laboratory values; 
 
MRI scans; 
 
12-lead ECGs; and 
 
C-SSRS. 
 
Open Label Extension: 
 
The incidence and severity of TEAEs; 
 
Vital signs and physical examinations; 
 
Laboratory values; 
 
12-lead ECGs; and 
 
C-SSRS. 
NOTE: Effective 16 February 2021, the OLE portion of the study was 
terminated by the Sponsor. 
Statistical 
Considerations 
 
The study is designed as an adaptive trial and will allow for stopping early 
for efficacy, futility and potential adjustment in sample size based on the 
results of a planned interim analysis. Approximately 573 subjects are 
planned to be randomized 1:1:1 per treatment group (191 per treatment 
group) assuming approximately 10% will drop out prior to 48 weeks. This 
sample size would provide approximately 90% power to detect a 2.5-point 
difference between active treatment group and placebo with respect to 
change from baseline ADAS-Cog 11 score at Week 48, assuming a 
standard deviation of 7.1 at a two-sided significance level of 0.05 using a 
two-sided test.  The ADCS-ADL was added as a co-primary outcome, with 
assumptions of a 3.9-point difference between the active treatment group 
compared to placebo with respect to change from baseline on ADCS-ADL, 
assuming a standard deviation of 10.5, providing approximately 95% 
power on this outcome measure, with approximately 90% power for the 
overall co-primary outcomes, depending on their correlation. 
An unblinded interim analysis will be conducted by a firewalled 
independent statistician (all clinical trial personnel will remain blinded) 
when approximately 100 subjects per arm have completed the Week 24 
visit.  Overwhelming efficacy, futility and sample size adjustment will be 
evaluated. The Lan-DeMets spending function will be used to determine 
the test boundaries. If the interim analysis is conducted when 
approximately 300 subjects have completed the Week 24 visit, then a 
significance level of 0.005 will be used for the interim analysis and a 


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significance level of approximately 0.0456 will be used for the final 
analysis.   
Further details are provided in the statistical analysis plan (SAP). 
 
 
 


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Table 1.  
Schedule of Evaluations – Double-blind study 
Study Period 
Screening 
Treatment Period 
Safety Follow-up  
(if not participating in 
open label extension 
portion12) 
Visit number 
1 
2 
3 
3a 
4 
4a 
4b 
5 
5a 
6  
6a 
7 
7a 
8  
9 
10/ET12 Phone Call 
11 
Week 
-6 to -1 
0 
2 
4 
6 
8 
10 
12 
15 
18 
21 
24 
28 
32 
40 
48 
49 
51 
54 
Day 
-42 to -1 
0 - 
7 
14 
± 2 
28 
± 3 
42 
± 3 
56 
± 3 
70 
± 3 
84 
± 3 
105 
± 3 
126 
± 3 
147 
± 3 
168 
± 3 
196 
± 3 
224 
± 3 
280 
± 8 
336  
± 8 
343 
± 2 
357 
± 2 
378  
± 8 
Evaluations 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X13 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X14 
 
 
 
Medical History and confirmation of 
cognitive decline in the last 12 
months 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Full Physical Examination, Height, 
and BMI Calculation 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRI (or CT) of the Brain 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X1 
 
 
 
Modified Hachinski  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MMSE2 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
 
 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ADAS-Cog 11 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
 
 
X 
ADCS-ADL 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
 
 
X 
CDR-SB 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
 
 
X 
NPI 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
Winterlight Speech Assessment 
(only in English speaking (primary 
language) subjects and only in the 
US and UK) 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Dispense Study Drug  
 
X 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
X15 
 
 
 
Concomitant Medications 
X 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Oral Examination and collection of 
oral biomarker samples (only at 
selected sites)3 
X 
 
 
 
 
 
 
 
 
 
 
X4 
 
 
 
X4,5 
 
 
 
Saliva Collection 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
Symptom-Based Physical 
Examination 
 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
 
X 
Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Vital Signs 
X 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
 
X 
Columbia-Suicide Severity Rating 
Scale 
X 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
 
X 
 
 
 
 
 
 
Footnotes appear on following page. 


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Table 1.  
Schedule of Evaluations – Double-blind study (Continued) 
 
Study Period 
Screening 
Treatment Period 
Safety Follow-up  
(if not participating 
in open label 
extension portion12) 
Visit number 
1 
2 
3 
3a 
4 
4a 
4b 
5 
5a 
6 
6a 
7 
7a 
8 
9 
10/ET12 
Phone Call 
11 
Week 
-6 to -1 
0 
2 
4 
6 
8 
10 
12 
15 
18 
21 
24 
28 
32 
40 
48 
49 
51 
54 
Day 
-42 to -1 
0 - 7 14 
± 2 
28 
± 3 
42 
± 3 
56 
± 3 
70 
± 3 
84 
± 3 
105 
± 3 
126 
± 3 
147 
± 3 
168 
± 3 
196 
± 3 
224 
± 3 
280 
± 8 
336  
± 8 
343 
± 2 
357 
± 2 
378  
± 8 
Evaluations 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Laboratory Tests16 
X 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
 
X 
Liver Safety Monitoring16 
 
 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
Lumbar Puncture (LP)6 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Adverse Events 
 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Blood Collection for PK7 
 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
 
 
 
12-Lead ECG 
X 
X8 
X8,9 
 
X 
 
 
X 
 
 
 
X8,9 
 
 
X8 
X8 
 
 
X 
ApoE Genotyping 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Collection Pregnancy10 
Test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Blood Collection for FSH11 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum and whole blood 
(PBMCs) for biomarkers 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
Blood Collection for Serology 
(HCV-Ab, HBsAg, HIV 1 and 
2) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Collection for Vit. B12, 
Thyroid function tests and 
Syphilis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Collection for Drug 
Screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. Visit 10/ET MRI will be done only in subjects who had a screening MRI performed and may be done up to 8 days prior to Visit 10/ET. CT scans of the brain 
can be used instead of MRIs, only in subjects who have an absolute contraindication for MRI. 
2. Administer the first MMSE as early in the screening period as possible. MMSE score should be 12 and 24 at both screening and Visit 2, and a 3-point 
difference between visits, for inclusion in the study. 
3. Oral biomarker samples include subgingival plaque and buccal cell swabs (only at selected sites). 
4. Subjects will have follow-up oral examinations at 24 and 48 weeks. 
5. Visit 10/ET oral examinations may be completed up to 8 days prior to Visit 10 (or ET) when applicable. 
6. Baseline (V2) LP must be done after the baseline MMSE score has been verified and subject’s eligibility has been confirmed, and prior to the first dose of 
study drug. To allow flexibility of scheduling the LP procedure, the MMSE and then the LP may be performed up to 7 days prior to baseline V2.  Likewise, the 
LP at Visit10/ET may be performed up to 7 days prior to the other visit procedures, even if the LP is outside the visit window. The LP procedures must be 


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performed as per SOC and site specific SOPs, if applicable (including imaging before and/or during the LP, if required).  
7. A pre-dose trough sample will be drawn at all visits 2, 3, and 7 immediately prior to the AM dose, and the subject will then take their dose of study drug on-
site. The exact times of AM dosing and PK sample collections at the site will be documented.  A single post-dose sample will be drawn from each subject 
while on-site at the clinic per the following schedule: V2 30 minutes - 4 hours; V3 60 minutes ± 30 minutes; V7 2 hours ± 30 minutes; V9 3 hours ± 30 minutes; 
and V10/ET 4 hours ± 30 minutes.  
8. At visits when the subject takes their dose of study drug on-site, ECGs should be measured approximately 1-1.5 hours after dosing.  
9. At Visit 3 and Visit 7, ECGs will also be performed at trough (prior to dosing).   
10. A urine pregnancy test will be conducted only in women of child bearing potential at screening and End of Treatment or Early Termination Visit 10, and at 
other visits only if indicated. If the urine pregnancy test is positive, a serum pregnancy test will be performed to confirm pregnancy. 
11. Only for peri-menopausal (irregular menstrual periods) or post-menopausal (no menstrual period for >12 months) female subjects. 
12. Subjects who want to participate in the open label extension portion of the study will complete the Week 48 visit and then continue with the Schedule of 
Evaluations in Table 2. NOTE: Effective 16 February 2021, the OLE portion of the study was terminated by the Sponsor. 
13. Informed consent will be obtained for subjects who agree to participate in the open label extension portion of the study. 
14. Inclusion/exclusion will be evaluated to determine eligibility for subjects who want to participate in the open label extension portion of the study. Laboratory 
testing and ECG results from Visit 9 will be used to evaluate eligibility. 
15. If a subject is eligible and agrees to participate in the open label extension, the OLE study drug (40 mg or 80 mg) will be dispensed at V10. The subject should 
be instructed to take the first dose in the morning of the next day. 
16. Liver Safety Monitoring (laboratory analyte testing) must be performed at each study visit within the prespecified visit window OR the study drug dosing must 
be interrupted until the testing is done.  
 
Abbreviations: AD = Alzheimer’s Disease; ADAS-Cog 11 = Alzheimer’s Disease Assessment Scale-Cognitive Subscale 11;  
ADCS-ADL = Alzheimer’s Disease Cooperative Study Group-Activities of Daily Living; AM = morning; ApoE = apolipoprotein E; BMI = body mass index;  
CDR-SB = Clinical Dementia Rating-Sum of Boxes; CSF = cerebrospinal fluid; CT = Computed Tomography; DNA = deoxyribonucleic acid;  
ECG = electrocardiogram; ET = Early Termination; FSH = Follicle Stimulating Hormone; HBsAg = Hepatitis B surface antigen; HCV-Ab = Hepatitis C virus 
antibodies; HIV 1 and 2 = Human Immunodeficiency Virus 1 and 2; MMSE = Mini-Mental State Examination;  
MRI = magnetic resonance imaging; NPI = Neuropsychiatric Inventory; PBMCs = peripheral blood mononuclear cells; Pg = Porphyromonas gingivalis;  
PK = pharmacokinetics; qPCR = quantitative polymerase chain reaction.  
 
 
 


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Table 2.  
Schedule of Evaluations – Open Label Extension4 
Study Period 
Treatment Period4 
Safety Follow-up  
Visit number 
OLE-
1 
OLE-
1a 
OLE-2 OLE-
2a 
OLE-
2b 
OLE-3 OLE-
3a 
OLE-
3b 
OLE-
3c 
OLE-4 
OLE-
4a 
OLE-5 
OLE-
6/ET 
OLE-Phone 
Call 
OLE-9 
 
 
 
 
 
 
 
OLE-7 OLE-8 
Week 
50 
52 
54 
56 
58 
60 
63 
66 
69 
72 
78 
84 
96 
97 
98 
102 
Day 
350 
± 3 
364 
± 3  
378 
± 3 
392 
± 3 
406 
± 3 
420 
± 3 
441 
± 3 
462 
± 3 
483 
± 3 
504 
± 3 
546 
± 6 
588 
± 6 
672  
± 8 
679 
± 2 
686 
± 2 
714  
± 8 
Evaluations 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ADAS-Cog 11 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
ADCS-ADL 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
CDR-SB 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
Dispense Study Drug  
X 
 
X 
 
 
X 
 
 
 
X 
 
X 
 
 
 
 
Concomitant Medications 
X 
 
X 
 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
Saliva Collection 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
Symptom-Based 
Physical Examination 
X 
 
X 
 
 
X 
 
 
 
X 
 
X 
X 
 
 
X 
Weight 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Vital Signs 
X 
 
X 
 
 
X 
 
 
 
X 
 
X 
X 
 
 
X 
Columbia-Suicide 
Severity Rating Scale 
X 
 
X 
 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
Liver Safety Monitoring3 
 
X 
 
X 
X 
 
X 
X 
X 
 
X 
 
 
 
 
 
Safety Laboratory Tests 
X 
 
X 
 
 
X 
 
 
 
X 
 
X 
X 
 
 
X 
Urine pregnancy test1 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Adverse Events 
X 
 
X 
 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
12-Lead ECG 
X 
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
Oral Examination and 
collection of oral 
biomarker samples (only 
at selected sites)2 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
1. 
A urine pregnancy test will be conducted only in women of childbearing potential. If the urine pregnancy test is positive, a serum pregnancy test will 
be performed to confirm pregnancy. 
2. 
Oral biomarker samples include subgingival plaque and buccal cell swabs (only at selected sites). Visit OLE-6/ET oral examinations may be 
completed up to 8 days prior to OLE-6 Visit (or ET) when applicable. 
3. 
Liver Safety Monitoring (laboratory analyte testing) must be performed at each study visit within the prespecified visit window OR the study drug 
dosing must be interrupted until the testing is done.  
4. 
NOTE: Effective 16 February 2021, the OLE portion of the study was terminated by the Sponsor. 


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TABLE OF CONTENTS 
Contact Information ............................................................................................... 2 
Investigator’s Agreement ....................................................................................... 3 
Protocol Signature Sheet ....................................................................................... 4 
1 
Protocol Synopsis ............................................................................................. 5 
Table of Contents ................................................................................................... 20 
List of Abbreviations ............................................................................................ 23 
2 
Introduction ..................................................................................................... 26 
3 
Study Objectives ............................................................................................. 28 
4 
Investigational Plan ......................................................................................... 28 
4.1   Overall Study Design and Plan ................................................................... 28 
4.1.1  
Scientific Rationale for Study Design ................................................... 29 
4.1.2  
Efficacy Evaluations ............................................................................. 30 
4.1.3  
End of Study Definition ........................................................................ 31 
5  
Study Drug Administration and Management ............................................... 31 
5.1 
Dose Preparation and Administration.......................................................... 31 
5.2 
Randomization to Treatment Groups .......................................................... 31 
5.3 
Packaging and Labeling .............................................................................. 32 
5.4 
Study Drug Supply, Storage, and Handling ................................................. 32 
5.4.1  
COR388 HCl ........................................................................................ 32 
5.4.2  
Placebo ................................................................................................ 32 
5.4.3  
Unblinding of Individual Study Subjects ............................................... 32 
5.5 
Drug Inventory and Accountability .............................................................. 33 
5.6 
Treatment Compliance ................................................................................ 33 
6  
Selection of Study Population ........................................................................ 33 
6.1 
Inclusion Criteria ......................................................................................... 33 
6.2 
Exclusion Criteria ........................................................................................ 35 
6.3 
Subject Restrictions .................................................................................... 38 
6.3.1  
Prior and Concomitant Medications ..................................................... 38 
7  
Study Visits ...................................................................................................... 39 
7.1 
Screening: Visit 1 (Day -42 to Day -1) ......................................................... 39 
7.2 
Study Treatment: Visit 2 (Day 0) ................................................................. 40 
7.3 
Study Treatment: Visit 3 (Day 14 ± 2) ......................................................... 42 
7.4 
Study Treatment: Visit 4 (Day 42 ± 3) ......................................................... 42 
7.5 
Study Treatment: Visit 5 (Day 84 ± 3) ......................................................... 42 
7.6 
Study Treatment: Visit 6 (Day 126 ± 3) ....................................................... 43 
7.7 
Study Treatment: Visit 7 (Day 168 ± 3) ....................................................... 43 
7.8 
Study Treatment: Visit 8 (Day 224 ± 3) ....................................................... 44 
7.9 
Study Treatment: Visit 9 (Day 280 ± 8) ....................................................... 44 
7.10  Study Treatment: Visit 10/Early Termination (Day 336 ± 8) ........................ 45 
7.11  Safety Follow-up Phone Calls: (Days 343 ± 2 and 357 ± 2) ........................ 46 
7.12  Safety Follow-up Visit: Visit 11 (Day 378 ± 8) ............................................. 46 
7.13  Increased Safety Laboratory Monitoring (Liver Safety Monitoring) ............. 47 


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7.14  Open Label Extension (OLE) ...................................................................... 48 
7.15  OLE Study Treatment: Visit OLE-1 (Day 350 ± 3) ....................................... 48 
7.16  OLE Study Treatment: Visit OLE-2 (Day 378 ± 3) ....................................... 48 
7.17  OLE Study Treatment: Visit OLE-3 (Day 420 ± 3) ....................................... 49 
7.18  OLE Study Treatment: Visit OLE-4 (Day 504 ± 3) ....................................... 49 
7.19  OLE Study Treatment: Visit OLE-5 (Day 588 ± 6) ....................................... 49 
7.20  OLE Study Treatment: Visit OLE-6/Early Termination (Day 672 ± 8) .......... 50 
7.21  OLE Safety Follow-up Phone Calls: Visits OLE-7 and OLE-8 (Days 679 ± 2 
and 686 ± 2) ................................................................................................ 50 
7.22  Unscheduled Visit(s) ................................................................................... 51 
7.23  Allowances in the Circumstance of a Public Health Emergency ................. 51 
8  
Study Procedures ............................................................................................ 52 
8.1 
Informed Consent ....................................................................................... 52 
8.2 
Medical and Medication History .................................................................. 53 
8.3 
Mini-Mental State Examination (MMSE) ..................................................... 53 
8.4 
Randomization ............................................................................................ 53 
8.5 
Dispense Study Drug .................................................................................. 54 
8.6 
Alzheimer’s Disease Assessment Scale-Cognitive Subscale 11 
(ADAS-Cog 11) ........................................................................................... 54 
8.7 
Clinical Dementia Rating-Sum of Boxes (CDR-SB) .................................... 54 
8.8 
Alzheimer’s Disease Cooperative Study Group-Activities of Daily Living 
(ADCS-ADL) ............................................................................................... 55 
8.9 
Neuropsychiatric Inventory (NPI) ................................................................ 55 
8.10  Winterlight Speech Assessment ................................................................. 55 
8.11  Saliva Collection ......................................................................................... 55 
8.12  Oral Examination ........................................................................................ 56 
8.12.1   Oral Examination Procedures .............................................................. 56 
8.12.2   Oral Samples Collection ...................................................................... 57 
8.13  Physical Examination .................................................................................. 58 
8.14  Brain Imaging .............................................................................................. 58 
8.15  Modified Hachinski ...................................................................................... 58 
8.16  Height, Weight, and Body Mass Index (BMI) .............................................. 58 
8.17  Vital Signs ................................................................................................... 58 
8.18  Columbia-Suicide Severity Rating Scale (C-SSRS) .................................... 58 
8.19  Laboratory Assessments ............................................................................. 59 
8.19.1   Monitoring of Laboratory Abnormalities ............................................... 60 
8.20  Urine Drug Screen ...................................................................................... 60 
8.21  Blood Pharmacokinetic (PK) Evaluations .................................................... 60 
8.22  Cerebrospinal Fluid (CSF) Evaluations ....................................................... 61 
8.23  Electrocardiograms (ECGs) ........................................................................ 61 
8.24  Safety Monitoring Plan for Potential Drug Induced Liver Injury ................... 61 
9  
Adverse Event Reporting ................................................................................ 63 
9.1   Definitions and Criteria ................................................................................ 63 
9.1.1  
Adverse Events .................................................................................... 63 
9.1.2  
Serious Adverse Events ....................................................................... 64 


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9.1.3 
Unexpected Adverse Drug Reactions .................................................. 64 
9.1.4 
Abnormal Laboratory Values ................................................................ 65 
9.1.5 
Assessing Intensity and Relationship ................................................... 65 
9.2   Reporting Procedures and Requirements ................................................... 66 
9.2.1 
Adverse Events .................................................................................... 66 
9.2.2 
Serious Adverse Events ....................................................................... 67 
9.3   Procedures for Documenting Pregnancy During Study ............................... 68 
9.4   Treatment of Investigational Product Overdose .......................................... 68 
10   Quality Control and Quality Assurance ......................................................... 69 
10.1  Bioanalytic Method Validation ..................................................................... 69 
11   Statistical and Analytical Plans ...................................................................... 69 
11.1  General Considerations .............................................................................. 69 
11.2  Determination of Sample Size ..................................................................... 69 
11.3  Final Analysis .............................................................................................. 70 
11.3.1   Analysis Populations ............................................................................ 70 
11.3.2   Efficacy Analysis .................................................................................. 70 
11.3.3   Safety Analysis .................................................................................... 73 
11.3.4   Demographic and Baseline Characteristics ......................................... 74 
11.3.5   Interim Analysis .................................................................................... 75 
11.3.6   Pharmacokinetic Analysis .................................................................... 75 
12   Study Management .......................................................................................... 75 
12.1  Regulations and Guidelines ........................................................................ 75 
12.2  Institutional Review Board/Independent Ethics Committee ......................... 76 
12.3  Discontinuation of the Study by the Sponsor .............................................. 76 
12.4  Study Documentation .................................................................................. 76 
12.5  Study Monitoring and Auditing .................................................................... 76 
12.6  Data Monitoring Committee ........................................................................ 77 
12.7  Retention of Records .................................................................................. 77 
12.8  Use of Study Findings ................................................................................. 77 
12.9  Publications ................................................................................................. 77 
12.10 
Subject Privacy .................................................................................... 78 
12.11 
Amendments to the Protocol ................................................................ 78 
12.12 
Case Report Form Completion ............................................................ 78 
12.13 
Removal of Subjects from Therapy or Assessment ............................. 79 
12.14 
End of the Study .................................................................................. 80 
13   References ....................................................................................................... 81 
Appendix A: Clinical Laboratory Analytes .......................................................... 83 
List of Tables 
Table 1.    Schedule of Evaluations – Double-blind study ........................................ 16 
Table 2.    Schedule of Evaluations – Open Label Extension .................................. 19 


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List of Abbreviations 
Abbreviation 
Term 
Abnormal CS 
Abnormal Clinically Significant 
Abnormal NCS 
Abnormal Not Clinically Significant 
AD
Alzheimer’s disease
ADAS-Cog 11 
Alzheimer’s Disease Assessment Scale-Cognitive Subscale 11 
ADCS-ADL 
Alzheimer’s Disease Cooperative Study Group-Activities of Daily 
Living 
ADR 
Adverse drug reaction 
AE
Adverse event
AL
Attachment level
ANCOVA 
Analysis of covariance 
ApoE
Apolipoprotein E
B
buccal
Bid
Twice daily
BMI 
Body mass index 
BOP 
Bleeding on Probing 
CAL 
Clinical Attachment Level 
CDC/AAP 
Centers for Disease Control/American Academy of 
Periodontology 
CDR-SB
Clinical Dementia Rating-Sum of Boxes 
CEJ
Cementoenamel junction
CFR 
Code of Federal Regulations 
CL
Creatinine clearance
CNS 
Central Nervous System 
CRA 
Clinical Research Associate 
CRO 
Contract Research Organization 
CS
Compound symmetry
CSF
Cerebrospinal fluid
CSH 
Heterogeneous compound symmetry 
C-SSRS
Columbia-Suicide Severity Rating Scale 
CT
Computed Tomography
CV
Coefficient of variation 
DB
Distobuccal
DL
Distolingual
DMC
Data Monitoring Committee 
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
eCRF
Electronic Case Report Form 


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Abbreviation 
Term 
FDA 
Food and Drug Administration 
FSH 
Follicle stimulating hormone 
GM 
Gingival margin 
ȕ-HCG 
Human chorionic gonadotropin 
HbA1C 
Hemoglobin A1C 
HBsAg 
Hepatitis B surface antigen 
HCV-Ab 
Hepatitis C virus antibodies 
HIPAA 
Health Insurance Portability and Accountability Act  
HIV 
Human Immunodeficiency Virus 
HPMC 
Hydroxypropyl methylcellulose 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation  
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRS 
Interactive Response System 
ITT 
Intent-to-Treat 
L 
Lingual 
LP 
Lumbar Puncture 
MAR 
Missing at random 
MB 
Mesiobuccal 
MedDRA 
Medical Dictionary for Regulatory Activities 
ML 
Mesiolingual 
MMRM 
Mixed-effects model for repeated measures 
MMSE 
Mini-Mental State Examination 
MNAR 
Missing not at random 
MRI 
Magnetic resonance imaging 
NIA-AA 
National Institute on Aging-Alzheimer’s Association 
NOAEL 
No observed adverse effect level 
NPI 
Neuropsychiatric Inventory 
PBMC 
PD 
Pg 
Peripheral blood mononuclear cell  
Pocket Depth 
Porphyromonas gingivalis (P. gingivalis [Pg]) 
PK 
Pharmacokinetics 
PP 
Per Protocol 
PT 
Preferred Term 


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Abbreviation 
Term 
qPCR 
Quantitative polymerase chain reaction 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
SGP 
Subgingival plaque 
t½ 
Half-life 
TEAE 
Treatment-emergent adverse event 
Tmax 
Time to maximum plasma concentration 
ULN 
Upper limit of normal 
 
 


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2 
INTRODUCTION 
Alzheimer’s disease (AD) continues to cause a tremendous impact on the lives of 
millions of patients and their caregivers and puts a huge burden on healthcare 
systems worldwide. In the absence of effective disease modifying treatments, AD 
continues to represent a major area of unmet medical need. Cortexyme is 
developing a novel small molecule, COR388 HCl, for the treatment of AD. The 
development of this compound represents a new paradigm for disease modification 
in AD that is based on a large body of emerging scientific data from both Cortexyme 
and independent researchers, as detailed in the Investigator’s Brochure (IB) and 
summarized in the sections below. 
Cortexyme has discovered evidence of Porphyromonas gingivalis (P. gingivalis [Pg]) 
in the brains of a large proportion of Alzheimer’s patients compared to controls. 
P. gingivalis is a Gram-negative asaccharolytic pathogen and a keystone bacterium 
in the development of periodontal disease. Gingipains are cysteine proteases 
produced by Pg that are critical for the survival of the bacteria, host cell toxicity, and 
immune evasion. P. gingivalis infection has been identified as a risk factor for a 
number of chronic inflammatory disease states including AD, atherosclerosis, and 
type 2 diabetes. P. gingivalis has been isolated from a variety of human tissues 
indicating systemic translocation beyond the oral cavity. A growing body of 
epidemiological evidence and prospective observational studies link periodontal 
disease, the most prevalent age-related chronic infection in humans, to diagnosis 
and rapid decline of AD. Cortexyme conducted a series of experiments to evaluate 
the presence of Pg and gingipains in the brains of AD patients and control groups, 
explore the role of Pg in the pathogenesis of AD, and evaluate gingipains as a 
therapeutic target. Based on the data summarized in the IB, Cortexyme believes this 
compound will slow or prevent further neurodegeneration, cognitive decline, and 
accumulation of pathology in AD patients. 
COR388 HCl is a proprietary small molecule that is a potent and selective 
irreversible inhibitor of the bacterial protease lysine gingipain (Kgp) that was 
selected as a lead compound to progress toward human clinical trials based on its 
selectivity, pharmacokinetics (PK), efficacy, and safety profiles.  
A comprehensive program was conducted to assess the PK, safety, and toxicity of 
COR388 HCl in 2 animal species and humans. COR388 HCl has a favorable PK 
profile in animals, and is readily bioavailable after oral administration, resulting in 
sufficient plasma and central nervous system (CNS) exposures for clinical efficacy. 
COR388 is a chiral molecule whose epimer COR490 is produced in vivo and has a 
similar potency, efficacy and PK profile. COR388 has a moderate level of plasma 
protein binding in animal species tested and human subjects. COR388 is cleared 
rapidly, with a terminal half-life ranging from 2-3.5 hours in different animal species 
to 4.5-5.0 hours at steady state in humans. 
No evidence of genotoxicity was found on either a battery of in vitro studies in 
bacteria and mammalian cells or in an in vivo micronucleus study. General 
toxicology studies in mice and dogs showed no change in serum chemistry, 


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hematology, and urinalysis laboratory parameters. Treatment with large doses of 
COR388 was associated with transient cardiovascular effects in dogs. 
Histopathology evaluation with light and fluorescent microscopy, as well as electron 
microscopy, revealed minimal increase in the size and number of intracytoplasmic 
lysosomes in the brain in mice and dogs and the kidney in dogs. There was no 
evidence of cellular injury. These were considered an adaptive response by the 
neurons and renal tubular cells aiming at clearing excess COR388 and metabolites, 
that may not be expected to occur with the lower exposure levels planned in human 
trials. These findings were considered non-adverse in dogs at all doses, and in mice 
treated with doses 100 mg/kg/day. After a 28-day recovery period, a complete 
reversal of the findings was found in the kidneys in dogs and the stratum radiatum in 
mice, with partial recovery in other parts of the mouse brain. 
Safety pharmacology studies revealed transient, and reversible effects on the 
cardiovascular and CNS systems. The no observed adverse effect levels (NOAELs) 
associated with these effects provide large safety margins over the doses used in 
this trial.  
Cortexyme has completed two Phase 1 safety and PK studies. The Phase 1 
program included a single ascending dose study in normal healthy volunteers, and a 
multiple ascending dose study in older healthy volunteers and AD subjects with 
clinical evidence of periodontitis.   
Results from the single ascending dose study showed that COR388 HCl was 
absorbed rapidly after oral administration and produced plasma concentrations in 
the presumed therapeutic range and dose proportional increases in exposures with 
doses ranging from 25 to 150 mg. Clearance was rapid, with a mean half-life (t½) of 
2 to 4 hours. Consumption of a high fat meal had a modest effect on COR388 HCl 
exposure, which is not likely to be of clinical relevance. Single doses of COR388 HCl 
ranging from 5 to 250 mg were safe and well tolerated when administered to healthy 
volunteers, although there was only 1 subject in the 250 mg dose cohort. 
Treatment-emergent adverse events (TEAEs) were infrequent, mostly mild in 
severity, and transient. There were no deaths, Serious Adverse Events (SAEs), or 
TEAEs leading to study drug discontinuation during the study. There were no 
clinically meaningful changes in safety laboratory findings, electrocardiograms 
(ECGs), vital signs, or physical examinations observed during the study.  
The multiple ascending dose study revealed that oral doses of COR388 HCl ranging 
from 25 to 100 mg every 12 hours were safe and well tolerated when administered 
to normal healthy volunteers 55 to 70 years of age and Alzheimer’s disease (AD) 
subjects 58 to 83 years of age. Subjects who received COR388 HCl experienced 
infrequent TEAEs, which were mostly mild in severity and transient. There were no 
deaths, SAEs, or TEAEs leading to study drug discontinuation during the study. 
There were no clinically meaningful changes in laboratory parameters, vital signs, 
ECGs, or physical examination findings observed during the study. COR388 HCl 
was readily bioavailable after oral administration, with good tissue distribution and 


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rapid clearance. The results of the Phase 1a/b trials are described in more detail in 
the IB.  
Safety and PK data from the Phase 1 a/b program along with appropriate preclinical 
chronic toxicology and other studies enabled Cortexyme to select appropriate doses 
and move forward with the Phase 2/3 program. 
3 
STUDY OBJECTIVES 
The objectives of the study are to:  

Assess the efficacy of 2 dose levels of COR388 HCl in Alzheimer’s disease
(AD) subjects; and

Assess the safety and tolerability of 2 dose levels of COR388 HCl in AD
subjects.
4 
INVESTIGATIONAL PLAN 
4.1 Overall Study Design and Plan 
This is a randomized, double-blind, placebo-controlled study that will assess the 
efficacy, safety, and tolerability of 2 dose levels of COR388 HCl in subjects with 
probable AD dementia according to the National Institute on Aging-Alzheimer’s 
Association (NIA-AA) criteria (McKhann 2011). The study will enroll approximately 
573 generally healthy male and female subjects, 55 and 80 years of age. Enrolled 
subjects must have a documented diagnosis of probable AD dementia with clinical 
evidence of progressive cognitive decline in the last year. Clinical decline will be 
defined as the evidence of progressive cognitive decline on subsequent evaluations 
based on information from informants and/or cognitive testing in the context of either 
formal neuropsychological evaluation or standardized mental status examinations for 
probable AD dementia (McKhann 2011). The subject should not have other 
conditions or brain imaging abnormality that can explain the symptoms of dementia. 
A Lumbar Puncture (LP) will be performed at baseline (Visit 2) and at end of 
treatment period week 48 (Visit 10) or early termination visit (ET). Cerebrospinal fluid 
(CSF) will be tested for measurement of bacterial DNA (Pg) using quantitative 
polymerase chain reaction (qPCR), biomarkers of AD, and gingipain activity. Saliva, 
and blood will be analyzed for measurements of biomarkers of AD and 
neuroinflammation, and for the presence of bacterial deoxyribonucleic acid (DNA) of 
Porphyromonas gingivalis (P. gingivalis [Pg]) using qPCR.   
A subset of sites will be selected to monitor subjects for clinical evidence of 
periodontitis in addition to AD. An oral examination will be conducted by a study 
dentist/hygienist at these sites to assess for the presence of clinical evidence of 
periodontitis. Subjects will have follow-up oral examinations at 24 and 48 weeks. 
Subgingival plaque (SGP) and buccal cell swabs will be collected in addition to 
saliva at these sites and analyzed for measurements of biomarkers associated with 
P. gingivalis DNA, proteins, and inflammation.


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Due to the nature of AD, subjects must identify a primary caregiver prior to 
enrollment in the study who will assist the subject with study participation. The 
primary caregiver must sign a caregiver informed consent.  
The safety of study participants will be evaluated throughout the study by repeated 
physical examinations, vital signs, safety laboratory tests,12-lead electrocardiograms 
(ECGs), Columbia-Suicide Severity Rating Scale (C-SSRS), magnetic resonance 
imaging (MRI), and assessments of treatment-emergent adverse events (TEAEs). 
Periodic safety reviews will be conducted during the study.  
The study will consist of 3 periods: a screening period of up to 6 weeks, a treatment 
period of up to 48 weeks, and a safety follow-up period of 6 weeks. An interim 
analysis may be conducted to reassess the sample size and evaluate for efficacy 
after 24 weeks of treatment on key outcome measures. 
During the screening period, the eligibility of subjects will be confirmed according to 
the Schedule of Evaluations (Table 1). 
Eligible subjects will be randomized 1:1:1 to receive one of the following treatments: 

80 mg COR388 HCl, twice daily (bid);

40 mg COR388 HCl, bid; or

Placebo, bid.
The study drug will be provided in capsule form for oral administration. All capsules 
will be identical in appearance. 
4.1.1 Scientific Rationale for Study Design 
The primary objective of the study is to assess the efficacy of COR388 HCl in the 
treatment of AD. Based on the postulated mechanism of action of this compound, 
treatment is expected to slow or prevent further neurodegeneration, cognitive 
decline, and accumulation of pathology in AD subjects should COR388 HCl be 
effective. Available data indicate that Alzheimer’s Disease Assessment Scale-
Cognitive Subscale 11 (ADAS-Cog 11) score increases by 2-4 points per year on 
average in subjects with mild to moderate AD (Ito 2013, Wattmo 2016). Therefore, a 
treatment period of 48 weeks was selected to allow sufficient time to demonstrate at 
least 2.5 points difference between active treatment and placebo on ADAS-Cog 11 
at the end of treatment period. The doses of 40 and 80 mg were selected to provide 
plasma levels of COR388 above the levels found to be therapeutic in animal models, 
while maintaining safe exposure levels based on preclinical and clinical data 
available to date. The objective of the open label extension portion of the study is to 
evaluate the safety and efficacy of COR388 HCl treatment in all subjects who want 
to participate and meet eligibility criteria.  
The frequency of visits is selected to provide close monitoring of subjects’ safety, 
without putting undue burden on the subjects and their caregivers. Similarly, study 
assessments are selected to provide the essential data needed to assess the 


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efficacy and safety of COR388 HCl, without burdening study subjects with 
unnecessary procedures or lengthy site visits. 
4.1.2 Efficacy Evaluations 
Primary Endpoint 
The two co-primary endpoints are: 
 Mean change in Alzheimer’s Disease Assessment Scale-Cognitive Subscale 11 
(ADAS-Cog 11) from baseline to the end of treatment period; and 
 Mean change in Alzheimer’s Disease Cooperative Study Group-Activities of Daily 
Living (ADCS-ADL) from baseline to the end of treatment period. 
 
Secondary Endpoints 
Secondary endpoints in all subjects include: 
 Change in Clinical Dementia Rating-Sum of Boxes (CDR-SB); 
 Change in Mini-Mental State Examination (MMSE); and 
 Change in Neuropsychiatric Inventory (NPI).  
 
Exploratory Endpoints 
Exploratory endpoints in all participating subjects include change from 
screening/baseline and/or Visit 2 to the end of treatment period in the following 
measures: 
 Blood-based biomarkers in serum and peripheral blood mononuclear cells 
(PBMCs); and 
 Saliva biomarkers of P. gingivalis infection and inflammation. 
 Cerebrospinal fluid: 
o CSF Aȕ42, total Tau, and phosphorylated Tau; 
o Bacterial DNA in the CSF on quantitative polymerase chain reaction (qPCR); 
and 
o CSF biomarkers. 
Exploratory endpoints in subjects participating in sub-studies include change from 
screening/baseline to the end of treatment period in the following measures: 
 Winterlight Speech Assessment (only in English speaking subjects (primary 
language and only in the US and UK); 
 Magnetic resonance imaging sub-study (subjects who have MRIs done in 
conjunction with the study): 
o Hippocampal volume; and 
o Cortical thickness. 


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 Clinical periodontitis sub-study (subjects enrolled at selected sites):  
o Pocket Depth (PD); 
o Clinical Attachment Level (CAL) at 6 sites per tooth (distobuccal [DB], buccal 
[B], mesiobuccal [MB], distolingual [DL], lingual [L], and mesiolingual [ML]); 
o The percentage of sites with Bleeding on Probing (BOP); and 
o Biomarkers of P. gingivalis infection and inflammation in subgingival plaque 
(SGP) and buccal cell swabs. 
Safety Endpoints 
Safety endpoints include: 
 The incidence and severity of TEAEs; 
 Vital signs and physical examinations; 
 Laboratory values; 
 MRI scans; 
 12-lead ECGs; and 
 C-SSRS. 
 
4.1.3 End of Study Definition 
End of study is Safety Follow-up Visit 11 or Visit OLE-9 (if subject participates in the 
open label extension portion of the study), unless the Investigator determines that 
treatment of a given subject should be stopped or interrupted for safety or tolerability 
reasons, the subject withdraws consent, or the Sponsor decides to stop the study.  
5 
STUDY DRUG ADMINISTRATION AND MANAGEMENT 
5.1 Dose Preparation and Administration 
Each subject will receive study treatment according to the randomization scheme. 
The study drug will be provided in capsule form for oral administration. Subjects will 
be instructed to take the capsules with water twice a day, one capsule after waking 
in the morning and one before bed, ideally 12 hours apart and no less than 6 hours 
apart. 
5.2  Randomization to Treatment Groups 
Subjects who meet all eligibility criteria will enter the treatment period and will be 
randomized 1:1:1 to receive 40 mg COR388 HCl, 80 mg COR388 HCl, or placebo 
twice a day. Randomization will be stratified by baseline MMSE (MMSE 12 and 
18, and MMSE 19 and 24) and Apolipoprotein E (ApoE4 positive either 
homozygous or heterozygous vs. all others) genotype to assure balanced 
distribution of mild and moderate AD and a balanced distribution of ApoE4 subjects, 
across treatment arms.  All participants will be centrally assigned to randomized 


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study intervention using an Interactive Response System (IRS). All subjects in the 
open label extension portion of the study will receive 40 mg or 80 mg COR388 HCl. 
5.3 Packaging and Labeling 
Study drug will be packaged in blister packs and assembled into weekly cards each 
containing 16 capsules: 2 capsules for each day of the week and 2 additional 
capsules to be used only if instructed by the Investigator (late visits, damaged or lost 
capsules, etc.). The capsules will be identical in appearance, but their contents will 
depend on the subject’s treatment assignment. The cards containing the blister 
packed capsules will be labeled in compliance with country-specific labeling 
requirements.  
5.4 Study Drug Supply, Storage, and Handling 
5.4.1 COR388 HCl 
The COR388 HCl capsules are orange, opaque, size 3 hydroxypropyl 
methylcellulose (HPMC) capsules containing the appropriate dose of COR388 HCl 
based on the treatment arm.  The capsules should be stored at room temperature.  
The study drug will be kept in a secure location that is accessible only to study 
personnel whom the Investigator has authorized to dispense/prepare study drug. 
5.4.2 Placebo 
The placebo capsules are orange, opaque, size 3 HPMC capsules containing 
microcrystalline cellulose. Placebo capsules must be stored at room temperature.  
The placebo capsules will be kept in a secure location that is accessible only to 
study personnel whom the Investigator has authorized to dispense/prepare study 
drug. 
5.4.3 Unblinding of Individual Study Subjects  
From Screening (Visit 1) through the Safety Follow-up Visit (Visit 11), the 
Investigator should not become unblinded unless knowledge of the treatment is 
required for the subject’s safety and medical care. 
In the event of an SAE requiring identification of the study drug administered to an 
individual subject, the Investigator will access the IRS using the emergency 
unblinding instructions. The IRS will record the name of the Investigator making the 
request, the date and time of the request, and the subject number and age. The 
Sponsor will be informed within 24 hours if unblinding occurs. 
The Investigator will attempt to consult with the Medical Monitor regarding the need 
to unblind the treatment assignment for the subject, if time allows. At all times, the 
safety and well-being of any subject outweighs the need to consult with the Medical 
Monitor. In any event, the Investigator will contact the Medical Monitor and 


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Cortexyme within 24 hours of breaking the blind. The Investigator will be responsible 
for documenting the time, date, and reason for the unblinding and the names of the 
personnel involved. Every effort should be made to avoid unblinding other study 
personnel. 
5.5 Drug Inventory and Accountability 
The Investigator must keep an accurate accounting of the number of investigational 
product units delivered to the site, dispensed to subjects, returned to the Investigator 
by the subject, and returned to the Sponsor or other disposition during and at the 
completion of the study. The investigational product must be dispensed to subjects 
only by an appropriately qualified person. The investigational product is to be used in 
accordance with the protocol by subjects who are under the direct supervision of the 
Investigator. Investigators should maintain records that document adequately that 
the subjects were provided the doses specified by the protocol and reconcile all 
investigational products received at the site before final disposition. At the end of the 
study, or as directed, all study drugs, including unused, partially used, and empty 
containers, will be returned to the Sponsor/designee or will be destroyed. 
5.6 Treatment Compliance 
Investigational product containers must be returned at each visit, as compliance will 
be assessed by capsule counts. Noncompliance is defined as taking less than 80% 
or more than 120% of investigational product during any outpatient evaluation period 
(visit to visit). Discontinuation for noncompliance is at the Investigator’s discretion 
and is to be noted on the electronic Case Report Form (eCRF). 
6 
SELECTION OF STUDY POPULATION 
Investigators should contact the Medical Monitor if they have questions about 
eligibility of specific subjects. 
6.1 Inclusion Criteria 
Subjects will be eligible to participate in this study if they meet all of the following 
criteria: 
1. Subject has provided full written informed consent prior to the performance of 
any protocol-specified procedure; or if unable to provide informed consent 
due to cognitive status, subject has provided assent and a legally authorized 
representative has provided full written informed consent on behalf of the 
subject. 
2. Caregiver has provided full written informed consent, on a separate informed 
consent form (ICF), on his/her own behalf prior to the performance of any 
protocol-specified procedure.  


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 Male and female subjects must be 55 years to 80 years of age, at the time of
consent.
 Subject has probable AD dementia according to the NIA-AA criteria
(McKhann 2011) with clinical evidence of progressive cognitive decline in the
last year. Clinical decline will be determined based on serial cognitive test
scores, if available, or subject/caregiver report as documented by the
Investigator.
 Subject has an MMSE score between 12 and 24 inclusive at both screening
and Visit 2 and a 3-point difference between these visits.
 Subject has a Modified Hachinski score 4 at screening.
 Subject has brain MRI scan consistent with the diagnosis of AD performed
during the screening period. Computed Tomography scan can be used only if
the subject has an absolute contraindication for MRI.
 Subject has a primary caregiver willing to accept responsibility for supervising
the treatment (e.g., administering study drug), accompanying the study
subject to clinic visits and assessing the condition of the subject throughout
the study in accordance with all protocol requirements.
 Subject is not likely to experience a change in living conditions (e.g.,
institutionalization, moving to a different city, etc.), or change in primary
caregiver, during participation in the trial.
 Subjects with background symptomatic therapy with acetylcholinesterase
inhibitors, and/or memantine, are allowed as long as the dose has been
stable for 90 days prior to screening and no changes are planned during the
study.
 Subjects who have occasional use of sedative agents are acceptable, but
these agents should not be given within 48 hours prior to cognitive
assessments.
 Subjects who have background medications used for stable chronic illnesses
that are not prohibited by the protocol are allowed. The dose of psychoactive
drugs must be stable for 30 days prior to screening, and no changes must be
planned during the study unless for safety reasons.
 Subject has body mass index <38 kg/m2 at Screening.
 Subject must be able to ingest oral medications and can swallow the study
drug without breaking or crushing.
 Subject must be willing to undergo Apolipoprotein E genotype (ApoE) genetic
testing (ApoE results may be disclosed after trial completion).
 Subjects participating in the study must meet one of the following criteria:
D Females: Surgically sterilized (e.g., hysterectomy, bilateral
oophorectomy or tubal ligation) for at least 6 months or
postmenopausal (postmenopausal females must have no menstrual
bleeding for at least 1 year). If not postmenopausal, agree to use a
highly effective method of contraception that can achieve a failure rate


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of less than 1% per year when used consistently and correctly, such as 
hormonal contraception or a double barrier method (e.g., intrauterine 
device plus condom or true abstinence defined as in line with the 
preferred and usual lifestyle of the subject. Periodic abstinence e.g. 
calendar, ovulation, symptothermal, post-ovulation methods are not 
acceptable. Declaration of abstinence for the duration of a trial, and 
withdrawal are not acceptable methods of contraception) from 30 days 
prior to dosing until 30 days after last dose and have negative human 
chorionic gonadotropin (ȕ-hCG) test for pregnancy at screening.  
b. Males who have not had a vasectomy must use appropriate
contraception methods (barrier or true abstinence defined as in line
with the preferred and usual lifestyle of the subject. Periodic
abstinence e.g. calendar, ovulation, symptothermal, post-ovulation
methods are not acceptable. Declaration of abstinence for the duration
of a trial, and withdrawal are not acceptable methods of contraception)
from 30 days prior to dosing until 90 days after last dose.
Open Label Extension: Subjects will be eligible to participate in the open label 
extension portion of the study if they meet inclusion criteria # 8, 9, 10, 11, 12, 14, 
and 16 above. Subjects with any change in their medical history that in the 
Investigator’s opinion will increase the subject’s risk of participating in the study or 
confounding study assessment should not continue in the open label extension 
portion of the study. The Investigator should contact the Sponsor with questions of 
eligibility for participation. NOTE: Effective 16 February 2021, the OLE portion of the 
study was terminated by the Sponsor. 
6.2 
Exclusion Criteria 
Subjects will not be eligible to participate in this study if they meet any of the 
following exclusion criteria:  
1. Subject has imaging consistent with other differential dementia diagnoses
other than the diagnosis of AD. For example, any suggestion of vascular
disease including multiple infarction involving large blood vessels or localized
single infarction (angular gyrus, thalamus, anterior cerebral artery and
posterior cerebral artery region), multiple lacunae of the basal nuclei or white
matter or extensive lesions of the periventricular white matter or combination
of several lesions are considered exclusionary. Additionally, any single lacune
in an area known to impact cognition such as the hippocampus will also be
exclusionary. Finally, Probable CAA with/without supporting pathological
evidence according to the modified Boston criteria, if in the opinion of the
investigator this may be contributing to symptoms overlapping with those of
AD or confound neuropsychological assessments, would be exclusionary.
Importantly, should there be any evidence of neurologic symptoms between
scanning and baseline visits, rescanning is necessary to ensure proper
patient selection.


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2. Subject has had an increase or restoration of cognition based on medical
history.
3. Subjects who meet the following imaging exclusion criteria will not be
included in this study:
a. Claustrophobia that will result in significant anxiety and difficulty lying
still for brain imaging (MRI or CT scan).
b. Severe motor problems or chronic pain indication that prevents the
subject from lying still for brain imaging.
4. Subject with history of cancer requiring systemic therapy in the last 5 years;
except for localized cancer of the skin and in-situ cervical cancer successfully
treated with surgical excision. Stable (for at least 90 days) prostate cancer is
allowed.
5. Subject has a contraindication for LP, such as infected skin over the needle
entry site, possible increased intracranial pressure, severe thrombocytopenia
or coagulopathy, suspected spinal epidural abscess, or spinal structural
abnormalities that would interfere with LP procedures.
6. Subject has evidence of clinically significant unstable cardiovascular,
pulmonary, renal, hepatic, gastrointestinal, neurologic or metabolic disease
within 6 months prior to Screening.
7. Subject has any of the following cardiovascular conditions:
a. Unstable angina, uncompensated and/or symptomatic congestive heart
failure (Grade 2 or higher on the New York Heart Association scale) or,
myocardial infarction within 6 months.
b. Acute or poorly controlled blood pressure >180 mmHg systolic or
>100 mmHg diastolic.
c. Current, or recent history of, any of the following that are clinically
significant in the investigator's judgment:  arrhythmia, hypotension,
heart block (1st, 2nd or 3rd degree AV block), ANY bundle branch
block, ventricular pacing, symptomatic ectopy, unstable arrhythmias
including atrial fibrillation; stable atrial fibrillation is allowed.
d. History of prolonged QT or prolonged QT on screening ECG
(QTcF 480 msec).
e. History of prolonged PR interval or prolonged PR interval on screening
ECG (PR >210 msec).
f.
History of prolonged QRS interval or prolonged QRS interval on
screening ECG (QRS >120 msec).
g. Supraventricular or ventricular ectopy on the screening ECG or
Brugada pattern on the ECG.


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8. Subject with major stroke, uncontrolled seizure disorder, or other medical
illnesses that in the Investigator’s opinion will increase the subject’s risk of
participation in the study or confound study assessments.
9. Subject with history or current evidence of major neurological or psychiatric
illness such as schizophrenia, bipolar disorder, Parkinson’s Disease, etc.
Subjects with major depressive disorder that may interfere with the patient’s
ability to perform the study and all assessments. NOTE: Mild depression or
depressive mood arising in the context of AD are not criteria for exclusion.
The use of anti-depressants or the use of anti-epileptic medication for non-
seizure-related treatment is allowed if the dose has remained stable for at
least 60 days prior to enrollment.
10. Subject with history of violent or aggressive behavior that requires medication
to control.
11. Subjects with active suicidal thoughts (Type 4 or 5 on the C-SSRS) in the
6 months preceding screening or at baseline; or have a history of a suicide
attempt in the previous 2 years, or more than 1 lifetime suicide attempt; or are
at serious suicide risk in the Investigator’s clinical judgment.
12. Subject with history of alcohol or drug use disorder within 12 months of
screening as defined by the Diagnostic and Statistical Manual of Mental
Disorders-5.
13. Subject with previous treatment with investigational vaccine therapy for AD.
14. Subject has participated in another Investigational New Drug (IND) research
study involving small molecule drugs within 60 days or biological drugs within
90 days prior to the first dose of study drug or 5 half-lives of the
investigational drug, whichever is longer.
15. Subject has a history of epilepsy or seizure disorder requiring ongoing
treatment, or any seizure or loss of consciousness within 6 months prior to
enrollment.
16. Subject has any of the following laboratory findings at screening:
a. Alanine aminotransferase >3 x upper limit of normal (ULN), aspartate
aminotransferase >3 x ULN, or history of clinically significant liver
disease in the Investigator’s judgment.
NOTE: Subjects with ALT or AST >2 x ULN at Visit 9/Week 40 will not
be eligible to participate in OLE.
NOTE: Effective 16 February 2021, the OLE portion of the study was
terminated by the Sponsor.
b. Hemoglobin 10 g/dl.
c. International Normalized Ratio (INR) >1.5 or total bilirubin >1.5 x ULN
(unless subject has evidence of Gilbert’s disease).
d. Creatinine clearance (CL) of <45 ml/min.
e. Poorly controlled diabetes as defined by hemoglobin A1C (HbA1C) >8.


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f.
Positive blood screen for Human Immunodeficiency Virus (HIV 1 and
2), Hepatitis B surface antigen (HBsAg), or Hepatitis C virus antibodies
(HCV-Ab) at Screening.
g. Positive urine screen for drugs of abuse that include opiates, cocaine,
amphetamines, or barbiturates.
17. Subject has abnormal laboratory tests that suggest an alternate etiology for
dementia, such as serum vitamin B12 deficiency, thyroid function abnormality,
severe anemia, electrolyte abnormality, or positive syphilis serology. In these
cases, the patient should be re-evaluated to determine if these potential
causes of dementia have been addressed. Only if these causes have been
ruled out as the cause of the dementia can the patient be enrolled.
18. Use of systemic (i.e., oral, intravenous, etc., but not topical) antibiotics in the
last 60 days or history of recurrent infection that requires chronic or repeated
courses of antibiotics.
Open Label Extension: Subjects will not be eligible to participate in open label 
extension portion of the study if they meet any of the following exclusion criteria # 1, 
4, 6, 7, 8-12, 15, 16 a, b, c, d and e. Laboratory testing and ECG results from Visit 9 
will be used to evaluate eligibility. Subjects with any change in their medical history 
that in the Investigator’s opinion will increase the subject’s risk of participating in the 
study or confounding study assessment should not continue in the open label 
extension portion of the study. The Investigator should contact the Sponsor with 
questions of eligibility for participation. NOTE: Effective 16 February 2021, the OLE 
portion of the study was terminated by the Sponsor. 
6.3 Subject Restrictions 
6.3.1 Prior and Concomitant Medications 
Subjects will not be allowed to use medications or combinations containing 
medications from prohibited classes during participation in the study (i.e., from 
Screening (Visit 1) through Safety Follow-up Visit 11 or Visit OLE-9 for subjects 
participating in OLE. Prohibited concomitant medication classes include: 
anticholinergics, CNS-penetrant antihistamines, and antipsychotics.  
The use of prescribed benzodiazepines and sedatives/hypnotics are allowed during 
the study but should not be used 48 hours before any study visit with cognitive 
testing.  
The use of prescribed acetyl cholinesterase inhibitors (e.g., donepezil, rivastigmine, 
etc.) or memantine is allowed during the study as long as the dose has been stable 
for at least 90 days prior to Screening and there are no plans to modify the dose or 
stop treatment during the study. Switching to a different drug in the same class is 
prohibited during the study.  
The use of prescribed medication for stable chronic illnesses, including psychoactive 
drugs, is allowed during the study as long as the medication class is not prohibited, 


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the dose has been stable for at least 30 days prior to Screening, and there are no 
plans to modify the dose or stop treatment during the study. Starting new medication 
during participation in the study should be avoided, unless deemed necessary by the 
Investigator. 
Systemic (i.e., oral, intravenous, etc., but not topical) antibiotics are prohibited in the 
last 60 days prior to Screening (Visit 1), or history of recurrent infection that requires 
chronic or repeated courses of antibiotics. 
Patients requiring treatment with prophylactic antibiotics in order to undergo 
minimally invasive oral examination procedures (measurements of pocket depth, 
gingival margin and bleeding on probing) due to preexisting medical conditions such 
as artificial heart valve, history of rheumatic fever or recent (within a year) joint 
replacement surgery, or currently receiving immunosuppressive therapy are eligible 
to participate in the study; however, they should be excluded from participating in 
oral examinations. 
The use of any over-the-counter medicinal products, including herbal and dietary 
supplements, are allowed unless, in the opinion of the Investigator, the 
administration of the over-the-counter medicinal product could affect the subject’s 
safety or the results of the study. 
All medications (including drug name, dose, and dose regimen) administered from 
30 days prior to Visit 1 through the Safety Follow-up Visit (Visit 11) will be recorded 
in the source documents and on the Prior and Concomitant Medication electronic 
Case Report Form (eCRF). 
7 
STUDY VISITS 
The study will consist of 3 periods: Screening period up to 6 weeks, treatment period 
up to 48 weeks, and a safety follow-up period of 6 weeks. When feasible, study visits 
should be performed at the same time of day for the same subject. 
7.1 Screening: Visit 1 (Day -42 to Day -1) 
During the screening period, the eligibility of subjects will be confirmed according to 
the Schedule of Evaluations in this protocol (see Table 1). The following evaluations 
will be performed at Screening in the following order as close as possible when 
feasible: 
1. Obtain informed consent from subject, and caregiver informed consent signed
by the primary caregiver;
2. Past medical history and confirmation of cognitive decline in the last
12 months;
3. Concomitant medications;
4. Inclusion/exclusion criteria for eligibility;
5. Modified Hachinski;
6. Columbia-Suicide Severity Rating Scale (C-SSRS);


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7. Mini-Mental State Examination (MMSE). Subjects with MMSE score of 12-24, 
inclusive, will have the rest of their screening procedures performed or 
scheduled); 
8. Alzheimer’s Disease Assessment Scale-Cognitive Subscale 11 
(ADAS-Cog 11); 
9. Clinical Dementia Rating, Sum of Boxes (CDR-SB); 
10. Winterlight Speech Assessment (only in English speaking (primary language 
subjects and only in the US and UK); 
11. 12-lead electrocardiogram (ECG); 
12. Weight; 
13. Vital signs; 
14. Full physical examination, including height and body mass index (BMI) 
calculation; 
15. Urine drug screen; 
16. Urine pregnancy test (women of child bearing potential only); 
17. Blood/urine sample collection for: 
a. Serology (Hepatitis C virus antibodies [HCV-Ab], Hepatitis B surface 
antigen [HBsAg], Human Immunodeficiency Virus [HIV] 1 and 2); 
b. Apolipoprotein E (Apo E) genotyping;  
c. Follicle stimulating hormone (FSH) for peri-menopausal (irregular 
menstrual periods) or post-menopausal (no menstrual period for 
>12 months) female subjects;  
d. Vitamin B12 
e. Thyroid function tests 
f. Syphilis 
g. Pregnancy test (only if urine pregnancy test is positive); and 
h. Safety laboratory tests; 
18. Saliva collection; 
19. Oral examination and collection of oral biomarker samples (subgingival 
plaque [SGP] and buccal cell swabs) (only at selected sites); and 
20. Magnetic resonance imaging (MRI) of the brain. Computed Tomography (CT) 
scans of the brain can used instead of MRIs only in subjects who have an 
absolute contraindication for MRI. 
Screening procedures can be done on multiple days if needed, with more invasive 
procedures done after other screening procedures are completed. A screen failure is 
any subject who signs the informed consent but does not qualify for the study or 
discontinues the study prior to randomization. A subject can be rescreened if the 
Principal Investigator thinks the subject may qualify for the study upon rescreening, 
and if the Medical Monitor agrees. 
7.2 Study Treatment: Visit 2 (Day 0) 
Subjects who meet all of the eligibility criteria will be scheduled for Visit 2.  
Note: To accommodate the logistics of performing the baseline LP procedure, a 
separate visit within 7 days prior to V2/Day 0 may be scheduled. At this visit, 


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baseline MMSE score will be verified, and the LP procedure will be performed. The 
remaining V2 assessments must be completed at Day 0, when the first dose of study 
drug will be administered. 
The following evaluations will be performed at this visit in the following order or as 
close as possible when feasible: 
1. MMSE;  
2. Lumbar puncture to collect cerebrospinal fluid (CSF) may be conducted up to 
7 days prior to other procedures listed below; 
3.  Inclusion/exclusion criteria to assess for continued eligibility.  
4. ADAS-Cog 11;  
5. Alzheimer's Disease Cooperative Study Group - Activities of Daily Living 
(ADCS-ADL); 
6. CDR-SB; 
7. Randomization; 
8. Concomitant medications; 
9. Symptom-based physical examination;  
10. Vital signs; 
11. Neuropsychiatric Inventory (NPI); 
12. C-SSRS; 
13. Urine drug screen; 
14. Blood/urine sample collection: 
a. Pharmacokinetics (PK): A pre-dose trough sample will be drawn 
immediately prior to the AM dose.  The exact times of AM dosing and 
PK sample collections at the site will be documented.  
b. Serum and whole blood (peripheral blood mononuclear cells [PBMCs]) 
for biomarkers; and 
c. Safety laboratory tests; 
15. Saliva collection; 
16. Winterlight Speech Assessment (only in English speaking (primary language) 
subjects and only in the US and UK); 
17. Adverse events;  
18. Administer study drug at the site;  
19. 12-lead ECG 1-1.5 hours post-dose; 
20. Blood sample collection: Second PK blood draw 30 minutes to 4 hours post-
dose; and 
21. Dispense study drug. 
 
A screen failure is any subject who signs the informed consent but does not qualify 
for the study or discontinues the study prior to randomization. A subject can be 
rescreened if the Principal Investigator thinks the subject may qualify for the study 
upon rescreening, and if the Medical Monitor agrees. 


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7.3 Study Treatment: Visit 3 (Day 14 ± 2) 
Note: Please make every effort possible to have the visit scheduled in the morning 
so the AM dose can be taken in the morning. Ideally, daily doses should be taken 12 
hours apart and no less than 6 hours apart. 
The following evaluations will be performed at this visit: 
1. Concomitant medications; 
2. Symptom-based physical examination; 
3. Vital signs; 
4. C-SSRS; 
5. Blood/urine sample collection: 
a. Safety laboratory tests; and 
b. PK - A pre-dose trough sample will be drawn. The exact times of AM 
dosing and PK sample collections at the site will be documented. 
6. 12-lead ECG before dosing drug (trough)  
7. Administer study drug at the site; 
8. Adverse events;  
9. 12-lead ECG 1-1.5 hours post-dose; 
10. Blood sample collection: Second PK blood draw 60 minutes ± 30 minutes 
post-dose; and 
11. Dispense study drug. 
7.4 Study Treatment: Visit 4 (Day 42 ± 3)  
The following evaluations will be performed at this visit: 
1. Concomitant medications; 
2. Symptom-based physical examination; 
3. Vital signs; 
4. C-SSRS; 
5. Blood/urine sample collection: 
a. Safety laboratory tests; 
6. 12-lead ECG; 
7. Adverse events; and  
8. Dispense study drug. 
7.5 Study Treatment: Visit 5 (Day 84 ± 3)  
The following evaluations will be performed at this visit in the following order or as 
close as possible when feasible: 
1. ADAS-Cog 11; 
2. MMSE; 
3. ADCS-ADL; 
4. CDR-SB; 
5. Concomitant medications; 


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6. Symptom-based physical examination; 
7. Vital signs; 
8. C-SSRS; 
9. Winterlight Speech Assessment (only in English speaking (primary language 
subjects and only in the US and UK); 
10. Blood/urine sample collection: 
a. Safety laboratory tests; 
11. 12-lead ECG; 
12. Adverse events; and 
13. Dispense study drug. 
7.6  Study Treatment: Visit 6 (Day 126 ± 3)  
The following evaluations will be performed at this visit in the following order or as 
close as possible when feasible: 
1. Concomitant medications;  
2. Symptom-based physical examination; 
3. Vital signs;  
4. C-SSRS; 
5. Blood/urine sample collection: 
a. Safety laboratory tests; and 
6. Adverse events. 
7.7 Study Treatment: Visit 7 (Day 168 ± 3)  
Note: Please make every effort possible to have the visit scheduled in the morning 
so the AM dose can be taken in the morning. Ideally, daily doses should be taken 12 
hours apart and no less than 6 hours apart. 
The following evaluations will be performed at this visit in the following order or as 
close as possible when feasible: 
 
1. ADAS-Cog 11; 
2. MMSE; 
3. ADCS-ADL; 
4. CDR-SB; 
5. NPI; 
6. Winterlight Speech Assessment (only in English speaking (primary language 
subjects and only in the US and UK); 
7. Concomitant medications; 
8. Oral examination and collection of oral biomarker samples (SGP and buccal 
cell swabs) (only at selected sites); 
9. Saliva collection;  
10. Symptom-based physical examination; 
11. Vital signs; 


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12. C-SSRS; 
13. Blood/urine sample collection: 
a. Safety laboratory tests; 
b. PK - A pre-dose trough sample will be drawn and the subject will then 
take their dose of study drug on-site. The exact times of AM dosing 
and PK sample collections at the site will be documented. 
c. Serum and whole blood (PBMCs) for biomarkers; 
14. Adverse events; 
15. 12-lead ECG before dosing drug (trough); 
16. Administer study drug at the site; 
17. 12-lead ECG 1-1.5 hours post-dose; 
18. Blood sample collection: Second PK blood draw 2 hours ± 30 minutes post-
dose; and 
19. Dispense study drug. 
7.8 Study Treatment: Visit 8 (Day 224 ± 3)  
The following evaluations will be performed at this visit in the following order or as 
close as possible when feasible: 
1. Concomitant medications;  
2. Symptom-based physical examination; 
3. Vital signs;  
4. C-SSRS; 
5. Blood/urine sample collection: 
a. Safety laboratory tests; and 
6. Adverse events. 
7.9 Study Treatment: Visit 9 (Day 280 ± 8)  
Note: Please make every effort possible to have the visit scheduled in the morning 
so the AM dose can be taken in the morning. Ideally, daily doses should be taken 12 
hours apart and no less than 6 hours apart. 
The following evaluations will be performed at this visit in the following order as 
close as possible when feasible: 
1. Administer study drug at the site 
2. Blood/urine sample collection 
a. Safety laboratory tests; 
b. PK – A single post-dose sample will be drawn from each subject while 
on-site at the clinic at 3 hours ± 30 minutes post-dose. The exact times 
of AM dosing and PK sample collection at the site will be documented. 
3. Adverse events; 
4. 12-lead ECG 1-1.5 hours post-dose;   
5. ADAS-Cog 11; 
6. MMSE; 


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7. ADCS-ADL; 
8. CDR-SB; 
9. Concomitant medications; 
10. Symptom-based physical examination; 
11. Vital signs; 
12. C-SSRS; and 
13. Dispense study drug. 
7.10 Study Treatment: Visit 10/Early Termination (Day 336 ± 8)  
Note: To accommodate the logistics of performing the LP procedure, it may be done 
up to 7 days prior to V10/Day 336. Please make every effort possible to have the 
visit scheduled in the morning so the AM dose can be taken in the morning. Ideally, 
daily doses should be taken 12 hours apart and no less than 6 hours apart. 
The following evaluations will be performed at this visit or at Early Termination in the 
following order as close as possible when feasible: 
 
1. Administer last dose of double-blind study drug at the site; 
2. Blood/urine sample collection: 
a. Safety laboratory tests; 
b. PK - A single post-dose sample will be drawn from each subject while 
on-site at the clinic at 4 hours ± 30 minutes post-dose. The exact times 
of AM dosing and PK sample collections at the site will be 
documented.  
c. Serum and whole blood (PBMCs) for biomarkers; 
d. Pregnancy test (only if urine pregnancy test is positive); 
3. Adverse events;  
4. Oral examination and collection of oral biomarker samples (SGP and buccal 
cell swabs) at selected sites (will be completed within 8 days before Visit 10 
[or Early Termination] when applicable). 
5. 12-lead ECG 1-1.5 hours post-dose 
6. MRI of the brain, only in subjects who had a screening MRI performed, and 
has to be done within 8 days prior to Visit 10. CT scans of the brain can be 
used instead of MRIs, only in subjects who have an absolute contraindication 
for MRI; 
7. ADAS-Cog 11; 
8. MMSE; 
9. ADCS-ADL; 
10. CDR-SB; 
11. NPI; 
12. Winterlight Speech Assessment (only in English speaking (primary language 
subjects and only in the US and UK); 
13. Concomitant medications; 
14. Symptom-based physical examination; 
15. Saliva collection; 


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16. Weight; 
17. Vital signs; 
18. Lumbar puncture to collect CSF;
19. Urine pregnancy test (women of child bearing potential only);
20. C-SSRS; 
21. Informed consent will be obtained for subjects who agree to participate in the
open label extension portion of the study; and
22. Inclusion/exclusion will be evaluated to determine eligibility for subjects who
want to participate in the open label extension portion of the study.
Dispense OLE study drug – subjects who participate in OLE only. The subject
should be instructed to take the first dose of COR388 in the morning of the
next day.
NOTE: Effective 16 February 2021, the OLE portion of the study was
terminated by the Sponsor.
7.11 Safety Follow-up Phone Calls: (Days 343 ± 2 and 357 ± 2) 
Adverse events and any changes to concomitant medications will be evaluated during 
these phone calls. The follow-up phone calls will be structured and scripted to ensure 
completeness and standardization. The general structure of the inquiry will be open 
ended inquiry about any new symptoms, specific questioning about any reported sign 
or symptom and then a structured questioning about neurologic and withdrawal sign 
and symptoms by body system as seen with benzodiazepines and opiates and 
amphetamines.  These will be conducted after either Visit 10 or Early Termination.  
NOTE: Subjects who choose to participate in the open label extension portion of the 
study will not complete the safety follow-up phone calls and continue with the 
Schedule of Evaluations in Table 2.   
NOTE: Effective 16 February 2021, the OLE portion of the study was terminated by 
the Sponsor. 
7.12 Safety Follow-up Visit: Visit 11 (Day 378 ± 8) 
After completion of study treatment, subjects will continue to be monitored on the 
study for 6 weeks and will return for the Safety Follow-up Visit (Week 54). 
For subjects with early termination, end of study procedures (Week 48) will be 
performed, and subjects will be encouraged to return to the clinic for the Safety 
Follow-up Visit after 6 weeks. 
NOTE: Subjects who choose to participate in the open label extension portion of the 
study will not complete the safety follow-up visit and continue with the Schedule of 
Evaluations in Table 2. 
NOTE: Effective 16 February 2021, the OLE portion of the study was terminated by 
the Sponsor. 


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The following evaluations will be performed at this visit in the following order or as 
close as possible when feasible: 
1. ADAS-Cog 11;
2. MMSE;
3. ADCS-ADL;
4. CDR-SB;
5. Concomitant medications;
6. Saliva collection;
7. Symptom-based physical examination;
8. Vital signs;
9. C-SSRS;
10. Blood/urine sample collection:
a. Safety laboratory tests
11. 12-lead ECG; and
12. Adverse events. 
7.13 Increased Safety Laboratory Monitoring (Liver Safety Monitoring) 
Per DMC recommendation (following the November 16, 2020 meeting) the following 
increased laboratory analyte testing is being implemented: 

Every 2 weeks for the initial 12 weeks

Every 3 weeks as of Week 12 through Week 24

Every 4 weeks as of Week 24 through Week 32
Liver Safety Monitoring (laboratory analyte testing) must be performed at each 
study visit within the prespecified visit window (see Table 1, Schedule of 
Evaluations) OR the study drug dosing must be interrupted until the testing is done.  


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7.14 Open Label Extension (OLE) 
NOTE: Effective 16 February 2021, the OLE portion of the study was terminated by 
the Sponsor. 
 
Subjects who complete Visit 10 may be eligible to participate in the open label 
extension portion of the study. If subjects meet inclusion and none of the exclusion 
criteria, and sign the informed consent, they will continue in the open label extension 
portion and not complete the Safety Follow-up Phone Calls or the Safety Follow-up 
Visit: Visit 11 (Day 378 ± 8). Laboratory testing and ECG results from Visit 9 will be 
used to evaluate eligibility. 
Subjects who are not eligible or do not consent to the open label extension will 
proceed to the Safety Follow-up Phone Calls (Days 343 ± 2 and 357 ± 2) and the 
Safety Follow-up Visit: Visit 11 (Day 378 ± 8). 
7.15 OLE Study Treatment: Visit OLE-1 (Day 350 ± 3)  
The following evaluations will be performed at this visit in the following order or as 
close as possible when feasible: 
1. Concomitant medications; 
2. Symptom-based physical examination; 
3. Vital signs; 
4. C-SSRS; 
5. 12-lead ECG; 
6. Blood/urine sample collection: 
a. Safety laboratory tests; 
7. Adverse events; and 
8. Dispense study drug. 
7.16 OLE Study Treatment: Visit OLE-2 (Day 378 ± 3)  
The following evaluations will be performed at this visit in the following order or as 
close as possible when feasible: 
1. Concomitant medications; 
2. Symptom-based physical examination; 
3. Vital signs; 
4. C-SSRS; 
5. 12-lead ECG;  
6. Blood sample collection:  
a. Safety laboratory tests; 
7. Adverse events; and 
8. Dispense study drug. 


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7.17 OLE Study Treatment: Visit OLE-3 (Day 420 ± 3)  
The following evaluations will be performed at this visit in the following order or as 
close as possible when feasible: 
1. ADAS-Cog 11; 
2. ADCS-ADL; 
3. CDR-SB; 
4. Concomitant medications; 
5. Symptom-based physical examination; 
6. Vital signs; 
7. C-SSRS; 
8. Blood/urine sample collection: 
a. Safety laboratory tests; 
9. Adverse events; and 
10. Dispense study drug. 
7.18 OLE Study Treatment: Visit OLE-4 (Day 504 ± 3)  
The following evaluations will be performed at this visit in the following order or as 
close as possible when feasible: 
1. ADAS-Cog 11;  
2. ADCS-ADL; 
3. CDR-SB; 
4. Concomitant medications; 
5. Saliva collection; 
6. Symptom-based physical examination; 
7. Vital signs; 
8. C-SSRS; 
9. 12-lead ECG;  
10. Blood sample collection:  
a. Safety laboratory tests; 
11. Adverse events; and 
12. Dispense study drug. 
7.19 OLE Study Treatment: Visit OLE-5 (Day 588 ± 6)  
The following evaluations will be performed at this visit in the following order or as 
close as possible when feasible: 
1. Concomitant medications; 
2. Symptom-based physical examination; 
3. Vital signs; 
4. C-SSRS; 
5. Blood/urine sample collection: 
a. Safety laboratory tests; 


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6. Adverse events; and 
7. Dispense study drug. 
7.20 OLE Study Treatment: Visit OLE-6/Early Termination (Day 672 ± 8)  
The following evaluations will be performed at this visit in the following order or as 
close as possible when feasible: 
1. ADAS-Cog 11; 
2. ADCS-ADL; 
3. CDR-SB; 
4. Concomitant medications; 
5. Saliva collection; 
6. Symptom-based physical examination; 
7. Weight 
8. Vital signs; 
9. C-SSRS; 
10. 12-lead ECG;  
11. Urine pregnancy test (women of child bearing potential only); 
12. Blood sample collection:  
a. Safety laboratory tests; 
b. Pregnancy test (only if urine pregnancy test is positive);  
13. Adverse events. 
14. Oral examination and collection of oral biomarker samples (SGP and buccal 
cell swabs) at selected sites (will be completed within 8 days before Visit 
OLE-6 [or Early Termination] when applicable). 
7.21 OLE Safety Follow-up Phone Calls: Visits OLE-7 and OLE-8 (Days 679 ± 2 
and 686 ± 2) 
Adverse events, the C-SSRS, and any changes to concomitant medications will be 
reviewed and evaluated during these phone calls. The follow-up phone calls will be 
structured and scripted to ensure completeness and standardization. The general 
structure of the inquiry will be open ended inquiry about any new symptoms, specific 
questioning about any reported sign or symptom and then a structured questioning 
about neurologic and withdrawal sign and symptoms by body system as seen with 
benzodiazepines and opiates and amphetamines. These will be conducted after 
either Visit OLE-6 or Early Termination.   
OLE Safety Follow-up Visit: Visit OLE-9 (Day 714 ± 8)  
The following evaluations will be performed at this visit in the following order or as 
close as possible when feasible: 
1. ADAS-Cog 11; 
2. ADCS-ADL; 
3. CDR-SB; 
4. Concomitant medications; 


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5. Saliva collection;
6. Symptom-based physical examination;
7. Vital signs;
8. C-SSRS;
9. 12-lead ECG;
10. Blood sample collection:
a. Safety laboratory tests;
11. Adverse events. 
Increased Safety Laboratory Monitoring (Liver Safety Monitoring) 
Per DMC recommendation (following the November 16, 2020 meeting), the following 
increased laboratory analyte testing is being implemented: 

Every 2 weeks for the initial 12 weeks

Every 3 weeks as of Week 60 through Week 72

Every 6 weeks as of Week 72 through Week 84
Liver Safety Monitoring (laboratory analyte testing) must be performed at 
each study visit within the prespecified visit window (see Table 2, Schedule of 
Evaluations) OR the study drug dosing must be interrupted until the testing is 
done.  
7.22 Unscheduled Visit(s) 
Subjects may return for an unscheduled visit at any time and evaluations will be 
performed, as necessary in the judgment of the Investigator.    
7.23 Allowances in the Circumstance of a Public Health Emergency 
If an investigative site or the patients associated with that site experience a public 
health emergency, such as a pandemic, then throughout that time, the following 
changes to what is written elsewhere in this protocol are permissible at the discretion 
of the PI: 
•
At-home and/or virtual visits: Even when an investigative site
remains open to clinical trial patients coming on site, social distancing
strategies may result in some patients being unwilling or unable to
attend protocol-specific clinic visits.  For such reasons, scheduled clinic
visits may be replaced by at-home or virtual visits. This may include
visits by Study Site staff (or home healthcare providers, if applicable)
or virtual visits by videoconference or telephone.
•
Safety assessments: Every effort should be made to continue
performing safety assessments on schedule. This may require visits by
Study Site staff (or home healthcare providers, if applicable).


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•
Transport of investigational product to support study drug 
administration: It is permissible for study drug to be shipped directlyto 
the patient and/or caregiver’s home.  It is also permissible forpatients 
or caregivers to ship used study drug back to the site.
•
Visit windows: For safety assessments, the visit windows will remain
as given in Table 1 and Table 2, Schedule of Evaluations.
•
Testing at local laboratories: If it is not practical to conduct testing on
site using kits from the central laboratory, then it is permissible to use a
local laboratory instead.
All instances when the above listed allowances are applied to the study conduct and 
its participants will be documented within the study source documents and reflected 
within the visit specific case report forms and protocol deviations log.     
8 
STUDY PROCEDURES 
8.1 Informed Consent 
For each trial subject, a written ICF will be obtained before any protocol-related 
activities at Screening (Visit 1).  An additional informed consent will be obtained at 
Visit 10 for subjects who qualify and want to participate in the open label extension 
portion of the study (NOTE: effective 16 February 2021, the OLE portion of the study 
was terminated by the Sponsor). As part of this procedure, the Investigator or a 
designated representative must explain orally and in writing the nature, duration, and 
purpose of the study, and the action of the investigational product in such a manner 
that the subject and (if applicable) subject’s legal representative are aware of the 
potential risks, inconveniences, or adverse effects that may occur. Subjects, or the 
subject’s legally authorized representative, must be given ample time to decide 
about the study participation and opportunity to inquire about details of the 
study.  Subjects should be informed that they may withdraw from the study at any 
time.  They will receive all information that is required by local regulations and 
International Conference on Harmonisation (ICH) guidelines. The Principal 
Investigator or a designated representative will provide the Sponsor or its 
representative with a copy of the Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC)-approved ICF before the start of the study. 
The subject or subject’s legally authorized representative must be given a copy of 
the signed ICF, and the original is to be maintained in the designated location at the 
site. A separate consent may be considered for subjects from sites participating in 
the dental portion of the study.  
The subject’s caregiver must also indicate their understanding of the study and their 
role as a caregiver to the subject during the study.  The subject’s caregiver must 
provide written agreement to their role as caregiver. 


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To be eligible for the study, subjects must provide an IRB/IEC-approved written 
informed consent, if mentally competent according to IRB/IEC and local guidelines 
for consenting vulnerable populations. If the subject is not able to provide written 
informed consent, written informed consent must be obtained from a legally 
authorized representative on the subject’s behalf, and written assent must be 
obtained from the subject.  
Due to the nature of AD, subjects must identify a primary caregiver prior to 
enrollment in the study who will assist the subject with study participation. The 
primary caregiver must meet specific criteria set by the protocol and be willing to 
sign a caregiver informed consent. 
8.2 Medical and Medication History 
A complete medical history will be obtained from each subject at Screening (Visit 1). 
The medical history will assess the subject for any disqualifying medical conditions 
as specified in the inclusion and exclusion criteria. The medical history will include all 
currently relevant history. When possible, only diagnoses and surgeries will be 
recorded. It is not necessary to collect history for remote, resolved conditions such 
as past pediatric illnesses or surgeries, which probably do not affect suitability of the 
subject, unless the examining physician deems these conditions relevant to the 
subject’s current health status. Medication history should include prescription and 
over the counter medications, herbs, vitamins, and minerals. 
Concomitant medications will be recorded at Screening and at all subsequent study 
visits. 
Open Label Extension: Concomitant medications will be recorded at all visits and 
phone calls. NOTE: Effective 16 February 2021, the OLE portion of the study was 
terminated by the Sponsor. 
8.3 Mini-Mental State Examination (MMSE) 
The Mini-Mental State Examination (MMSE) (Folstein 1975) is a widely used and 
validated assessment to be used to evaluate inclusion eligibility as well as an 
exploratory measure. The MMSE will be administered by a trained rater to assess 
the level of cognitive impairment. MMSE will be assessed as early in the screening 
period as possible. Subjects with MMSE score of 12-24, inclusive, will have the rest 
of their screening procedures performed or scheduled. The MMSE will be 
administered at Screening (Visit 1), Visit 2, Visit 5, Visit 7, Visit 9, Visit 10 (or Early 
Termination), and Visit 11 (Safety Follow-up Visit). The MMSE score should be 
12 and 24 at both Screening (Visit 1) and Visit 2, and a 3-point difference 
between these visits, for inclusion in the study. The MMSE takes approximately 20 
minutes to complete. 
8.4 Randomization 
Subjects who meet all eligibility criteria will enter the treatment period and will be 
randomized 1:1:1 to receive 40 mg COR388 HCl, 80 mg COR388 HCl, or placebo 


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twice a day at Visit 2. Randomization will be stratified by baseline MMSE (MMSE 
12 and 18, and MMSE 19 and 24) and Apolipoprotein E (ApoE4 positive either 
homozygous or heterozygous vs all others) genotype to assure balanced distribution 
of mild and moderate AD and a balanced distribution of ApoE4 subjects, across 
treatment arms.  All participants will be centrally assigned to randomized study 
intervention using an Interactive Response System (IRS). 
8.5 Dispense Study Drug 
Study drug will be dispensed to eligible subjects at Visit 2, Visit 3, Visit 4, Visit 5, 
Visit 7, and Visit 9. 
Open Label Extension: Study drug will be dispensed to eligible subjects at Visits 10, 
OLE-1, OLE-2, OLE-3, OLE-4 and OLE-5. Approximately the same number of 
subjects will be assigned to 80 mg and 40 mg, per the Sponsor’s instructions. 
NOTE: Effective 16 February 2021, the OLE portion of the study was terminated by 
the Sponsor. 
8.6 Alzheimer’s Disease Assessment Scale-Cognitive Subscale 11 
(ADAS-Cog 11) 
The Alzheimer's Disease Assessment Scale-Cognitive items (ADAS-Cog) is an 
11-item scale which has been widely used in AD therapeutic research to assess
memory, other cognitive functions and praxis (Mohs 1988). The ADAS-Cog 11 willbe
performed by an experienced and trained clinician as the primary endpoint to
measure cognitive ability and to evaluate change from Baseline. The ADAS-Cog 11
is to be administered at Screening (Visit 1), Visit 2, Visit 5, Visit 7, Visit 9, Visit 10 (or
Early Termination), and Visit 11 (Safety Follow-up Visit). The ADAS-Cog 11 takes
approximately 30 minutes to complete.
Open Label Extension: The ADAS-Cog 11 is to be administered at Visits OLE-3, 
OLE-4, OLE-6 (or Early Termination) and OLE-9 (OLE Safety Follow-up Visit). 
NOTE: Effective 16 February 2021, the OLE portion of the study was terminated by 
the Sponsor. 
8.7 Clinical Dementia Rating-Sum of Boxes (CDR-SB) 
The Clinical Dementia Rating Scale (Hughes 1982) is a global rating of the function of 
AD subjects assessed in six categories: memory, orientation, judgement and problem 
solving, community affairs, home and hobbies, and personal care. It is based on a 
semi-structured interview conducted with the subject and identified primary caregiver. 
The Clinical Dementia Rating-Sum of Boxes (CDR-SB) tool will be administered by a 
certified clinician and will be used to assess disease progression with cognitive and 
functional changes.  The CDR-SB will be administered at Screening (Visit 1), Visit 2, 
Visit 5, Visit 7, Visit 9, Visit 10 (or Early Termination), and Visit 11 (Safety Follow-up 
Visit). The CDR-SB takes approximately 45 minutes to 1 hour to complete. 


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Open Label Extension: The CDR-SB will be administered at Visits OLE-3, OLE-4, 
OLE-6 (or Early Termination) and OLE-9 (OLE Safety Follow-up Visit). NOTE: 
Effective 16 February 2021, the OLE portion of the study was terminated by the 
Sponsor. 
8.8 Alzheimer’s Disease Cooperative Study Group-Activities of Daily Living 
(ADCS-ADL) 
The Alzheimer’s Disease Cooperative Study Group-Activities of Daily Living 
(ADCS-ADL) will be performed to assess the subject’s ability to perform activities of 
daily living and will be administered at Visit 2, Visit 5, Visit 7, Visit 9, Visit 10 (or Early 
Termination), and Visit 11 (Safety Follow-up Visit). The ADCS-ADL takes 
approximately 20 to 25 minutes to complete. 
Open Label Extension: The ADCS-ADL will be administered at Visits OLE-3, OLE-4, 
OLE-6 (or Early Termination) and OLE-9 (OLE Safety Follow-up Visit). NOTE: 
Effective 16 February 2021, the OLE portion of the study was terminated by the 
Sponsor. 
8.9 Neuropsychiatric Inventory (NPI) 
The Neuropsychiatric Inventory (NPI) is a 12-item scale which assesses behavioral 
disturbances commonly occurring in dementia subjects. Through a structured 
interview with the identified primary caregiver 12 behavioral domains are assessed. 
The NPI will be administered by a trained clinician at Visit 2, Visit 7, and Visit 10 (or 
Early Termination). The NPI takes approximately 15 minutes to complete, depending 
on psychopathology. 
8.10 Winterlight Speech Assessment 
The Winterlight Speech Assessment is an analysis of spontaneous speech detecting 
cognitive impairment to be administered by a trained clinician at Screening (Visit 1), 
Visit 2, Visit 5, Visit 7, and Visit 10 (or Early Termination).  The Winterlight Speech 
Assessment will be administered to English speaking (primary language) subjects 
and only in the US and UK. The assessment takes approximately up to 10 minutes 
to complete. 
8.11 Saliva Collection 
Saliva will be collected at the investigative sites at Screening (Visit 1), Visit 2, Visit 7, 
Visit 10 (or Early Termination), and Visit 11 (Safety Follow-up Visit). Saliva will be 
collected using provided kits following the procedure described in the Laboratory 
Manual.  
Saliva samples collected at sites, and other oral fluids (SGP and buccal swabs) 
collected by the dentist, will be processed and shipped to the central laboratory 
according to the Laboratory Manual, for analysis of bacterial DNA and biomarkers. 


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Open Label Extension: Saliva will be collected at Visits OLE-4, OLE-6 (or Early 
Termination) and OLE-9 (OLE Safety Follow-Up Visit). NOTE: Effective 16 February 
2021, the OLE portion of the study was terminated by the Sponsor. 
8.12 Oral Examination 
An oral examination will be conducted at selected sites by a study dentist or trained 
dental hygienist, to assess for the presence of periodontitis during Screening 
(Visit 1). Subjects will have follow-up oral examinations at Visit 7, Visit 10 and Visit 
OLE-6 or Early Termination.  
Visit 10/ET and Visit OLE6/ET oral examinations may be completed up to 8 days 
prior to Visit 10 (or ET), when applicable. 
8.12.1 Oral Examination Procedures 
8.12.1.1 
Oral Examination 
The screening examination includes tooth count, identification of any hard or soft 
tissue lesions, assessment for presence of severe dental disease, determination of 
Pocket Depth (PD) and Clinical Attachment Level (CAL) at 6 sites per tooth 
(distobuccal [DB], buccal [B], mesiobuccal [MB], distolingual [DL], lingual [L], 
mesiolingual [ML]), and assessment of Bleeding on Probing (BOP). All examination 
findings will be entered into the scoring tool, which will assist in the determination of 
the presence or absence of periodontitis. Please note that subjects who are 
otherwise eligible for this GAIN trial, but do not have at least 8 teeth, can still enroll 
in the study, but they are exempt from the oral examination component of the study.   
8.12.1.2 
Measurement of Pocket Depths 
Pocket depths will be measured for each tooth present with a periodontal probe with 
1 mm gradations on 6 tooth surface sites (MB, B, DB, ML, L, DL) and will be 
rounded down to the nearest millimeter. 
8.12.1.3 
Assessment of Bleeding on Probing 
Bleeding on Probing on all 6 sites of each tooth will be recorded as present (“1”) or 
absent (“0”) immediately following the PD measures for each of the 4 probed 
sections of the dentition. 
8.12.1.4 
Measurement of Gingival Margin Position 
The distance of the gingival margin (GM) to the cementoenamel junction (CEJ) on 
each of the 6 sites on the examined teeth will be measured with a periodontal probe 
and rounded down to the nearest millimeter.   
Clinical attachment levels will be calculated as a derived variable at the time of 
statistical analysis from the recorded measures of PDs and GM to the CEJ. 


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8.12.1.5 
Determination of the Presence of Moderate to Severe 
Periodontitis 
Measurements of pocket depth (PD) and gingival margin (GM) and calculated 
attachment levels (AL) will be used to determine the presence of periodontitis 
according to the Centers for Disease Control/American Academy of Periodontology 
(CDC/AAP) criteria:  
No periodontitis  
No evidence of mild, moderate or severe periodontitis 
Mild periodontitis 
 2 interproximal sites with AL  3 mm, and  2 interproximal 
sites with PD  4 mm (not on same tooth)  
Or  
one site with PD  5 mm 
Moderate 
Periodontitis 
 2 interproximal sites with AL  4 mm (not on same tooth),  
Or  
 2 interproximal sites with PD  5 mm (not on same tooth) 
Severe 
Periodontitis  
 2 interproximal sites with AL  6 mm (not on same tooth)  
And 
 1 interproximal site with PD  5 mm 
AL will be calculated as algebraic sum of PD - GM (PD minus GM). 
8.12.2 Oral Samples Collection  
The following samples will be collected by the study dentist or dental hygienist or 
other appropriately trained site staff at Screening (Visit 1), Visit 7, Visit 10 and Visit 
OLE-6 or Early Termination (see Section 8.12.1.5). Oral samples will be sent to the 
central laboratory to be distributed to a specialty laboratory for biomarker analysis.   
8.12.2.1 Collection of Buccal Cells 
The subject will be instructed to refrain from drinking or eating 30 minutes prior to 
sample collection. Sterile cytology brushes will be used to collect 4 samples by 
twirling the crush on the inner cheek away from the teeth and gum in the oral 
quadrants. The brushes will be sent to the clinical site laboratory for processing. The 
details of sample collection and processing procedures will be provided in the 
Laboratory Manual. Buccal cell collection may take place at the dental office or main 
research clinic. 
8.12.2.2 Collection of Subgingival Plaque (SGP) 
The examiner will collect SGP samples using sterile endodontic paper point from 
teeth identified to have the maximum pocket depth by the study dentist. Multiple 
teeth can be used for sampling, and the same teeth used during the Screening visit 
will be used at the Follow-up visit in subjects with evidence of periodontitis. The 


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details of sample collection and processing procedures will be provided in the 
Laboratory Manual. 
8.13 Physical Examination 
A full physical examination will be performed at Screening (Visit 1). A full physical 
examination includes assessment of the following: head, neck and thyroid; eyes; 
ears; nose; throat; chest; lungs; heart; cervical lymph nodes; abdomen; skin; and the 
musculoskeletal and neurological systems. A symptom-based physical examination 
will be performed at all clinic visits after the Screening visit. Symptom-based physical 
examination of other organs and systems (e.g., breast, rectal, and 
genitourinary/pelvic exams) will be conducted only when clinically indicated and 
consented to by the subject. It is not necessary to collect information regarding 
well-healed surgical scars or tattoos. 
8.14 Brain Imaging 
Magnetic resonance imaging of the brain will be performed in all subjects at 
Screening (Visit 1). Subjects who have an absolute contraindication for MRI can 
have a Computed Tomography (CT) scan of the brain instead. A follow-up MRI or 
CT will be performed within 8 days prior to Visit 10 (or Early Termination) in subjects 
who had a baseline MRI performed at screening. Technical details of the MRI and 
CT scans will be provided in the Imaging Manual for the study.  
8.15 Modified Hachinski 
The Modified Hachinski ischemic scale will be utilized to differentiate Alzheimer’s 
type dementia from multi-infarct dementia and will be administered at Screening 
(Visit 1). The Modified Hachinski will be administered by a trained clinician with a 
medical background. 
8.16 Height, Weight, and Body Mass Index (BMI) 
Height (cm) and weight (kg) will be measured and BMI will be calculated only at 
Screening (Visit 1). Only weight will be measured at Visit 10 (or Early Termination). 
8.17 Vital Signs 
Vital signs will include systolic and diastolic blood pressure, pulse, respiratory rate, 
and temperature. Blood pressure and pulse will be recorded first after the subject 
has been in a supine position for at least 5 minutes. 
Vital signs will be recorded once at Screening (Visit 1), and once at each clinic visit; 
vital signs should be recorded at approximately the same time of day on each visit. 
8.18 Columbia-Suicide Severity Rating Scale (C-SSRS)  
The C-SSRS will be administered by a certified rater trained by the Research 
Foundation for Mental Health at all visits except at the Safety Follow-up Phone Calls 
after Visit 10 or Early Termination. Subjects will be assessed for both suicidal 


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behavior and suicidal ideation using the C-SSRS in order to confirm the absence of 
suicidal behavior or ideation with at least some intent to act on it (Folstein 1975; 
Columbia University Medical Center 2017). 
In the event a subject has suicidal ideation or clinically significant depression, 
appropriate action will be initiated at the discretion of the Investigator and/or Medical 
Monitor.  
Open Label Extension: The C-SSRS will be administered at all visits. NOTE: 
Effective 16 February 2021, the OLE portion of the study was terminated by the 
Sponsor. 
8.19 Laboratory Assessments 
Follicle stimulating hormone will be measured at Screening (Visit 1) for 
peri-menopausal (irregular menstrual periods) or post-menopausal (no menstrual 
period for >12 months) female subjects. A urine pregnancy test will be conducted 
only in women of child bearing potential at Screening (Visit 1) and the End of 
Treatment or Early Termination Visit (Visit 10), and at other visits only if indicated. If 
the urine pregnancy test is positive, a serum pregnancy test will be performed to 
confirm pregnancy. 
Open Label Extension: A urine pregnancy test will be conducted only in women of 
child bearing potential at the OLE End of Treatment or Early Termination Visit 
(OLE-6), and at any other visits only if indicated.  NOTE: Effective 16 February 
2021, the OLE portion of the study was terminated by the Sponsor. 
Serology will be performed at Screening (Visit 1). Serology will include HCV-Ab, 
HBsAg, and HIV 1 and 2. 
Blood will be collected at Screening (Visit 1) to assess ApoE genotype. 
Serum and whole blood will be collected to measure PBMCs and biomarkers at 
Visit 2, Visit 7, and Visit 10 (or Early Termination). 
Safety laboratory tests will be performed at Screening (Visit 1), Visit 2, Visit 3, 
Visit 4, Visit 5, Visit 6, Visit 7, Visit 8, Visit 9, and Visit 10 (or Early Termination) and 
the Safety Follow-up Visit (Visit 11). Safety laboratory tests will include chemistry, 
hematology, and urinalysis. See  Appendix A: Clinical Laboratory Analytes for a 
complete list of analytes.  
Open Label Extension: Safety laboratory tests will be performed at Visits OLE-1, 
OLE-2, OLE-3, OLE-4, OLE-5, OLE-6 (or Early Termination) and OLE-9 (OLE Safety 
Follow-Up Visit). NOTE: Effective 16 February 2021, the OLE portion of the study 
was terminated by the Sponsor. 
For more detail refer to the Laboratory Manual. 
Per DMC recommendation (following the November 16, 2020 meeting), the following 
increased laboratory analyte testing (liver safety monitoring) is being implemented: 

Every 2 weeks for the initial 12 weeks


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
Every 3 weeks as of Week 12 through Week 24

Every 4 weeks as of Week 24 through Week 32

Every 2 weeks for the initial 12 weeks (OLE)

Every 3 weeks as of Week 60 through Week 72 (OLE)

Every 6 weeks as of Week 72 through Week 84 (OLE)
NOTE: Effective 16 February 2021, the OLE portion of the study was
terminated by the Sponsor
8.19.1 Monitoring of Laboratory Abnormalities 
All laboratory values will be assessed by the Investigator to determine clinical 
significance. All abnormal laboratory values considered clinically significant by the 
Investigator will be recorded in the adverse event page of the eCRF. Abnormal 
laboratory values may be considered clinically significant if they are accompanied by 
signs/symptoms and/or require medical intervention. Abnormal laboratory values 
occurring during the clinical study are to be followed until repeat test results return to 
normal (or baseline), stabilize, or the subject is lost to follow-up. 
8.20 Urine Drug Screen 
A urine drug screen will be performed at Screening (Visit 1) and at Visit 2. The 
analytes will include opiates, cocaine, amphetamines, and barbiturates. 
8.21 Blood Pharmacokinetic (PK) Evaluations 
At Visit 2 a pre-dose trough sample will be drawn immediately prior to the AM dose. 
The subject will take their first dose at the site with the dose time and date recorded 
in the eCRF. A PK blood draw will be collected within the first 4 hours after the dose 
(at any time between 30 minutes to 4 hours post-dose). 
At Visit 3, Visit 7, Visit 9, and Visit 10 (or Early Termination), subjects will return to 
the clinic prior to taking their AM dose. A pre-dose trough sample will be drawn at 
Visit 3 and Visit 7 immediately prior to the AM dose. The subjects will then take their 
dose of study drug on-site and the exact time of the dose ingestion will be recorded. 
A single post-dose sample will be drawn from each subject while on-site at the clinic 
at 60 minutes ± 30 minutes, and at 2 hours ± 30 minutes, respectively.   
At Visit 9 and Visit 10 single post dose sample will be drawn from each subject while 
on-site at the clinic at 3 hours ± 30 min and at 4 hours ± 30 min, respectively. The 
exact time of the last dose of study drug will be recorded. 
In all cases, the exact clock time of each PK sample will be recorded. 
Plasma samples will be quantified for COR388 (and potential metabolites of 
interest). Data will be analyzed by a population pharmacokinetic approach to derive 
COR388 (and potential metabolites of interest) systemic exposure metrics. A 


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detailed population PK analysis plan will be generated and finalized prior to the PK 
analysis being initiated. 
8.22 Cerebrospinal Fluid (CSF) Evaluations 
The LP procedures, and medical care of the subject, will be administered as per 
clinical site standards including imaging prior to procedure, if applicable. 
Cerebrospinal fluid will be tested for measurement of bacterial DNA (Pg) using 
qPCR, biomarkers of AD, and gingipain activity. The details of sample collection and 
processing procedures will be provided in the Laboratory Manual. CSF samples will 
be sent to the central laboratory to be distributed to a specialty laboratory for 
biomarker analysis. 
Assessments will be performed up to 7 days prior to study drug dosing at Baseline 
(Visit 2) and Visit 10 (or Early Termination). 
8.23 Electrocardiograms (ECGs) 
Standard 12-lead electrocardiograms (ECGs) will be performed at Screening 
(Visit 1), Visit 2, Visit 3, Visit 4, Visit 5, Visit 7, Visit 9, Visit 10 (or Early Termination), 
and Visit 11 (Safety Follow-up Visit). The Investigator will review ECGs for any 
changes from baseline. At Visit 2, Visit 3, Visit 7, Visit 9, and Visit 10 (or Early 
Termination), subjects will take their dose on-site and the exact time of the dose 
ingestion will be recorded. The time to maximum plasma concentration of COR388 
(Tmax) is approximately 1-1.5 hours. At visits when the subject takes their dose of 
study drug on-site, ECGs should be measured approximately 1-1.5 hours after 
dosing. At Visit 3 and Visit 7, ECGs will also be performed at trough (prior to dosing). 
ECGs will be reviewed by a cardiologist at the central ECG laboratory to identify any 
abnormalities and verify automatically calculated values of RR, PR, QRS, and QTc 
intervals. Clinically significant ECG events and abnormalities will be recorded as 
adverse events. 
Open Label Extension: Standard 12-lead ECGs will be performed at Visits OLE-1, 
OLE-2, OLE-4, OLE-6 (or Early Termination) and OLE-9 (OLE Safety Follow-Up 
Visit). NOTE: Effective 16 February 2021, the OLE portion of the study was 
terminated by the Sponsor. 
8.24 Safety Monitoring Plan for Potential Drug Induced Liver Injury 
This study is being conducted in compliance with FDA Guidance for Industry on 
Drug-Induced Liver Injury (DILI), which can be accessed at: 
https://www.fda.gov/media/116737/download.  
If a study patient experiences any signs or symptoms of hepatic illness including loss 
of appetite, nausea, vomiting, fever, weakness, tiredness, right upper quadrant 
tenderness, itching, yellowing of the skin and eyes, light colored bowel movements 
or dark colored urine, or AST or ALT elevation at any time during subject’s 


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participation in COR388-010 study, the following safety measures will be 
implemented: 
1. Verify previous liver enzymes (ALT, AST) as well as any other liver-related
lab parameters (e.g., INR, alkaline phosphatase, bilirubin (total, direct,
indirect), etc.)
2. Perform detailed review of medical history, especially prior evidence of viral
hepatitis, cholestasis and other associated conditions and ensure complete
and accurate data entry in EDC.
3. Perform detailed review of concomitant medications including OTC or herbal
products and ensure complete and accurate data entry in EDC.
4. Contact the Study Medical Monitor and report on the clinical subject status.
5. Arrange a confirmatory testing within 48-72 hours and repeat until the
abnormality is stabilized or resolved.
6. Between V4/Week 6 – V8/Week 32 and OLE-2/Week 54 – OLE-5/Week 84
subject must have LFT testing performed at each per protocol required visit. If
such testing is not performed at any of the visits, the IP administration must
be halted until the testing is done.
7. If a patient reports any gastrointestinal symptoms at any time during the
study, safety laboratory testing must be performed promptly (stat labs).
If AST or ALT is >2x ULN – perform weekly testing until the abnormality 
resolves. 
If AST or ALT is >3x ULN, please continue as follows: 
1. Ensure repeat testing (ALT, AST, ALP, GGT, bilirubin, eosinophils (differential
count) 2-3 times weekly until baseline levels are re-established or another
frequency is agreed upon with the medical monitor.
2. Rule out acute viral hepatitis (A, B, C, D, and E) and arrange for an
abdominal ultrasound/MRI/CT.
3. Obtain additional tests to evaluate liver function, as appropriate (e.g., INR,
direct bilirubin, auto-antibodies, bile salts/acids).
4. Tests for infection with cytomegalovirus, Epstein-Barr virus, and herpes
simplex virus, if fever, rash or lymphadenopathy occur.
5. Serum anti-nuclear antibody, anti-smooth muscle antibody, and IgG
concentrations.
6. Consider gastroenterology or hepatology consultations.
7. Please ask the patient to:

Give detailed history of any symptoms and prior or concurrent diseases
(please ask with same frequency as repeated blood tests are performed).

Confirm concomitant drug use (incl. non-prescription drugs, herbal
supplements, etc.)

Provide information about any alcohol use


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
Provide information about any exposure to environmental chemical
agents.
Treatment should be stopped if: 

ALT or AST >8xULN

ALT or AST >5xULN for more than 2 weeks

ALT or AST >3xULN and (TBL >2xULN or INR >1.5)

ALT or AST >3xULN with the appearance of worsening of fatigue, nausea,
vomiting, right upper quadrant pain or tenderness, fever, rash, or eosinophilia
Rechallenge should not be attempted if: 

ALT or AST >5xULN

ALT or AST >3xULN and (TBL >2xULN or INR >1.5)

ALT or AST >3xULN with the appearance of worsening of fatigue, nausea,
vomiting, right upper quadrant pain or tenderness, fever, rash, or eosinophilia
9 
ADVERSE EVENT REPORTING 
Throughout the course of the study, all adverse events (AEs) will be monitored and 
recorded on an AE eCRF, including the AE’s description, start and end date, 
seriousness, severity, action taken, and relationship to the investigational product. If 
AEs occur, the first concern will be the safety of the study subjects. All AEs will be 
followed until resolved or stable and the outcome documented on the eCRF.  
Open Label Extension: Adverse events will be monitored at all visits and phone 
calls. NOTE: Effective 16 February 2021, the OLE portion of the study was 
terminated by the Sponsor. 
9.1 Definitions and Criteria  
9.1.1 Adverse Events  
Per ICH E2A: An AE is any untoward medical occurrence in a subject or clinical 
investigation subject administered a pharmaceutical product and which does not 
necessarily have to have a causal relationship with this treatment.  An AE can 
therefore be any unfavorable and unintended sign (including an 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.  
Medical interventions such as surgeries, diagnostic procedures, and therapeutic 
procedures are not AEs but the action taken to treat the medical condition.  They 
should be recorded as treatment of the AEs. 


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9.1.2 Serious Adverse Events  
A serious adverse event (SAE) or reaction is any untoward medical occurrence that 
at any dose:  
• Results in death
• Is life-threatening
• Requires inpatient hospitalization or prolongation of existing hospitalization
• Results in persistent or significant disability or incapacity
• Is a congenital anomaly or birth defect
• Is an important medical event (e.g., intensive treatment in an emergency room
or at home for allergic bronchospasm; blood dyscrasias, or convulsions that do
not result in hospitalization; or development of drug dependency or drug abuse;
malignancy tumors [histologically different from primary tumor])
Note: The term “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 that hypothetically might have caused death if it were more severe.  
In this study, hospitalization is defined to be at least 24-hours in duration. 
Medical and scientific judgement should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the subject or may require intervention to prevent one of the other 
outcomes listed in the definition above. These should also usually be considered 
serious.  
Examples of such events are intensive treatment in an emergency room or at home 
for allergic bronchospasm; blood dyscrasias, or convulsions that do not result in 
hospitalization; or development of drug dependency or drug abuse.  
The term “severe” is often used to describe the intensity (severity) of a specific event 
(as in mild, moderate, or severe); the event itself, however, may be of relatively 
minor medical significance (such as a severe headache). This is not the same as 
“serious,” which is based on the outcome or action associated with events, as 
described above. Seriousness (not severity) serves as a guide for defining 
regulatory reporting obligations.  
9.1.3 Unexpected Adverse Drug Reactions  
An unexpected adverse drug reaction (ADR) is a reaction for which the nature or 
severity is not consistent with the applicable product information (IB, Package Insert 
for marketed products). Until product information is amended, expedited reporting is 
required for additional occurrences of the reaction. Reports that add significant 


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information on specificity or severity of a known, already documented SAE constitute 
unexpected events. For example, an event more specific or more severe than 
described in the IB would be considered "unexpected.” Specific examples would be 
(a)acute renal failure as a labeled ADR with a subsequent new report of interstitial
nephritis and (b) hepatitis with a first report of fulminant hepatitis.
Guidance on reporting AEs and SAEs is described in Section 9.2. 
9.1.4 Abnormal Laboratory Values  
Any abnormality in a laboratory value that is new in onset or which has worsened in 
severity or frequency from the baseline condition and meets 1 of the following 
criteria will be recorded on the AE pages of the eCRF:  
• Requires therapeutic intervention or diagnostic tests;
• Leads to discontinuation of investigational product;
• Has accompanying or inducing symptoms or signs; and/or
• Is judged by the Investigator as clinically significant.
9.1.5 Assessing Intensity and Relationship  
All AEs will be assessed on 2 descriptive parameters: intensity and relationship to 
the investigational product: 

Intensity refers to the severity of an event and references impact on a subject’s
functioning.

Relationship refers to the likelihood that the event being assessed was caused
by the investigational product.
Intensity  
Each AE will be classified according to the following criteria: 
Mild:  
The AE does not interfere in a significant manner with the 
subject’s normal level of functioning.  
Moderate:  
The AE produces some impairment of functioning but is not 
hazardous to the subject’s health.  
Severe:  
The AE produces significant impairment of functioning or 
incapacitation and is a definite hazard to the subject’s 
health.  
Relationship 


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Each AE will be assessed as to its relationship to the investigational product, based 
on the following criteria. Although the attribution by the Investigator will be collected 
for reported events, for analytic purposes a temporal association with the use of the 
investigational product will be assumed sufficient for at least plausible association. 
Not related: 
No causal relationship exists between the investigational 
product and the AE, but an obvious alternative cause 
exists, e.g., the subject’s underlying medical condition or 
concomitant therapy.  
Possibly related: 
A connection with the administration of the investigational 
product appears unlikely but cannot be ruled out with 
certainty. An AE may be considered possibly related if or 
when it meets 2 of the following criteria: (1) it follows a 
reasonable temporal sequence from administration of the 
investigational product; (2) it could not readily have been 
produced by the subject’s clinical state, environmental or 
toxic factors, or other modes of therapy administered to 
the subject; or (3) it follows a known pattern of response 
to the investigational product.  
Related: 
There is a reasonable/plausible possibility that the AE 
may have been caused by the investigational product. 
When assessing the relationship to the investigational product, the following criteria 
will be considered:  
• Positive re-challenge (restart of IP dosing following dosing interruption); 
Note: In this study re-challenge of IP will not be allowed if IP dosing was 
discontinued for IP-related safety reasons e.g. when a DILI protocol is 
triggered and/or due to an AE that was assessed as possibly or probably 
related to the IP. 
• Positive de-challenge (resolution upon stopping suspect the investigational 
product, in absence of other intervention or treatment); 
• Known class effect; 
• Biological plausibility; and 
• Lack of alternative explanation—concomitant drug or disease. 
9.2 Reporting Procedures and Requirements  
9.2.1 Adverse Events  
Adverse events (AEs) occurring from when the subject signs the ICF until the last 
study event will be recorded. Any AEs occurring before the start of treatment (i.e., 
before the first dose of the investigational product) will be recorded in the medical 


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history. Also, the sign, symptom, or disease present before starting the treatment 
period are only considered AEs if they worsen after starting the treatment period. 
If the Investigator detects an AE in a study subject after the last scheduled follow-up 
visit and considers the event possibly related or related to prior study treatment, the 
Investigator should report it to the Sponsor/ Contract Research Organization (CRO). 
The Investigator should report all AEs on the AE page(s) of the eCRF and source 
documents, regardless of seriousness, severity, and causality. Whenever possible, 
an AE will be reported using a diagnostic term, (e.g., “common cold” or “upper 
respiratory infection” rather than “runny nose, cough, mild fever”) and should be 
described with the attributes described in Section 9.1.5. 
9.2.2 Serious Adverse Events 
Each AE will be assessed to determine whether it meets seriousness criteria 
(Section 9.1.2). If the AE is considered serious, the Investigator should report this 
event to the Sponsor and CRO as outlined below and also to the IRB/IEC according 
to its standard operating procedures.  
If the Investigator detects an SAE in a study subject after the last scheduled 
follow-up visit, and considers the SAE related or possibly related to prior study 
treatment, the Investigator should report it to the Sponsor and CRO.  
All information about SAEs will be collected and reported via the SAE form and sent 
by e-mail message or facsimile (contact information will be contained in the 
Investigator site file). The Investigator should send the initial report within 24 hours 
of becoming aware of the SAE. At minimum, the initial report should include the 
following information:  

Event;

Study code;

Subject number, initials, and date of birth;

Investigational product; and

Reporter name and contact information.
In the case of a “minimum report” (one that solely comprises the information bulleted 
above), a more detailed follow-up report should be sent as soon as more information 
becomes available, but no later than 7 calendar days after the date of the initial 
report. Each SAE should be followed up until resolution or stabilization and for 
reported deaths, the Investigator should supply Sponsor/ CRO and the IRB/IEC with 
any additional requested information (e.g., autopsy reports and terminal medical 
reports).  
The original SAE form should be kept at the study site. The Sponsor or its 
representative will be responsible for determining and in turn, reporting SAEs to 
regulatory authorities according to the applicable regulatory requirements.  


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Serious adverse events that are ongoing at Safety Follow-up Visit 11 of OLE-9 
should be followed until resolved or stabilized. 
9.3 Procedures for Documenting Pregnancy During Study  
If a female subject becomes pregnant during the study, the Investigator will notify 
Sponsor/CRO immediately following 9.1.5 confirmation. The Investigator will also: (1)
notify the subject’s physician that the subject may have been treated withCOR388 
HCl and (2) follow the progress of the pregnancy to term and document theoutcome 
of the pregnancy. Subjects who become pregnant during the study will notbe eligible 
for any further study treatments. Pregnancy outcome information shouldbe 
forwarded to Sponsor/CRO when available. The Investigator and Cortexyme will
determine, on a case-by-case basis, whether the subject will continue in the study
and, if so, which study measures will be collected.
9.4 Treatment of Investigational Product Overdose 
There is currently no information available regarding potential overdosing of 
COR388 HCl. Based on the effects observed in preclinical safety and toxicology 
studies, adverse effects that could be anticipated from exposure to overdoses of 
COR388 HCl are cardiovascular, CNS, and respiratory effects. 
As there are no data available with regard to overdose of COR388 HCl in humans, 
there is no specific treatment to be used in the event of an overdose.  Investigators 
should use their clinical judgment in treating cases of overdose as dictated by the 
subject’s clinical status. 
In the event of a suspected overdose, and if in the opinion of the Investigator the 
patient does not require emergency clinical treatment, the Investigator or treating 
physician should: 

Contact the Medical Monitor immediately.

Have the subject come to the clinic as soon as possible to draw blood for
clinical laboratory testing.

Closely monitor the subject for AEs/SAEs and laboratory abnormalities
and ensure appropriate clinical management. Overdose in the absence of
other AEs will not be reported as an AE in its own right.

Document the quantity of the excess dose, as well as the time of
administration of the overdose, in the eCRF.

Subjects should be observed closely in a medical facility where
appropriate supportive care is available, if required.


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10 QUALITY CONTROL AND QUALITY ASSURANCE 
10.1 Bioanalytic Method Validation 
Bioanalytic methods employed in this study have been validated according to 
existing standard operating procedures of the Sponsor and of the laboratory 
performing the analysis, in compliance with relevant regulation. 
11 STATISTICAL AND ANALYTICAL PLANS 
11.1 General Considerations 
The statistical analyses are described in this section. Further details will be provided 
in the Statistical Analysis Plan (SAP), which will be finalized prior to database lock 
and unblinding for the interim analysis.  Any deviations from the analyses described 
below will be included in the SAP.   
All efficacy and safety measures over the course of the study will be presented.  
Continuous data will be summarized by means, standard deviations (SDs), medians, 
maximum, minimum, and number of subjects.  Categorical data will be summarized 
by counts and percentages. 
11.2 Determination of Sample Size 
The study will have an adaptive design that allows for potential adjustment in sample 
size and evaluation of efficacy based on the results of a planned interim analysis.  
An unblinded interim analysis will be conducted by a firewalled independent 
statistician (all clinical trial personnel will remain blinded) when approximately 100 
subjects per arm have completed the Week 24 visit.   Approximately 573 subjects 
are planned to be randomized 1:1:1 per treatment group (191 per treatment group) 
assuming approximately 10% will drop out prior to 48 weeks.  Due to the planned 
interim analysis, adjustments will be made to the alpha level used in the final 
analysis to control for overall Type I error.  The final criterion for efficacy to be used 
at the interim and final analysis depends on when the interim analysis occurs. The 
Lan-DeMets method modified according to Chen et al. (2004) to account for 
correlation between endpoints used at the interim and final analyses will be used to 
calculate the level of significance for each analysis. As originally planned, with 573 
subjects randomized, an expected 10% discontinuation rate, and a single primary 
outcome, a total of 172 subjects per treatment group would provide approximately 
90% power to detect a 2.5-point difference between the active treatment group 
compared to placebo with respect to change from baseline on the ADAS-Cog 11, 
assuming a standard deviation of 7.1, respectively at a significance level (alpha) of 
0.05 using a two-sided test.  The ADCS-ADL was added as a co-primary outcome, 
with assumptions of a 3.9-point difference between the active treatment group 
compared to placebo with respect to change from baseline on ADCS-ADL, assuming 
a standard deviation of 10.5, providing approximately 95% power on this outcome 


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measure, with approximately 90% power for the overall co-primary outcomes, 
depending on their correlation.   
These results assume that 2 sequential tests will be made using the Lan-DeMets 
spending function to determine the test boundaries. Therefore, if an interim analysis 
is conducted when approximately 300 subjects have completed the Week 24 visit, 
then a significance level of 0.005 will be used for the interim analysis and a 
significance level of approximately 0.0456 will be used for the final analysis.  As 
discussed by Chen et al 2004, the sample size re-estimation procedure based on 
promising zone will not inflate the type I error and no statistical adjustment is 
necessary.  However, the adjusted alpha at the end of the study will be based on the 
new sample size at the final analysis. 
11.3 Final Analysis 
11.3.1 Analysis Populations 

Intent-To-Treat Population (ITT): The ITT population will include all subjects who
are randomized regardless of whether or not they took study drug. This
population will serve as the basis for all efficacy analyses. When change from
baseline is assessed, subjects will be included in the analysis only if both a
baseline and a postbaseline measure are available.

The Per Protocol population (PP): The PP population will include all ITT subjects
who do not have any major protocol deviations that would affect efficacy (e.g.,
<80% treatment compliance, taking a prohibited medication).  Major protocol
deviations will be reviewed and determined prior to unblinding.  The
PP population will be used for supportive sensitivity analyses.

Safety Population: The Safety population will include all subjects who receive at
least one dose of study drug. Safety analyses will be performed using the Safety
population, and subjects will be analyzed according to the treatment they actually
receive.
11.3.2 Efficacy Analysis 
11.3.2.1 
Primary Efficacy Analysis 
The co-primary endpoints are the mean change from baseline in ADAS-Cog 11 at 
the end of the study (average of Weeks 40 and 48), and the mean change from 
baseline in the Alzheimer’s Disease Cooperative Study – Activities of Daily Living 
(ADCS-ADL) at the end of the study (average of Weeks 40 and 48).   
Each of the coprimary endpoints will be analyzed using a mixed-effects model for 
repeated measures (MMRM) with SAS PROC MIXED to compare change from 
baseline for COR388 HCl vs placebo.  The MMRM model will include treatment 
group, study visit, site/country, treatment group by study visit interaction as fixed 
effects, and baseline MMSE (average of the last two non-missing assessments 


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collected prior to or at the day of first dose of the IP), ApoE4 status, and 
acetylcholinesterase inhibitor and/or memantine usage at baseline as factors with 
baseline score as a covariate using the ITT population. The analysis will be based 
on unstructured covariance matrix to model the within-subject errors. A Kenward-
Roger approximation will be used for the denominator degrees of freedom.   
Summary statistics (n, mean, standard deviation, minimum, median, and maximum) 
will be presented for the observed values for each of the coprimary endpoints at 
each time point for the ITT population, including weeks 40 and 48 separate as well 
as averaged.  Summary statistics will also be presented for the change from 
baseline values to each postbaseline time point as listed above.   
The Type I error for the interim and final analysis will be adjusted using the Lan-
DeMets spending function. Detailed of the adjustment is presented in 
Section 11.3.2.3 and in the SAP. 
Treatment comparisons of 40 mg and 80 mg COR388 HCl to placebo will be 
adjusted using Benjamini-Hochberg multiplicity adjustment procedure (Benjamini 
and Hochberg, 1995 and Benjamini and Yekutieli, 2001).  Both treatment 
comparisons, 40 mg (low dose) and 80 mg COR388 HCl (high dose) to placebo are 
considered of equal interest.  
11.3.2.1.1 
Sensitivity Analyses 
The following sensitivity analyses will be performed on each of the co-primary 
endpoints: 

Repeat above analysis using the PP population.

Impute missing values using a last z-score carried forward method
(converted back to the original scale) and analyze the primary endpoint
(Average of Weeks 40 and 48 only) using analysis of covariance (ANCOVA)
with fixed effects of treatment group, ApoE4 status, acetylcholinesterase
inhibitor and/or memantine usage, site/country and baseline MMSE with
baseline score as a covariate.

Pattern mixture model:
The pattern-mixture model approach uses a control-based pattern imputation
(Ratitch and O’Kelly, 2011). With this approach, subjects who discontinued
from the COR388 HCl 80 mg or COR388 HCl 40mg treatment group will be
assumed to follow a similar outcome trajectory as subjects from the placebo
(control) arm and subjects who discontinued from placebo (control) treatment
are modeled as completers within their own arm (MAR within control arm).
That is, the imputation model for the missing observations in the active
treatment groups are constructed not from the observed data in the
corresponding active treatment group but rather from the observed data in the
placebo treatment group. This model is also the imputation model that will be
used to impute missing observations in the placebo treatment group. This will


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be implemented by utilizing the MONOTONE REG statement of SAS® PROC 
MI with the option nimpute=5. 
Pattern mixture model tends to overestimate the already very large variability 
in Alzheimer’s disease data, these model results are likely to be much less 
able to discriminate treatment differences than the primary model. The results 
of this imputation method will primarily be used to assess the potential bias of 
the main model estimates due to dropout by comparing the estimates 
between the primary and sensitivity models. 
Additional subgroups including gender, demographic, and other baseline 
characteristics may be performed.  Further details will be given in the SAP. 
11.3.2.2 
Secondary Endpoint Analyses 
Secondary endpoints will be analyzed for the ITT population only. 
The analysis of secondary endpoints will use the same methodology as that for the 
primary endpoint analysis but adjusting for corresponding baseline value as a 
covariate. Treatment comparisons of 40 mg and 80 mg COR388 HCl to placebo for 
the secondary endpoints at 24-week or 48-week will be performed only if both co-
primary endpoints compared to placebo are statistically significant. Otherwise, 
secondary endpoints will be presented using descriptive statistics  
11.3.2.3 
Multiplicity 
To control for type I error, for the interim and final analysis will be adjusted using the 
Lan-DeMets spending function.  If the study does not stop at the interim analysis 
(i.e., 24 weeks ADAS-Cog and CDR-SB as co-primary endpoints) for overwhelming 
efficacy or futility, the study will retain its original design and the final analysis will be 
based on 48 weeks of treatment with ADAS-Cog and ADCS-ADL as co-primary 
endpoints. Because of the changes in co-primary endpoint at 48 weeks (i.e., CDR-
SB 24-week replaced by ADCS-ADL at 48-week and ADAS-Cog 24-week replaced 
by ADAS-Cog 48-week), the Lan-DeMets correction for sequential analysis will be 
further adjusted as described in Chen et al., (2014). This adjustment will account for 
the correlation between the outcomes and time points. The boundaries will be 
calculated to account for the change in timing of evaluation and endpoint and the 
more conservative boundary will be used for final analysis at 48-week.   
At both the interim analysis at 24 weeks and final analysis at 48 weeks, to adjust for 
comparison between placebo and each of the two doses, Benjamini-Hochberg 
multiplicity adjustment procedure (Benjamini and Hochberg, 1995 and Benjamini and 
Yekutieli, 2001) will be used.  Both treatment comparisons, 40 mg (low dose) and 80 
mg COR388 HCl (high dose) to placebo are considered of equal interest.   
Treatment comparisons of 40 mg and 80 mg COR388 HCl to placebo for the 
secondary endpoints at 24-week or 48-week will be performed only if both co-


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primary endpoints compared to placebo are statistically significant at the level of 
approximately 0.005 or 0.0456 for the interim analysis and final analysis, 
respectively. Otherwise, secondary endpoints will be presented using descriptive 
statistics.  
11.3.2.4 
Exploratory Endpoints 
Exploratory endpoints will be analyzed for the ITT population only.  No adjustment 
for multiplicity will be done.   
Further details of the analyses to be performed will be provided in the SAP. 
11.3.3 Safety Analysis 
11.3.3.1 
Adverse Events 
Adverse events will be coded by Preferred Term (PT) using the Medical Dictionary 
for Regulatory Activities (MedDRA) classification.  
A treatment-emergent adverse event (TEAE) is defined as any AE that has an onset 
on or after the first dose of study drug, or any pre-existing condition that has 
worsened on or after the first dose of study drug. The incidence of TEAEs, 
treatment-related TEAEs, SAEs including deaths, TEAEs that lead to discontinuation 
of investigational product, and TEAEs by maximum severity and relationship to study 
drug will be summarized by MedDRA system organ class, PT, and treatment group.   
To assess the potential for abuse associated with the administration of 
COR388 HCl, a systematic review of TEAE terms suggestive of the potential for 
abuse will be conducted for all clinical studies in subjects who received at least 1 
dose of COR388 HCI and a summary of this information will be included in the 
regulatory submission. As a general framework for data collection and analysis we 
will use the overall abuse flag terms in the FDA Guidance (2017). 
Since the target patient population are elderly, have substantial comorbidity and are 
often on other medications, a careful assessment and documentation of adverse 
event causality will be made in order to ensure that false positive TEAE signals for 
abuse are not generated. For example, dizziness and sedation or sleepiness are 
common clinical events in elderly patients with Alzheimer’s disease. 
Since to date no abuse related TEAE attributable to COR388 HCl have occurred, 
focus will be on a restricted set of index events for which narratives will only be 
prepared where the causality relationship to COR388 HCl is probable or definite. 
Information included in the narratives will consist of time to onset/offset, time course 
of severity, all concurrent events, concurrent medications, and time of onset of 
events relative to ingestion of COR388 HCl. 


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The index TEAEs will include: 
• Any reports of altered perception or hallucinations 
• Dizziness 
• Euphoric mood 
• Feeling drunk 
• Feeling of relaxation 
• Sedation 
• Somnolence 
11.3.3.2 
Laboratory Data 
Laboratory data (hematology, blood chemistry, and urinalysis parameters) will be 
presented for each treatment group using descriptive statistics, including mean and 
mean change from baseline values at each scheduled time point. Shift tables will 
display numbers of subjects with normal/abnormal values at baseline versus 
post-treatment. The frequency of laboratory abnormalities will be tabulated. 
By-subject data listings will flag laboratory values that are outside normal reference 
ranges or markedly abnormal findings. 
11.3.3.3 
Vital Signs  
Descriptive statistics for observed values and change from baseline in vital sign 
parameters [blood pressure (systolic and diastolic), body temperature, pulse, and 
respiratory rate] will be presented by visit and treatment group.  
11.3.3.4 
Electrocardiograms 
Descriptive statistics for observed values and change from baseline in (continuous) 
ECG parameters (e.g., RR, PR, QTc) will be presented by visit and treatment group.   
Shift tables in relation to overall interpretation (Normal, Abnormal Not Clinically 
Significant [NCS] and Abnormal Clinically Significant [CS]) from baseline to each 
post-baseline visit will be presented. 
11.3.3.5 
Other Safety Assessments 
The C-SSRS will be summarized at each visit by treatment using descriptive 
statistics. 
Abnormal physical examinations and MRI results will be summarized descriptively 
by visit and treatment group. 
11.3.4 Demographic and Baseline Characteristics 
Treatment groups will be compared with respect to subject demographics, and 
baseline characteristics will be summarized using descriptive statistics. No formal 
statistical analysis tests will be performed. 


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11.3.5 Interim Analysis 
The purpose of the interim analysis is to determine if COR388 HCl is efficacious and 
conduct a sample size re-estimation. One unblinded interim analysis will be performed 
after approximately 300 subjects have completed 24 weeks of treatment. The DMC 
will review unblinded data for the mean change from baseline in ADAS-Cog 11 and 
the mean change from baseline in the CDR-SB post 24 weeks of treatment. Both 
treatment comparisons will be assessed at the interim analysis: 40 mg COR388 HCl 
and 80 mg COR388 HCl vs. placebo for the two co-primary endpoints (i.e., mean 
change from baseline in ADAS-Cog 11 and mean change from baseline in CDR-SB 
at Week 24). Analyses will be performed as specified in the approved final study SAP. 
The DMC should return to the Sponsor one of four recommendations as follows: 
 Stop the study early for overwhelming efficacy defined as p<0.005 adjusted for
multiplicity using the Benjamini-Hochberg procedure for both ADAS-Cog 11 and
CDR-SB in favor of either 40 mg COR388 or 80 mg COR388 HCl over placebo;
 Stop either or both arms (stopping both arms would mean stopping the study)
early for futility defined as p<0.05 on either ADAS-Cog 11 or CDR-SB in favor of
placebo over active dose(s), and the other endpoint for the same dose is
directionally favoring placebo;
 Continue with no sample size adjustment; or
 Continue with an appropriate sample size adjustment
Interim comparative data will be most securely protected from inadvertent or 
inappropriate access by the Sponsor. Sponsor will remain blinded to all information 
except the DMC recommendations.   
11.3.6 Pharmacokinetic Analysis 
Plasma levels of COR388 will be determined from blood samples collected at Visit 2, 
Visit 3, Visit 7, Visit 9, and Visit 10 (or Early Termination). 
Descriptive statistics (sample size, mean, SD, minimum, median, and maximum) will 
be calculated for all results. Geometric mean and geometric coefficient of variation 
(CV)% will also be calculated for PK parameters. 
12 STUDY MANAGEMENT 
12.1 Regulations and Guidelines 
The study will be performed in accordance with this protocol, United States IND 
regulations (21 Code of Federal Regulations [CFR] 312) or local national laws (as 
applicable), ICH guidelines for Good Clinical Practice, and the most recent 


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guidelines of the Declaration of Helsinki. These guidelines are on file at the Sponsor 
and/or CRO. 
12.2 Institutional Review Board/Independent Ethics Committee 
Conduct of the study must be approved by an appropriately constituted IRB or IEC. 
Approval is required for the study protocol, investigational drug brochure, protocol 
amendments, ICFs, subject information sheets, and advertising materials. No 
investigational product will be shipped to a site until written IRB/IEC authorization 
has been received by the Sponsor or its representative. 
12.3 Discontinuation of the Study by the Sponsor 
The Sponsor reserves the right to discontinue the study at this site or at multiple 
sites for safety or administrative reasons at any time. In particular, a site that does 
not recruit at a reasonable rate may be discontinued. Should the study be terminated 
and/or the site closed for whatever reason, all documentation and investigational 
product pertaining to the study must be returned to the Sponsor or its representative. 
12.4 Study Documentation 
By signing a copy of Form FDA 1572 or other country-specific regulatory forms, the 
Principal Investigator acknowledges that he/she has received a copy of the IB on 
COR388 HCl and assures the Sponsor that he/she will comply with the protocol and 
the provisions stated in Form FDA 1572 and other country-specific forms. No 
changes in this protocol can be made without the Sponsor’s written approval. 
12.5 Study Monitoring and Auditing 
This study will be monitored for quality assurance at all stages of its development by 
the clinical research personnel employed by the Sponsor or its representative. 
Monitoring will include remote (virtual) data reviews, personal visits, and telephone 
communication to assure that the investigation is conducted according to the 
protocol, standard operating procedures, Guidelines of Good Clinical Practice, and 
applicable regulatory requirements. Quality control procedures will be applied to 
each stage of data handling to ensure that all data are reliable and have been 
processed correctly. On-site and remote review of eCRFs will include a review of 
forms for completeness and clarity, and consistency with source documents 
available for each subject. Note that a variety of original documents, data, and 
records will be considered as source documents in this trial. Procedures for handling 
source documents remotely will be described in the Clinical Monitoring Plan. The 
eCRF itself is not to be used as a source document under any circumstances.  
Medical advisors and Clinical Research Associates (CRAs) or assistants may 
request to witness subject evaluations occurring as part of this protocol. The 
Investigator and appropriate personnel will be periodically requested to attend 


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meetings/workshops organized by the Sponsor to assure acceptable protocol 
execution. The study may be subject to audit by the Sponsor or by regulatory 
authorities. If such an audit occurs, the Investigator must agree to allow access to 
required subject records. By signing this protocol, the Investigator grants permission 
to personnel from the Sponsor, its representatives, and appropriate regulatory 
authorities, for remote and on-site monitoring of all appropriate study documentation, 
as well as on-site review of the procedures employed in eCRF generation, where 
clinically appropriate. 
12.6 Data Monitoring Committee 
An independent Data Monitoring Committee (DMC) will be established to review 
accumulating study data to monitor the safety of subjects enrolled in COR388-010 
on an ongoing basis and review the interim analysis (see Section 11.3.5).  All 
members will be independent of the study (e.g., not a participating site employee, 
Cortexyme employee, etc.). 
The DMC will review data on a regular basis.  After reviewing the safety data, the 
DMC may make a recommendation to continue the study with or without 
modification or terminate the study.  The DMC Charter defines all DMC 
responsibilities, functions, membership, meeting structure, communications, DMC 
SAP, and rules for decision making. 
12.7 Retention of Records 
The Investigator must arrange for retention of study records at the site. The nature of 
the records and the duration of the retention period must meet the requirements of 
the relevant regulatory authority. In addition, because this is an international study, 
the retention period must meet the requirements of the most stringent authority. The 
Investigator should take measures to prevent accidental or premature destruction of 
these documents. 
12.8 Use of Study Findings 
By signing the study protocol, the Investigator agrees to the use of results of the 
study for the purposes of national and international registration. If necessary, the 
authorities will be notified of the Investigator’s name, address, qualifications, and 
extent of involvement. Reports covering clinical and biometric aspects of the study 
will be prepared by the Sponsor or its representative. 
12.9 Publications 
As a multicenter trial, the Sponsor intends to publish clinical data from all centers 
participating in the investigation. A publication committee selected by the Sponsor 
will submit draft manuscripts to all participating investigators for their comments. In 
conformity with the Uniform Requirements for Manuscripts Submitted to Biomedical 
Journals published by the International Committee of Medical Journal Editors (see 


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discussion in Kassirer & Angell, 1991), investigators whose contribution consists 
solely in the collection of data will not be named individually as authors. Rather, 
those investigators will receive a collective authorship as the “COR388 Study Group” 
and will be identified in a note.  
Individual investigators and/or their associates subsequently may publish additional 
findings of this study in scientific journals or present them at scientific meetings, 
provided that the Sponsor is given ample opportunity to review any proposed 
abstract, manuscript, or slide presentation before its submission. This review is 
required to ensure that the Sponsor is aware of all written and oral presentations of 
the data and does not imply any editorial review or restriction of the contents of the 
presentation or use. 
12.10 Subject Privacy 
To maintain subject confidentiality, all eCRFs, study reports, and communications 
relating to the study will identify subjects by initials and assigned subject numbers.  
As required by federal regulations, the Investigator will allow Cortexyme and/or the 
CRO CRA access to all pertinent medical records in order to allow for the verification 
of data gathered in the eCRFs and for the review of the data collection process. The 
FDA (or other regulatory authority) may also request access to all study records, 
including source documentation for inspection. 
As applicable, in accordance with Health Insurance Portability and Accountability Act 
(HIPAA) and associated privacy regulations, a subject authorization to use 
personally identifiable health information may be required from each subject prior to 
research activities. This authorization document must clearly specify what parties will 
have access to a subject’s personal health information, for what purpose, and for 
how long. 
12.11 Amendments to the Protocol 
Any amendments to the study protocol will be communicated to the investigators by 
the CRO or the Sponsor. All protocol amendments will undergo the same review and 
approval process as the original protocol. A protocol amendment may be 
implemented after it has been approved by the IRB/IEC, and, where appropriate, 
competent regulatory authority approval prior to implementation, unless immediate 
implementation of the change is necessary for subject safety. In this case, the 
situation must be documented and reported to the IRB within 5 working days and in 
the countries outside of the United States according to the national regulation. 
Any departures from protocol must be fully documented in the source documentation 
and in a protocol deviation log. 
12.12 Case Report Form Completion 
Electronic CRFs (eCRFs) will be employed for this study.  Completed eCRFs for this 
study will be forwarded to the Sponsor or its representative, where editing and 


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construction of a quality-assured database will occur.  Data will be quality checked, 
double-entered, and electronically verified before entry into the database. Queries 
will be issued for any inconsistencies, omissions, and discrepancies and will be 
resolved by the appropriate parties.  The statistical analysis of these data will be 
performed by the Sponsor or its representative.  All AEs will be coded using the 
latest version of the Medical Dictionary for Regulatory Activities (MedDRA).  
Concomitant medications will be coded using the latest version of the World Health 
Organization Drug Dictionary.  Data management details will be outlined in a 
separate data management plan. 
12.13 Removal of Subjects from Therapy or Assessment 
Liver Safety Monitoring (laboratory analyte testing) must be performed at each study 
visit within the prespecified visit window (see Table 1 and Table 2, Schedule of 
Evaluations) OR the study drug dosing must be temporarily halted until the testing is 
done.  
Subjects who discontinue IP dosing for IP-related safety reasons will not be 
permitted to resume IP treatment and must be followed until the safety concern (e.g. 
transaminase elevations) or an existing AE has stabilized or resolved/returned to 
baseline. At that time subject’s participation in the study must be terminated early 
and V10/ET procedures must be performed. Subjects should remain in the study 
through final 6-weeks safety follow up period which ends with a final study visit. 
A subject will be considered to have completed the study when he or she completes 
Visit 11. If a subject is discontinued at any time after randomization into the study, 
the Investigator will make every effort to follow the subject and complete the 
Visit 10/Early Termination assessments.  
A termination electronic case report form (eCRF) page should be completed for 
every subject who receives investigational product, whether or not the subject 
completes the study. The reason for any early discontinuation should be indicated 
on this form. The primary reason for a subject discontinuing early should be selected 
from the following standard categories of early termination:  
• Adverse Event (Adverse Reaction): Clinical or laboratory events occurred that,
in the medical judgment of the Investigator for the best interest of the subject, 
are grounds for discontinuation. This includes serious and nonserious 
adverse events (AEs) regardless of relation to the investigational product.  
• Death: The subject died.
• Withdrawal of Consent: The subject desired to withdraw from further
participation in the study in the absence of an Investigator-determined 
medical need to withdraw. If the subject gave a reason for withdrawing, it 
should be recorded in the eCRF.  


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• Protocol Violation: The subject’s findings or conduct failed to meet the protocol 
entry criteria or failed to adhere to the protocol requirements (e.g., drug 
noncompliance, failure to return for defined number of visits). The violation 
necessitated early discontinuation from the study.  
• Lost to Follow-Up: The subject stopped coming for visits and study personnel 
were unable to contact the subject.  
• Other: The subject was discontinued for a reason other than those listed above, 
such as theft, loss of investigational product, or termination of study by 
Sponsor. 
12.14 End of the Study 
For regulatory purposes, the definition of the end of the study is database lock. 
 
 


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13 REFERENCES 
Benjamini, Y; Hochberg, Y. "Controlling the false discovery rate: a practical and 
powerful approach to multiple testing" (PDF). Journal of the Royal Statistical 
Society, Series B. 1995; 57 (1): 289–300. MR 1325392. 
Benjamini, Y, Yekutieli, D. "The control of the false discovery rate in multiple 
testing under dependency" (PDF). Annals of Statistics. 2001; 29 (4): 1165–
1188. doi:10.1214/aos/1013699998. MR 1869245. 
Chen, LM, Ibrahim, J.G; Chu, H.  Flexible Stopping Boundaries When 
Changing Primary Endpoints after Unblinded Interim Analyses. J Biopharm 
Stat. 2014; 24(4): 817–833. 
Chen YH, DeMets DL, Lan KK. Increasing the sample size when the unblinded 
interim result is promising. Stat Med. 2004;23:1023-1038. 
Columbia University Medical Center. Columbia-Suicide Severity Rating Scale 
(C-SSRS). Center for Suicide Risk Assessment. http://cssrs.columbia.edu/. 
Accessed 15 November 2017. 
Dmitrienko A, Millen BA, Brechenmacher T, Paux G. Development of 
gatekeeping strategies in confirmatory clinical trials. Biom J. 2011;53(6):875-
893. 
Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A practical method 
for grading the cognitive state of patients for the clinician. J Psychiatr Res. 
1975;12:189-198. 
Hughes CP, Berg L, Danzinger WL, Coben LA, Martin RL. A new clinical scale 
for the staging of dementia. Br J Psychiatry. 1982;140:566-572. 
Ito K, Corrigan B, Romero K, et al. Understanding placebo responses 
in Alzheimer's disease clinical trials from the literature meta-data and CAMD 
database. J Alzheimers Dis. 2013;37(1):173-183.  
Jennison, C; Turnbull, BW. Group Sequential Methods with Applications to 
Clinical Trials. Chapman & Hall/CRC, 2000, pp 205-208. 
Kassirer JP, Angell M. On authorship and acknowledgments. N Engl J 
Med. 1991;21;325(21):1510-1512. 
McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due 
to Alzheimer's disease: recommendations from the National Institute on Aging-
Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's 
disease. Alzheimers Dement. 2011;7:263-269. 


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Mohs RC, Cohen L. Alzheimer’s Disease Assessment Scale (ADAS). 
Psychopharmacol Bull. 1988;24:627-628. 
Wattmo C, Minthon L, Wallin ÅK. Mild versus moderate stages 
of Alzheimer's disease: three-year outcomes in a routine clinical setting of 
cholinesterase inhibitor therapy. Alzheimers Res Ther. 2016;8:7.  
 
 


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APPENDIX A: CLINICAL LABORATORY ANALYTES  
Safety Chemistry Panel 
Alanine transaminase 
Albumin 
Alkaline phosphatase 
Amylase 
Aspartate transaminase 
Bicarbonate 
Gamma-glutamyl transferase 
Calcium 
Blood urea nitrogen 
Creatinine kinase 
Chloride 
Estimated glomerular filtration rate 
Creatinine 
Glucose 
Inorganic phosphorus 
HbA1c 
Lipase 
Lactate dehydrogenase 
Sodium 
Potassium 
Total protein 
Total bilirubin 
Uric acid 
Direct bilirubin 
Magnesium 
Indirect bilirubin 
 
Hematology 
White blood cell count and differential [1] 
Hemoglobin 
Red blood cell count 
Mean corpuscular volume 
Platelets 
Mean corpuscular hemoglobin 
Hematocrit 
Mean corpuscular hemoglobin concentration 
Prothrombin time  
Partial thromboplastin time  
Vitamin B12 
1. 
Manual microscopic review is performed only if white blood cell count and/or differential values are out of 
reference range. 
Immunochemistry 
Thyroid Function [T4, T4 (Free), T3, T3 (Free), TSH] 
Syphilis 
Endocrinology 
Follicle-stimulating hormone [1] 
 
1. 
Follicle-stimulating hormone in in peri-menopausal (irregular menstrual periods) or post-menopausal (no 
menstrual period for >12 months) female subjects at screening. 
 
Serology 
Hepatitis B surface antigen 
Hepatitis C virus antibodies 
Human immunodeficiency virus 1 and 2 
antibodies 
 
 
Urinalysis 
Bilirubin 
Blood 
Glucose 
Ketones 
Leukocyte esterase 
Microscopy [1] 
Nitrite 
pH 
Protein 
Specific gravity 
Urobilinogen 
 
1. 
Microscopy will be performed only as needed based on positive dipstick test results. 


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APPENDIX A: CLINICAL LABORATORY ANALYTES (CONTINUED) 
Drug Screen 
Opiates 
Amphetamines 
Cocaine
Barbiturates
Cerebrospinal Fluid Biomarkers 
Porphyromonas gingivalis DNA qPCR 
Total tau protein 
Neuroinflammation panel 
Phosphorylated tau protein 
Amyloid beta peptides 
Exploratory AD biomarkers  
DNA = deoxyribonucleic acid; qPCR = quantitative polymerase chain reaction. 
Saliva/Oral Fluids Biomarkers- 
Porphyromonas gingivalis and oral microbiome 
DNA qPCR and biomarkers 
 
DNA = deoxyribonucleic acid; qPCR = quantitative polymerase chain reaction. 
Blood Biomarkers 
Porphyromonas gingivalis biomarkers in serum 
and PBMCs  
Neuroinflammatory markers 
PBMCs = Peripheral blood mononuclear cells.  
Liver Safety Monitoring
Alanine transaminase 
Aspartate transaminase 
Gamma-glutamyl transferase 
Alkaline Phosphatase 
Total Bilirubin 
Direct bilirubin 
Indirect bilirubin 
Eosinophils (% and Abs) 
Prothrombin Time as INR 
Extended Liver Safety Testing for AST or ALT >3x ULN 
INR 
Direct bilirubin 
Auto-antibodies 
Bile salts/acids 
Cytomegalovirus 
Epstein-Barr virus 
Herpes simplex virus 
Anti-nuclear antibodies 
Anti-smooth muscle antibodies 
Immunoglobulin G 
See liver safety monitoring procedures in Section 8.24 

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN (SAP) 
 
Protocol Number: COR388-010 
Protocol Title: A Randomized, Double-Blind, Placebo-Controlled Study 
of COR388 HCl in Subjects with Alzheimer’s Disease 
Product Name or Number: COR388 HCl 
Sponsor: Cortexyme, Inc. 
 
 
 
NCT03823404 
 
 
SAP Version Number (Date): Version 5.0 (27 August 2021) 
 
 


Statistical Analysis Plan-Double-Blind Phase 
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STATISTICAL ANALYSIS PLAN (SAP) 
Protocol Number: 
COR388-010 
Protocol Title: 
A Randomized, Double-Blind, Placebo-Controlled Study 
of COR388 HCl in Subjects with Alzheimer’s Disease   
Product Name or Number: 
COR388 HCl 
Sponsor: 
Cortexyme, Inc. 
269 East Grand Ave.  
South San Francisco, CA  94080 
SAP Version 5 prepared by: 
Earlier SAP versions prepared by: 
Consulting Statistician: 
Sarah Horine, MS and Craig Mallinckrodt, PhD 
Cortexyme Inc. 
269 East Grand Ave 
South San Francisco, CA 94080 
Kimberly T. Perry, PhD 
Innovative Analytics, Inc. 
161 East Michigan Ave 
Kalamazoo, MI 49007 USA 
Suzanne Hendrix, PhD 
Pentara Corporation 
2261 East 3300 South 
Suite 200 
Millcreek, UT 84109 
SAP Version Number (Date): 
Version 5.0 (27 August 2021) 


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TABLE OF CONTENTS 
1 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ......................................4 
2 
STUDY OVERVIEW ..........................................................................................................6 
3 
STUDY OBJECTIVES, ENDPOINTS, and estimands .......................................................8 
4 
GENERAL METHODS.....................................................................................................11 
4.1 
Analysis Populations ....................................................................................................11 
4.2 
Summarization of Data ................................................................................................11 
4.3 
Visit Windows .............................................................................................................11 
4.4 
Randomization .............................................................................................................12 
4.5 
Sample Size Justification .............................................................................................12 
4.6 
Output Production and Validation ...............................................................................13 
5 
PROTOCOL DEVIATIONS .............................................................................................14 
6 
SUBJECT DISPOSITION .................................................................................................14 
7 
DEMOGRAPHIC CHARACTERISTICS .........................................................................15 
8 
MEDICAL HISTORY .......................................................................................................15 
9 
PRIOR AND CONCOMITANT MEDICATIONS ...........................................................15 
10 
EXTENT OF EXPOSURE ................................................................................................15 
11 
STUDY DRUG INTERRUPTION ....................................................................................15 
12 
EFFICACY ANALYSES ..................................................................................................16 
12.1 
Primary Endpoint Analyses .........................................................................................16 
12.2 
Sensitivity and Supplementary Analyses .....................................................................18 
12.3 
Subgroup Analyses ......................................................................................................19 
12.4 
Secondary Endpoint Analyses .....................................................................................22 
12.5 
Multiplicity ..................................................................................................................23 
12.6 
Exploratory Endpoint Analyses ...................................................................................25 
13 
SAFETY ANALYSES.......................................................................................................34 
13.1 
Adverse Events ............................................................................................................34 
13.2 
Laboratory Tests (Hematology, Serum Chemistry, Coagulation, and Urinalysis) ......34 
13.3 
Vital Signs ....................................................................................................................35 
13.4 
Physical Examinations .................................................................................................36 
13.5 
Electrocardiograms ......................................................................................................36 
13.6 
Columbia Suicide Severity Rating Scale (C-SSRS) ....................................................37 


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13.7 
MRI Safety Readings from the Brain ..........................................................................37 
14 
PHARMACOKINETIC ANALYSES ...............................................................................38 
15 
SUBJECT LISTINGS ........................................................................................................38 
16 
INTERIM ANALYSES .....................................................................................................39 
16.1 
Interim Analysis for Efficacy .......................................................................................39 
16.2 
Sample Size Re-estimation ..........................................................................................41 
17 
REFERENCES ..................................................................................................................45 
18 
FINAL SIGN-OFF FOR CORTEXYME, INC, PROTOCOL COR388-010 
STATISTICAL ANALYSIS PLAN ..................................................................................46 
19 
REVISIONS TO STATISTICAL ANALYSIS PLAN ......................................................47 
20 
APPENDIX ........................................................................................................................48 
20.1 
Conventions for Statistical Tables and Subject Listings ..............................................48 


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1 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or Term 
Definition 
AD 
Alzheimer’s Disease 
ADAS-Cog 11 
Alzheimer’s Disease Assessment Scale-Cognitive Subscale 11 
ADCS-ADL 
Alzheimer’s Disease Cooperative Study Group-Activities of Daily Living  
ANCOVA 
Analysis of Covariance  
ApoE 
Apolipoprotein E  
ATC 
Anatomical Therapeutic Chemical  
B 
Buccal  
BMI 
Body Mass Index  
BOP 
Bleeding on Probing  
CAL 
Clinical Attachment Level  
CDC/AAP 
Centers for Disease Control/American Academy of Periodontology 
CFB 
Change from Baseline 
CDR-SB 
Clinical Dementia Rating-Sum of Boxes  
CSF 
Cerebrospinal Fluid 
C-SSRS 
Columbia-Suicide Severity Rating Scale  
CT 
Computed Tomography  
DB 
Distobuccal  
DL 
Distolingual  
DMC 
Data Monitoring Committee 
DNA 
Deoxyribonucleic Acid  
ECGs 
Electrocardiograms  
ET 
Early Termination  
GM 
Gingival margin 
ID 
Identification 
IP 
Investigational Product 
IRS 
Interactive Response System  
ITT 
Intent-to-Treat Population  
JCP 
Joint Conditional Power 
L 
Lingual  
LPs 
Lumbar Punctures  
MAR 
Missing at Random  
MB 
Mesiobuccal  
MedDRA 
Medical Dictionary for Regulatory Activities  
ML 
Mesiolingual  
MMRM 
Mixed-Effects Model for Repeated Measures  


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Abbreviation or Term 
Definition 
MNAR 
Missing Not a Random  
MRI 
Magnetic Resonance Imaging 
MMSE 
Mini-Mental State Examination  
NIA-AA 
National Institute on Aging-Alzheimer’s Association  
NPI 
Neuropsychiatric Inventory  
PBMCs 
Peripheral Blood Mononuclear Cells  
PD 
Pocket Depth  
Pg 
Porphyromonas gingivalis (P. gingivalis) 
PP 
Per Protocol Population  
pPCR 
Quantitative Polymerase Chain Reaction  
SDs 
Standard Deviations  
SGP 
Subgingival Plaque  
SOPs 
Standard Operating Procedures  
TEAEs 
Treatment-Emergent Adverse Events  
UK 
United Kingdom 
US 
United States 
WHODRUG 
World Health Organization Drug Dictionary 


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2 STUDY OVERVIEW 
This is a Phase 2/3, multi-site, randomized, double-blind, placebo-controlled study that will 
assess the efficacy, safety, and tolerability of 2 dose levels of COR388 HCl in subjects with 
probable Alzheimer’s Disease (AD) dementia according to the National Institute on Aging-
Alzheimer’s Association (NIA-AA) criteria (McKhann 2011).   
The study will enroll approximately 573 generally healthy male and female subjects ≥55 and ≤80  
years of age.  Enrolled subjects must have a documented diagnosis of probable AD dementia 
with clinical evidence of progressive cognitive decline in the last year. Clinical decline will be 
defined as the evidence of progressive cognitive decline on sequential evaluations based on 
information from informants and/or cognitive testing in the context of either formal 
neuropsychological evaluation or standardized mental status examinations for probable AD 
dementia (McKhann 2011).  Subjects should not have other conditions or brain imaging 
abnormalities that can explain the symptoms of dementia.  All subjects will have lumbar 
punctures (LPs) performed at baseline (Visit 2) and at end of treatment Week 48 (Visit 10) or 
early termination visit (ET). Cerebrospinal fluid (CSF) will be tested for evidence of 
Porphyromonas gingivalis (Pg) infection and biomarkers of AD and neuroinflammation.  Blood 
(serum and plasma) will be analyzed for biomarkers of AD and neuroinflammation and 
antibodies specific for Pg.  Saliva collected in the form of an oral rinse will be tested for the 
measurement of Pg bacterial DNA using qPCR. 
A subset of sites will be selected to monitor subjects for clinical evidence of periodontitis in 
addition to AD.  An oral examination will be conducted by a study dentist/hygienist at these sites 
to assess for the presence of clinical evidence of periodontitis at screening, 24 and 48 weeks. 
Subgingival plaque (SGP) and buccal swabs will be collected at these sites and analyzed for 
measurements of biomarkers associated with P. gingivalis DNA, proteins, and inflammation. 
Due to the nature of AD, subjects must identify a primary caregiver prior to enrollment in the 
study who will assist the subject with study participation.  The primary caregiver must sign a 
caregiver informed consent.  The safety of study participants will be evaluated throughout the 
study by repeated physical examinations, vital signs, safety laboratory tests, 12-lead 
electrocardiograms (ECGs), Columbia-Suicide Severity Rating Scale (C-SSRS), magnetic 
resonance imaging (MRI), and assessments of treatment-emergent adverse events (TEAEs). 
Periodic safety reviews will be conducted during the study.  The study will consist of 3 periods: a 
screening period of up to 6 weeks, a treatment period of up to 48 weeks, and a safety follow-up 
period of 6 weeks. An interim analysis may be conducted to reassess the sample size and 
evaluate for overwhelming efficacy after 24 weeks of treatment on key outcome measures. 
Screening 
During the screening period, the eligibility of subjects will be confirmed according to the 
Schedule of Evaluations in this protocol. The Mini-Mental State Examination (MMSE) will be 
administered by a trained rater to assess the level of cognitive impairment.  MMSE will be 
assessed as early in the screening period as possible.  Subjects with MMSE score of 12-24, 
inclusive, will have the rest of their screening procedures performed or scheduled.  Magnetic 
resonance imaging (MRI) of the brain will be performed in all subjects at screening, except 
subjects with an absolute contraindication for MRI, who can have a Computed Tomography 


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(CT) scan of the brain instead. Screening procedures can be done on multiple days if needed, 
with more invasive procedures done after less invasive screening procedures are completed.  A 
screen failure is any subject who signs the informed consent but does not qualify for the study or 
discontinues the study prior to randomization.  A subject can be rescreened if the Principal 
Investigator thinks the subject may qualify for the study upon rescreening, and if the Medical 
Monitor agrees. 
Treatment Period 
Subjects who meet all eligibility criteria will enter the treatment period and will be randomized 
1:1:1 to receive 40 mg COR388 HCl, 80 mg COR388 HCl, or placebo twice a day.  
Randomization will be stratified by baseline MMSE (MMSE ≥12 and ≤18, and MMSE ≥19 and  
≤24) and Apolipoprotein E [ApoE4 Carries (Positive either Homozygous or Heterozygous) vs. 
Non-Carriers (ApoE4 All Others)] genotype to assure balanced distribution of mild and moderate 
AD and a balanced distribution of ApoE4 subjects, across treatment arms.  Subjects will receive 
their assigned blinded study treatment orally twice a day for up to 48 weeks and will come back 
to the investigative site periodically for scheduled efficacy and safety evaluations.  Blood 
samples for pharmacokinetics levels and biomarkers will be collected during selected visits.  
Baseline LP will be performed prior to the first dose of study drug, and follow-up LP will be done 
at the end of the treatment period.  Subjects will continue to receive the study drug for 48 weeks, 
unless the Investigator determines that treatment of a given subject should be stopped or 
interrupted for safety or tolerability reasons, the subject withdraws consent, or the Sponsor 
decides to stop the study.  
Safety Follow-up Period 
After completion of study treatment, subjects will continue to be monitored on the study for         
6 weeks and will have a phone call to assess safety at Weeks 49 and 51 and will return for the 
Safety Follow-up Visit (Week 54).  For subjects with early termination, end of study procedures 
(Week 48) will be performed, and subjects will be encouraged to return to the clinic for the 
Safety Follow-up Visit after 6 weeks.  Phone calls will be performed to assess safety at Week 1 
and Week 3 after end of study procedures are performed.  
Open Label Extension Period 
Subjects who choose to participate in the open label extension portion of the study and meet all 
eligibility criteria will begin the treatment period after completing the Week 48 Visit.  Subjects 
will receive COR388 HCl 80 mg or 40 mg treatment orally twice a day for up to 48 weeks and 
will come back to the investigative site periodically for scheduled efficacy and safety 
evaluations.  Subjects will continue to receive the study drug for 48 weeks, unless the 
Investigator determines that treatment of a given subject should be stopped or interrupted for 
safety or tolerability reasons, the subject withdraws consent, or the Sponsor decides to stop the 
study. 
Open Label Extension Safety Follow-up Period 
After completion of study treatment for the open label extension, subjects will continue to be 
monitored on the study for 6 weeks and will have 2 phone calls to assess safety at Week 97 and 
Week 98 and will return for the Safety Follow-up Visit at Week 102. 


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For subjects with early termination, end of study procedures (Week 96) will be performed, and 
subjects will be encouraged to participate in the Safety Follow-up phone calls and return to the 
clinic for Safety Follow-up Visit.  
3 STUDY OBJECTIVES, ENDPOINTS, AND ESTIMANDS 
This statistical analysis plan (SAP) document is the complete and final statement of the pre-
planned assessments for the Double-Blind Phase of Protocol COR388-010. This version 
supersedes and replaces all such language in the protocol and earlier versions of this 
document. The SAP for the Open Label Extension Phase will be in a separate document.  
This study was designed to assess the efficacy of COR388 HCL in treating Alzheimer’s 
disease. Therefore, a comprehensive set of primary, secondary, and exploratory objectives 
are pre-specified for these endpoints. However, a sub-study nested within the main study 
was implemented to explore the efficacy of COR388 HCL in treating periodontitis. 
Therefore, a second, independent set of objectives are pre-specified for the periodontitis 
sub-study.   
Alzheimer’s Disease 
The primary objective of this study is to assess the efficacy of COR388 HCl in the 
treatment of AD. Based on the postulated mechanism of action, an effective treatment is 
expected to slow or prevent further accumulation of AD pathology, neurodegeneration, 
cognitive decline, and loss of function in activities of daily living.   
The primary endpoints of this study are:  
• Mean change in Alzheimer’s Disease Assessment Scale-Cognitive Subscale 11 (ADAS
Cog 11), from baseline to the end of the double-blind treatment period, defined as the 
average of the week 40 and week 48 assessments.   
• Mean change in Alzheimer’s Disease Cooperative Study Group-Activities of
Daily Living (ADCS-ADL), from baseline to the end of the double-blind treatment
period, defined as the average of the week 40 and week 48 assessments. 
The primary estimands for the primary endpoints are based on a hypothetical strategy for dealing 
with the intercurrent event (ICE) of early study discontinuation to assess what would have been 
observed if the ICE had not occurred. Supplementary estimands for these endpoints are based on 
a composite strategy in which subjects with relevant ICEs are ascribed poor outcomes regardless 
of observed outcomes up to the occurrence of ICEs.  See Section 12.2 for more details.  
For study success, contrasts with placebo must be statistically significant on both 
primary endpoints in at least one of the active arms. However, for publication 
purposes, successful proof of concept will be reported if the ADAS-Cog 11 shows 
statistical significance for either or both active arms regardless of the outcome on the 
ADCS-ADL.   
The secondary endpoints of this study are:  


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• Mean change in Clinical Dementia Rating-Sum of Boxes (CDR-SB) from baseline to
the end of treatment period.  
• Mean change in Mini-Mental State Examination (MMSE) from baseline to the end
of treatment period.
• Mean change in Neuropsychiatric Inventory (NPI) Total Score from baseline to the
end of treatment period. 
Exploratory endpoints assessed in all subjects include change from screening (Visit 1) 
and/or baseline (Visit 2) to the end of treatment in the following measures:  
• NPI Caregiver Distress Score;
• Magnetic resonance imaging:
• Hippocampal volume; and
• Cortical thickness.
• Biomarkers of AD
• Biomarkers of P. gingivalis infection
• Biomarkers of inflammation and neuroinflammation
Exploratory endpoints in subsets of subjects who participated in the various 
sub-studies include change from screening/baseline to the end of the double-
blind treatment period in the following measures:  
• Winterlight Speech Assessment (only in English speaking subjects (primary language
and only in the US and UK);  
Exploratory Population Pharmacokinetics (Pop PK) will also be assessed in this study.  
• There will be a pre-specified subgroup analysis of subjects with adequate drug
exposure on the co-primary outcomes.  
• There will also be post-hoc exploratory analyses comparing drug exposures to
key efficacy and safety endpoints.   
Correlations of biomarkers with clinical endpoints will also be evaluated. The primary biomarker 
endpoint is bilateral hippocampal volume as measured by MRI. This is the primary biological 
endpoint of interest due to its inherent role in Alzheimer’s disease pathology and its ability to 
predict “likely clinical benefit” supportive of accelerated approval. 
The safety endpoints for this study are:  
• The incidence and severity of TEAEs;
• Vital signs and physical examinations;
• Laboratory values;
• MRI scans;


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• 12-lead ECGs; and
• C-SSRS
Periodontitis sub-study 
For the exploratory clinical periodontitis sub-study, subjects will be enrolled at selected study 
sites. The primary objective of this sub-study is to assess the efficacy of COR388 HCl in the 
treatment of periodontitis. The primary endpoint of the sub-study is mean change in 
Pocket Depth (PD) from baseline to the end of the double-blind treatment period for tooth sites 
with depth => 4mm at any time during the study. As with the primary endpoints for the AD 
study, a hypothetical strategy will be used to deal with the ICE of early study discontinuation. 
Successful proof of concept will be reported if the primary endpoint is statistically significant at 
the 0.10 level (p ≤ 0.10). 
The secondary endpoints of the clinical periodontitis sub-study are:  
• Mean change in Clinical Attachment Level (CAL) from baseline to the end of
treatment period for tooth sites with depth => 3mm.
• Mean change in percentage of sites with Bleeding on Probing (BOP) from baseline to
the end of treatment period.  


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4 GENERAL METHODS 
4.1 Analysis Populations 
Analysis datasets will be defined as follows: 
• Intent-To-Treat Population (ITT): The ITT population will include all subjects who
are randomized regardless of whether they took study drug. This population will be the
primary basis for efficacy analyses. When change from baseline is assessed, subjects 
will be included in the analysis only if both a baseline and a postbaseline measure 
are available because both measures are needed to derive change from baseline, the 
analysis variable. 
• The Per Protocol population (PP): The PP population will include all ITT subjects who do
not have any major protocol deviations that would affect efficacy (e.g., <80% treatment
compliance, taking a prohibited medication). Major protocol deviations will be reviewed 
and determined prior to unblinding. The PP population will be used for supportive 
analyses.  
• Safety Population: The Safety population will include all subjects who receive at
least one dose of study drug. Safety analyses will be performed using the Safety
population, and subjects will be analyzed according to the treatment they actually
received.
4.2 Summarization of Data 
Study results will be summarized by treatment group unless otherwise specified.   
Continuous data will be summarized using means, standard deviations (SDs), medians, 
maximum, minimum, and number of subjects.  Categorical data will be summarized by counts 
and percentages. 
4.3 Visit Windows 
Although stricter windows were used for scheduling visits, for analysis, the visit windows will be 
defined as follows: 
Double-blind Phase 
Scheduled 
in-clinic Visit 
Scheduled 
Week 
Scheduled 
Day  
Time Window (Days) for 
assessment collected at 
each in-clinic visit 
Time Window (Days) for 
ECG assessments 
1
Screening
Assigned as collected (if applicable) 
2
Baseline 
(Week 0) 
1 
Assigned as collected (if applicable) 
3
Week 2 
14 
2
28
2
28
4
Week 6 
42
29
63
29
63
5
Week 12 
84 
64
105 
64
126


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6
Week 18 
126 
106
147
7
Week 24 
168 
148
196
127
224
8
Week 32 
224 
197
252
9
Week 40 
280 
253
308
225
308
10
Week 48# 
336 
309
343
309
343
11
Follow-up 
378 
Assigned as collected (if applicable) 
# For subjects withdrawing early (prior to Day 309), their Week 48/Early Termination visit will be 
windowed.  Otherwise assigned as collected (Week 48).   
The following example illustrates how this visit window will be implemented.  Week 6 is 
scheduled at study day 42.  If the assessment occurs within study days 29 through 63 then the 
assessment will be deemed a Week 6 result.  If the assessment occurs before study day 29 then 
the Week 2 window will be examined.  If the assessment occurs after study day 63 then the 
Week 12 window will be examined.  Any assessments that are scheduled at less frequent visits 
will use the same approach with contiguous visit windows between scheduled visits, and the first 
post-baseline visit window will start at day 2. 
If two assessments are collected during the same visit window, the assessment which is closest to 
the actual planned study day will be used in the analysis for safety outcomes. For efficacy 
outcomes with more than one assessment in a visit window, the non-missing assessments will be 
averaged prior to analysis. 
4.4 Randomization 
Subjects who meet all eligibility criteria will enter the treatment period and will be randomized 
1:1:1 to receive 40 mg COR388 HCl, 80 mg COR388 HCl, or placebo twice a day.   
Randomization will be stratified by baseline MMSE (MMSE ≥12 and ≤18, and MMSE ≥19 and  
≤24) and Apolipoprotein E [ApoE4 Carriers (Positive for ApoE4, either Homozygous or 
Heterozygous) vs. Non-Carriers (All Others)] genotype to assure balanced distribution of mild 
and moderate AD and a balanced distribution of ApoE4+ subjects, across treatment arms.  All 
subjects will be centrally assigned to randomized study intervention using an Interactive 
Response System (IRS).  
4.5 Sample Size Justification 
The study will have an adaptive design that allows for potential adjustment in sample size 
based on the results of a planned interim analysis. An unblinded interim analysis will be 
conducted by a firewalled independent statistician (all clinical trial personnel will remain 
blinded) when approximately 100 subjects per arm have completed the Week 24 visit. 
Approximately 573 subjects are planned to be randomized 1:1:1 per treatment group (191 per 
treatment group) assuming approximately 10% missing data at the primary endpoint. Due to 
the planned interim analysis, adjustments will be made to the alpha level used in the final 
analysis to control for overall Type I error. The final criterion for efficacy to be used at the 
interim and final analysis depends on when the interim analysis occurs. The Lan-DeMets method 
modified according to Chen et al. (2004) to account for correlation between 
endpoints used at the interim and final analyses will be used to calculate the level of 
significance for each analysis.  


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With 573 subjects randomized (191 per group) and 10% missing data (172 completers per 
group) this study has approximately 90% power to detect a 2.5-point difference between each 
active treatment group compared to placebo based on change from baseline in the ADAS-
Cog 11, assuming a standard deviation of 7.1 and a significance level (alpha) of 0.05 using a 
two-sided test. For the co-primary outcome of ADCS-ADL, a 3.9-point difference between 
the active treatment groups and placebo is assumed for mean change from baseline to the end 
of treatment, with a standard deviation of 10.5. These assumptions lead to approximately 
95% power on this outcome measure, with up to 90% power for the joint success of the co-
primary outcomes, depending on their correlation.   
These power estimates further assume that 2 sequential sets of analyses, interim and final, 
will be conducted, with the Lan-DeMets spending function used to determine the test 
boundaries. Therefore, if an interim analysis is conducted when approximately 300 subjects 
have completed the Week 24 visit, then a significance level of 0.005 will be used for the 
interim analysis and a significance level of approximately 0.0456 will be used for the final 
analysis. See Section 12.5 for more details on multiplicity adjustment.  
As discussed by Chen et al 2004, the sample size re-estimation procedure based on the 
promising zone methodology (i.e., conditional power 50% to 90%) will not inflate the type 
I error and no statistical adjustment is necessary. However, the adjusted alpha at the end of 
the study will be based on the updated sample size at the final analysis, thereby causing the 
level of significance at the final analysis to potentially differ slightly from the 0.0456 quoted 
above that is based on the currently anticipated sample size.  
The actual enrollment for this study was 643 subjects randomized, approximately 12% greater 
than originally anticipated. The over-enrollment was appropriate to offset the higher rate of 
missing data anticipated as a result of COVID.  
4.6 Output Production and Validation 
All analyses will be performed using SAS V 9.3 or higher (SAS Institute, Inc, Cary, North 
Carolina, USA).  Validation and quality control of the tables and listings, which display the 
results of the statistical analysis of the data from this study, will follow the appropriate 
Innovative Analytics standard operating procedures (SOPs). 


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5 PROTOCOL DEVIATIONS 
Prior to database lock, a full list of protocol deviations will be compiled and reviewed by the 
clinical team to identify major versus minor deviations.  Major protocol deviations will be 
displayed for the safety population in subject listing. 
  
6 SUBJECT DISPOSITION 
The number of subjects who are enrolled, who are randomized, who are randomized but not 
dosed, who are in the ITT population, who are in the safety population, who complete the study, 
and who discontinue from the study, along with reason for study discontinuation, will be 
summarized in tabular format for all enrolled subjects in the double-blind phase.  The number of 
subjects with early withdrawal will also be summarized for the safety population in tabular 
format as follows:  <2 weeks, 2 to <6, 6 to <12, …, >=48 weeks in the study in the double-blind 
phase.  
Subject disposition information will be displayed for the safety population in a subject listing. 
The number of subjects randomized by country and site will be summarized in tabular format for 
the randomized population. 
 
 


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7 DEMOGRAPHIC CHARACTERISTICS 
For quantitative variables (e.g., age, height, weight, body mass index [BMI], MMSE total score 
at baseline), summary statistics (n, mean, standard deviation, minimum, median, and maximum) 
will be presented for all subjects in the safety population.  For qualitative variables (e.g., sex, 
race, ethnicity, MMSE stratum, ApoE4 stratum, participated in Alzheimer’s Disease study 
clinical trial previously), results will be summarized for all subjects in the safety population as 
counts and percentages.  Individual demographic information for the safety population will be 
displayed in subject listings. 
 
8 MEDICAL HISTORY 
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
coding system (using MedDRA Version stated in Data Management Plan).  Frequency tables by 
System Organ Class and Preferred Term will be present for prior medical history and on-going 
medical history, separately, for the safety population. 
Medical history will be listed for the safety population.   
 
9 PRIOR AND CONCOMITANT MEDICATIONS 
Medications will be coded using World Health Organization Drug Dictionary (WHODRUG, 
version specified in the Data Management Plan).  Prior and concomitant medications will be 
listed for each subject according to Anatomical Therapeutic Chemical (ATC) Level 4 term, 
preferred name, and verbatim term.   
 
10 EXTENT OF EXPOSURE 
Extent of exposure (number of days of exposure to study drug) will be presented by treatment 
group for the Safety Population.   
 
11 STUDY DRUG INTERRUPTION 
The number of interruption(s) of study medication (e.g., 0, 1, 2, >=3) will be tabulated by 
treatment group.  Duration of study medication interruption (e.g., longest duration within each 
subject) will be summarized by treatment group the Safety Population.   


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12 EFFICACY ANALYSES 
12.1 Primary Endpoint Analyses 
The co-primary endpoints are mean changes from baseline to the end of study (average of 
the assessments at Weeks 40 and 48, calculated for each patient prior to analysis) in the 
ADAS-Cog 11 total score and the Alzheimer’s Disease Cooperative Study – Activities of 
Daily Living (ADCS-ADL) total score. For ADAS-Cog 11, baseline will be defined as the 
average of the last two non-missing values (either scheduled, unscheduled or repeat 
evaluations) performed between screening and Week 0 (i.e., before or at the day the subject 
receives the first dose of study drug). If only one baseline ADAS-Cog 11 assessment is 
available, it will be used. For ADCS-ADL, baseline will be the last non-missing value 
(either scheduled, unscheduled or repeat) before or at the day the subject receives the first 
dose of study drug. For publication purposes, successful proof of concept will be reported if 
the ADAS-Cog 11 shows statistical significance for either or both active arms regardless of 
the outcome on the co-primary outcome.   
Sites will be pooled for Europe and the US as follows:   
For Europe, all sites within a country will be pooled and considered as single site. After 
pooling sites within a country, all countries are expected to have at least 2 patients in each 
treatment arm. If this condition is not satisfied, the countries with less than 2 patients per 
treatment arm will then be pooled with the nearest country. For Great Britain, this will be 
France, for Spain, this will also be France, for France, it will be pooled with Great Britain. If 
any 2 of those 3 countries do not have at least 2 patients per arm, only those 2 countries will 
be pooled. For Netherlands, it will be Poland and for Poland, it will be Netherlands. 
US sites will be pooled within each state with the following exceptions: Each state will be a 
separate site except KS will be pooled with ID, MS will be pooled with IL, NM will be 
pooled with AZ, and NY will be 2 sites: Albany and others, and CA will be 2 sites: CT 
Trials and other, GA will be 2 sites. Florida sites with at least 2 subjects in each treatment 
arm will be separate sites. Any remaining Florida sites will be put into the pooling 
algorithm. Any of the above defined sites or state groups that do not meet the requirement of 
2 subjects per treatment arm will also be put into the pooling algorithm.   
The pooling algorithm will start with the largest site and pool it with the smallest site, then 
next smallest, continuing until it has at least 2 patients in each treatment arm. The sort order 
will be by site size and then site name alphabetically. At the end of the pooling process, if 
the remaining patients do not result in a site with at least 2 patients per arm, the extra 
sites/patients will be pooled with the last site created in the pooling process.  
The adequacy of the pooling mechanism will be evaluated post database lock prior to 
unblinding and analysis. Any modification will be described in the CSR.  
Summary statistics (n, mean, standard deviation, minimum, median, and maximum) will 
be presented for the observed values for each of the co-primary endpoints at each time point 
for the ITT population, including weeks 40 and 48 separate as well as averaged. Summary 
statistics will also be presented for the change-from-baseline values to each postbaseline time 
point as listed above.   


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Each of the co-primary estimands/endpoints will be analyzed using a likelihood-based 
mixed-effects model for repeated measures (MMRM) with SAS PROC MIXED to compare 
mean change from baseline for COR388 HCl vs placebo. The primary analysis will be 
applied to the ITT dataset. The MMRM model will include treatment group, study visit, 
site/country, ApoE4 status, acetylcholinesterase inhibitor and/or memantine (AD Med) 
usage at baseline (yes/no), and the interactions of Visit with treatment group, ApoE4 status, 
and AD Med usage all as categorical fixed effects. Baseline MMSE score and the baseline 
score for the variable being analyzed, along with their interactions with visit will be 
included as continuous fixed effects. The analysis will use an unstructured covariance 
matrix to model the within-subject errors. The Kenward-Roger approximation will be used 
to estimate the denominator degrees of freedom.  
If the model fails to converge, the model will be simplified by excluding the terms for 
acetylcholinesterase inhibitor and memantine usage and its interaction with visit. If the 
model still fails to converge, the site term will be replaced with 3 regions in the US (Pacific 
time zone, Eastern time zone without Florida and other (includes Florida), and Europe will 
be one region. If this analysis still fails to converge, more parsimonious correlation 
structures will be implemented in this order: heterogeneous Toeplitz, heterogeneous 
compound symmetric, and compound symmetric. The first correlation structure to yield 
convergence will be the primary analysis. 
The following SAS code implements the MMRM primary analysis.  
Proc Mixed;  
Class trtgrp subj Visit site_country APOE4_status acetylcholinesterase_  
      inhibitor_memantine_usage;  
Model cfb = trtgrp Visit site_country APOE4_status acetylcholinesterase_              
      inhibitor_memantine_usage baselineMMSE baseline_score 
      trtgrp*Visit APOE4_status*Visit acetylcholinesterase_inhibitor_memantine_    
      usage*Visit baselineMMSE*Visit Baseline_score*Visit  
     /CL solution ddfm=kenwardroger residual outp=testresid covb;  
           Repeated visit / subject = subj(trtgrp) type=un rcorr;  
Lsmeans trtgrp*visit / pdiff cl slice=Visit;  
Run; 
where cfb is the change from baseline for that endpoint. As for ADAS-Cog 11 and ADCS-
ADL, Baseline MMSE will be defined as the average of the last two non-missing values 
(either scheduled, unscheduled or repeat) before or at the day subject receives the first dose 
of study drug.  
The primary inferences will be drawn from the adjusted treatment differences 
(LSMEANS) at end of treatment, defined as the average of Weeks 40 and 48 assessments. 
Treatment differences for each post-baseline visit will also be derived using the MMRM 
model, which will entail a second (sensitivity) analysis in which outcomes from each visit 
are included without averaging the Weeks 40 and 48 assessments.  
Estimated treatment differences for each visit will be presented along with corresponding 
95% confidence intervals and p-values.  


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12.2 Sensitivity and Supplementary Analyses 
Sensitivity to choice of covariates 
The analysis specified below is included as a sensitivity analysis because it was used in analysis 
of interim data and is used for secondary endpoints in the final analysis. It differs from the 
current primary analysis in that it does not include interactions of covariates with visit, except for 
the treatment group by visit interaction.     
Proc Mixed; 
Class trtgrp subj visit site_country APOE4_status acetylcholinesterase_ 
    inhibitor_memantine_usage; 
Model cfb = trtgrp visit trtgrp*visit site_country APOE4_status 
   Acetylcholinesterase_inhibitor_memantine_usage baselineMMSE 
   baseline_score /CL solution ddfm=kenwardroger residual outp=testresid 
   covb; 
Repeated visit / subject = subj(trtgrp) type=un rcorr; 
Lsmeans trtgrp*visit / pdiff cl slice=visit; 
Run; 
Sensitivity to protocol violations 
The influence of lack of adherence to the protocol will be evaluated by repeating the primary 
analysis on the per-protocol data set. 
Sensitivity to missing data assumptions 
The primary MMRM analysis assumes that the missing data arise from a missing at 
random (MAR) mechanism. To assess the robustness of the results to departures from 
MAR, a sensitivity analysis will be conducted such that the monotone missing data is 
imputed assuming a missing not at random (MNAR) mechanism that provides a stress test 
of the MAR assumption and a conservative estimate of the treatment effect.  
For this sensitivity analysis, a pattern-mixture model will be implemented using multiple 
imputation (100 imputed datasets) and inference will be based on the combined estimates 
using Rubin’s rules, the standard multiple imputation technique, in SAS. 
The missing data will be imputed using the controlled-based pattern-mixture model 
approach outlined by Ratitch and O’Kelly (2011). With this approach, subjects 
who discontinue from the COR388 HCl 80 mg or COR388 HCl 40mg treatment groups, for 
reasons not related to COVID, will be assumed to follow the outcome trajectory of 
otherwise similar subjects in the placebo (control) arm.  Missing values will be imputed as 
if subjects had been on placebo throughout the study, thereby ascribing placebo-like 
outcomes to these subjects. Subjects who discontinued from placebo (control) treatment will 
have missing values imputed based on the MAR assumption. That is, missing values for 
reasons not related to COVID will be imputed for the active arms using the imputation 
model developed for the placebo group, thereby attenuating the treatment effects in the 
active arms commensurate with the rate of non-COVID related missing data. Missing values 


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due to COVID will be left as missing in this sensitivity analysis and thereby assumed to be 
MAR. 
Because pattern mixture models overestimate the already very large variability in 
Alzheimer’s disease data, these model results are likely to be much less able to discriminate 
treatment differences than the primary model. These results will focus on the potential bias 
in the primary model due to dropout by comparing the estimates from the primary and 
sensitivity models, not by preservation or loss of statistical significance.  
Sensitivity to non-normality 
Inspection of blinded data suggested the potential for violation of the assumption of 
normally distributed residuals in the primary MMRM analysis. Therefore, a non-parametric 
analysis will be implemented. To account for missing data via MAR as in the primary 
MMRM analysis, multiple imputation will be implemented using SAS PROC MI, with an 
imputation model congenial with the MMRM analysis model, and each imputed dataset 
analyzed via the Wilcoxon rank sum test implemented via SAS PROC NPAR1WAY. The 
resulting z scores and standard errors of 1 will be combined via Rubin’s rules for final 
inference using SAS PROC MIANALYZE.   
 
Supplementary Estimands and analyses 
The supplementary estimand for the co-primary endpoints is based on a composite strategy for 
dealing with the ICE of early study withdrawal. The outcomes in this analysis are a composite of 
the observed outcomes and whether the subjects completed the study. Subjects who discontinued 
early will be assigned poor outcomes regardless of observed outcomes prior to withdrawal. Data 
will be analyzed using the Wilcoxon rank sum test via SAS NPAR1WAY, with the worst rank 
assigned to patients who withdrew early.  
 
12.3 Subgroup Analyses 
Demographics and Baseline Characteristics Subgroup Analyses  
To assess the effects of various demographic and baseline characteristics on treatment 
outcome, subgroup analyses for the co-primary endpoints, the mean change from baseline in 
ADAS-Cog 11 at the average of Weeks 40 and 48, and the mean change from baseline in 
ADCS-ADL at the average of Weeks 40 and 48, will be as follows:  
 
• Baseline MMSE severity (baseline MMSE 12-18 (moderate); Baseline MMSE 19-
24 (mild); and  
• *Baseline MMSE severity as a continuous variable  
• *ApoE4 status (e.g., ApoE4 Carriers (Positive either Homozygous or 
Heterozygous); Non-Carriers (All Others)).  
• Amyloid positive and negative using Ab42/Ab40 Ratio status at baseline (ratio 
<=0.095, ratio >0.095) from cerebrospinal fluid (EuroImmun Assay)  


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• Acetylcholinesterase inhibitor and/or Memantine status at baseline (yes, 
no)  
• Region (US; all other)  
Biomarker Subgroup Analyses  
The following subgroups will be used to understand the mechanism of action better and 
inform future trials and biomarker selection:  
• *Porphyromonas gingivalis antibody status at baseline (High vs Low)  
• *Porphyromonas gingivalis DNA status at baseline (not detected, detected) from 
oral samples (saliva in oral rinse, buccal swab, or subgingival plague)  
• *Evidence of Porphyromonas gingivalis infection (not detected, detected) 
from cerebrospinal fluid   
• *Evidence of target inhibition based on reduction of gingipain activity  
These subgroup analyses may also be performed for the secondary and exploratory 
endpoints. The subgroups marked with an asterisk are the most relevant ones and are 
expected to show differences.  
Two of the subgroup analyses are based on continuous scores that have been classified into 
2 groups: baseline MMSE group and Ab42/Ab40 ratio group. For these subgroup 
analyses, the interaction between treatment and covariate and the 3-way interaction of 
treatment by covariate by time will be assessed to determine whether any differences 
between groups are related to an effect on the continuous underlying variable.   
Following is the SAS code which will be used for the MMRM analysis of 
subgroups:  
Proc Mixed;  
Class trtgrp subj visit subgroup_factor site_country APOE4_status  
acetylcholinesterase_inhibitor_memantine_usage;  
Model cfb = trtgrp visit subgroup_factor trtgrp*visit     
         trtgrp*subgroup_factor trtgrp*visit*subgroup_factor site_country  
   APOE_status acetylcholinesterase_inhibitor_memantine_usage  
   Baseline_score BaselineMMSE /CL solution ddfm=kenwardroger residual        
   outp=testresid covb;  
Repeated visit / subject = subj(trtgrp) type=UN rcorr;  
Lsmeans trtgrp*subgroup_factor / pdiff cl; 
Run;  
where cfb is the change from baseline for that endpoint. Country/site, visit, 
ApoE4, and acetylcholinesterase inhibitor and/or memantine usage at baseline 
are categorical terms. Baseline MMSE and baseline score will be treated as 
continuous variables.  Baseline will be defined as the average of the last two 
non-missing values, or if one is missing, the last non-missing value (either 


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scheduled, unscheduled or repeat) before or at the day the subject receives the 
first dose of study drug. The baseline MMSE values will be removed from the 
model for the MMSE severity subgroups.  
Cmax and AUC(0-24 Hours) Subgroup Analyses  
Subjects in the 80 mg COR388 HCl group with the highest plasma Cmax exposures, 
defined as the top 60% of the 80 mg COR388 HCl group, will be compared to the placebo 
group using the MMRM analysis. This MMRM analysis will be repeated for the highest 
plasma AUC (0-24 hours) exposures using the top 60% of the 80 mg COR388 HCl group 
compared to the placebo group.  
Following is the SAS code which will be used for the MMRM analysis for the ‘highest’ 
Cmax and ‘highest’ AUC(0-24 hours) subgroups:  
 
Proc Mixed;  
Class trtgrp subj visit site_country APOE4-status acetylcholinesterase_   
          inhibitor_memantine_usage;  
Model cfb = trtgrp visit trtgrp*visit site_country APOE4_status  
Acetylcholinesterase_inhibitor_memantine_usage   
baseline_score baselineMMSE /CL solution ddfm=kenwardroger 
residual outp=testresid covb;  
Repeated visit / subject = subj(trtgrp) type=UN rcorr;  
Lsmeans trtgrp*visit / diff pdiff cl slice=visit;  
Run;  
where cfb is the change from baseline for that endpoint. Country/site, visit, ApoE4, 
and acetylcholinesterase inhibitor and/or memantine usage at baseline are categorical terms. 
Baseline MMSE and baseline score will be treated as a continuous variable. Baseline will be 
defined as the average of the last two non-missing value (either scheduled, unscheduled or 
repeat) before or at the day the subject receives the first dose of study drug.  
COVID-19 Subgroup Analyses  
The following subgroup analyses will be used to examine the exclusion of subjects with 
adverse event preferred terms of COVID-19:  
• Exclusion of subjects with preferred terms of COVID-19, COVID-19 
pneumonia, asymptomatic COVID-19, or exposure to SARS-CoV-2  
Following is the SAS code which will be used for the MMRM analysis for COVID-19 
subgroup analysis:  
Proc Mixed;  
Class trtgrp subj visit site_country APOE4-status acetylcholinesterase_  
    inhibitor_memantine_usage; 
Model cfb = trtgrp visit trtgrp*visit site_country APOE4_status  
Acetylcholinesterase_inhibitor_memantine_usage   


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baseline_score baselineMMSE /CL solution ddfm=kenwardroger 
residual  outp=testresid covb;  
Repeated visit / subject = subj(trtgrp) type=UN rcorr;  
Lsmeans trtgrp*visit / diff pdiff cl slice=visit;  
Run;  
where cfb is the change from baseline for that endpoint. Country/site, visit, ApoE4, 
and acetylcholinesterase inhibitor and/or memantine usage at baseline are categorical terms. 
Baseline MMSE and baseline score will be treated as continuous variables. Baseline will be 
defined as the average of the last two non-missing value (either scheduled, unscheduled or 
repeat) before or at the day the subject receives the first dose of study drug.  
 
Additional subgroup analysis may be performed, such as excluding subjects based on the 
presence of COVID-19 antibodies that indicate recent infection." 
 
12.4 Secondary Endpoint Analyses 
Secondary endpoints will be analyzed for the ITT population only.  
Clinical Dementia Rating-Sum of Boxes (CDR-SB)  
Summary statistics (n, mean, standard deviation, minimum, median, and maximum) will 
be presented for the observed values for the CDR-SB at each time point for the ITT 
population. Summary statistics will also be presented for the change-from-baseline values 
to each postbaseline time point. Baseline will be defined as the average of the last two non-
missing value (either scheduled, unscheduled or repeat) before or at the day the subject 
receives the first dose of study drug.  
The change from baseline in CDR-SB at the average of Weeks 40 and 48 will be analyzed 
using the MMRM model below: 
 
Proc Mixed; 
Class trtgrp subj visit site_country APOE4_status acetylcholinesterase_ 
    inhibitor_memantine_usage; 
Model cfb = trtgrp visit trtgrp*visit site_country APOE4_status 
   Acetylcholinesterase_inhibitor_memantine_usage baselineMMSE 
   baseline_score /CL solution ddfm=kenwardroger residual outp=testresid 
   covb; 
Repeated visit / subject = subj(trtgrp) type=un rcorr; 
Lsmeans trtgrp*visit / pdiff cl slice=visit; 
Run; 
CDR-SB information for the ITT population will be displayed in subject listings.  
 
 
 


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Mini-Mental State Examination (MMSE)  
Summary statistics (n, mean, standard deviation, minimum, median, and maximum) will 
be presented for the observed values for the MMSE total score at each time point for the 
ITT population. Summary statistics will also be presented for the change-from-baseline 
values to each postbaseline time point. Baseline will be defined as the average of the last two 
non-missing value (either scheduled, unscheduled or repeat) before or at the day the subject 
receives the first dose of study drug.  
The change from baseline in MMSE Total Score at the average of Weeks 40 and 48 will use 
the same model as for CDR above, except that baseline score is not included because for 
this outcome baseline score and baseline MMSE are identical.   
MMSE information for the ITT population will be displayed in subject listings. 
Neuropsychiatric Inventory (NPI) Total Score  
Summary statistics (n, mean, standard deviation, minimum, median, and maximum) will 
be presented for the observed values for the NPI Total Score at each time point for the 
ITT population. Summary statistics will also be presented for the change-from-baseline 
values to each postbaseline time point. Baseline will be defined as the last non-missing value 
(either scheduled, unscheduled or repeat) before or at the day the subject receives the first 
dose of study drug.  
The change from baseline in NPI Total Score at Week 48 will use the same model as for 
the CDR above   
NPI information for the ITT population will be displayed in subject listings.  
 
Correlations of Biomarkers with Co-primary endpoints 
 
The primary biomarker endpoint is bilateral hippocampal volume as measured by MRI. This is 
the primary biological endpoint of interest due to its inherent role in Alzheimer’s disease 
pathology and its ability to predict “likely clinical benefit” supportive of accelerated approval. 
 
Correlations between bilateral hippocampal volume as measured by MRI with the co-primary 
clinical endpoints will be assessed using Pearson’s and Spearman’s correlations via PROC 
CORR in SAS. Other correlations of interest include correlations between hippocampal volume, 
measures of gingivalis infection, biomarkers of AD pathology or neurodegeneration, and clinical 
endpoints.  
 
12.5 Multiplicity 
Strong, family-wise protection of Type I error will be maintained at 5% through multiplicity 
adjustments for multiple looks at the data (interim and final), multiple dose arms, and 
multiple endpoints. 
The Type I error for the interim and final analysis will be adjusted using the Lan-DeMets 
spending function. If the study does not stop at the interim analysis for overwhelming 
efficacy or futility, the study will retain its original design and the final analysis will be based 


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on 48 weeks of treatment with ADAS-Cog and ADCS-ADL as co-primary endpoints (see 
Figure 1). Because of the changes in co-primary endpoints for the final analysis (i.e., CDR-
SB at Week 24 replaced by ADCS-ADL at Week 40/48 and ADAS Cog at Week 24 replaced 
by ADAS-Cog at Week 40/48), the Lan-DeMets correction for sequential analysis will be 
further adjusted as described in Chen, et al. (2014). This adjustment will account for the 
correlation between the outcomes and time points. The correlations used for this adjustment 
will be 0.56 between ADAS-Cog at Weeks 24 and 48, and -0.30 between CDR-SB at Week 
24 and ADCS-ADL at 48-week. These correlations were estimated using pooled data from 
placebo patients from 3 ADCS studies (i.e., NSAID, Selegiline, and Homocysteine 
studies) described in Sano, et al. 1997, Aisen, et al. 2003, and Aisen, et al. 2008. The 
boundaries will be calculated to account for the change in timing of evaluation and endpoint 
and the more conservative boundary will be used for final analysis at Week 40/48. Using the 
planned enrollment at interim and final analyses, the final alpha was expected to be 0.0456. 
Using the actual enrollments, the actual alpha is 0.0455.   
At both the interim analysis and the final analysis, the Benjamini-Hochberg multiplicity 
adjustment procedure (Benjamini and Hochberg, 1995 and Benjamini and Yekutieli, 2001) 
will be used to adjust for the multiple comparisons between placebo and the two active dose 
arms. Both treatment comparisons, 40 mg (low dose) and 80 mg COR388 HCl (high dose) 
vs. placebo are of equal interest. Therefore, the Benjamini-Hochberg adjustment will be 
applied as follows: α = i/m*Q, where α is the appropriate critical p value (actual alpha), Q= 
0.0455, i is the rank of the endpoint (1 or 2 in this case) and m = the number of tests (2 in 
this case). The resulting critical p value for declaring significance of the dose arm with the 
best outcome = ½*0.0455 = 0.0228, and the appropriate p value for declaring significance 
of the other dose arm = 2/2*0.0.0455 = 0.0455.   
Treatment comparisons of 40 mg and 80 mg COR388 HCl vs. placebo for the secondary 
endpoints will be performed only if both co-primary endpoints compared to placebo are 
statistically significant at the respective interim or final analysis. Otherwise, secondary 
endpoints will be presented using descriptive statistics. 
Multiplicity is controlled across the two co-primary endpoints within each dose arm by 
requiring both endpoints to be statistically significant to conclude that dose was effective. 


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Figure 1: Diagram of alpha spending at interim and final analyses based on planned sample 
sizes.  
 
Summary statistics (n, mean, standard deviation, minimum, median, and maximum) will be 
presented for the observed values for ADAS-Cog 11, CDR-SB, and ADCS-ADL endpoints at 
each time point for the ITT population.  Summary statistics will also be presented for the 
change-from-baseline values to each post baseline time point.  
ADAS-Cog 11, CDR-SB, and ADCS-ADL information for the ITT population will be displayed, 
separately, in subject listings. 
No adjustment for multiplicity will be done for MMSE and NPI total score. 
 
12.6 Exploratory Endpoint Analyses 
NPI Caregiver Distress Total Score 
Summary statistics (n, mean, standard deviation, minimum, median, and maximum) will be 
presented for the observed values for the NPI caregiver distress total score at each time point for 
the ITT population.  Summary statistics will also be presented for the change-from-baseline 
values to each postbaseline time point.  Baseline will be defined as the last non-missing value 
(either scheduled, unscheduled or repeat) before or at the day the subject receives the first dose 
of study drug. 


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The change from baseline in NPI caregiver distress total Score at the Week 48 will use the same 
methodology as that for the secondary endpoint analysis.  
NPI information for the ITT population will be displayed in subject listings. 
 
Winterlight Speech Assessment 
The Winterlight speech assessment will only be conducted in English speaking (primary 
language) subjects and only in the United States and United Kingdom.  
Summary statistics (n, mean, standard deviation, minimum, median, and maximum) will be 
presented for the observed values for each of 3 scores from the Winterlight Speech Assessment 
at each time point for the ITT population.  The 3 scores are prepositions, information units, and 
global coherence.  Summary statistics will also be presented for the change-from-baseline values 
to each postbaseline time point.  Baseline will be defined as the last non-missing value (either 
scheduled, unscheduled or repeat) before or at the day the subject receives the first dose of study 
drug. 
The change from baseline in each of 3 scores from the Winterlight Speech Assessment at the 
Week 48 will use the same methodology as that for secondary endpoint analysis.    
Information on the 3 scores above from the Winterlight Speech Assessment for the ITT 
population will be displayed in subject listings. 
For the above exploratory endpoints (i.e., MMSE Total Score, NPI Total Score, and 4 
Winterlight Speech Assessment Scores), no adjustment for multiplicity will be done. 
Magnetic Resonance Imaging (MRI) Volumetric Measures of the Brain 
MRI volumetric measures (right, left, and total hippocampal volume and cortical thickness) of 
the brain will be performed in all subjects at Screening. Subjects who have an absolute 
contraindication for MRI can have a CT scan of the brain instead. A follow-up MRI or CT will 
be performed within 8 days prior to Visit 10 (or Early Termination) in subjects who had a 
baseline MRI performed at screening.   
Summary statistics (n, mean, standard deviation, minimum, median, and maximum) will be 
presented for the observed values for each of 4 scores, the right, left and total hippocampal 
volume and the Mayo cortical thickness, at each time point for the ITT population.  Summary 
statistics will also be presented for the change-from-baseline values to each postbaseline time 
point.  Baseline will be defined as the last non-missing value (either scheduled, unscheduled or 
repeat) before or at the day the subject receives the first dose of study drug. 
For each of these 4 MRI scores, the change from baseline at the Week 48 will be analyzed using 
ANCOVA with fixed effects of treatment group, ApoE4 status, acetylcholinesterase inhibitor 
and/or memantine usage, site_country and baseline score as a covariate for the ITT population. 
Right hippocampal volume is historically more sensitive to change than left hippocampal volume 
and will be the primary region of interest for this analysis, with left and total hippocampal 
volume and cortical thickness providing additional evidence for a treatment effect. 
 
Following is the SAS code which will be used for the ANCOVA analysis: 
Proc GLM; 


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Class trtgrp site_country APOE4_status                  
               acetylcholinesterase_inhibitor_memantine_usage; 
 
Model cfb = trtgrp site_country APOE4_status acetylcholinesterase_   
               inhibitor_memantine_usage baseline_score; 
 
 
Lsmeans trtgrp / pdiff cl; 
Run; 
where cfb is the change from baseline for that endpoint.  Baseline will be defined as the last non-
missing value (either scheduled, unscheduled or repeat) before or at the day the subject receives 
the first dose of study drug. 
Right, left, and total hippocampal volume and the Mayo cortical thickness information will be 
displayed in subject listings for the ITT population. 
For the above exploratory endpoints, no adjustment for multiplicity will be done, but the listed 
order will be considered an informal hierarchy. 
Oral Examination to Determine Presence of Periodontitis 
Oral examinations were done in subjects at selected sites. The examination included tooth count, 
identification of any hard or soft tissue lesions, assessment for presence of severe dental disease, 
determination of Pocket Depth (PD) and Clinical Attachment Level (CAL) at 6 sites per tooth 
(distobuccal [DB], buccal [B], mesiobuccal [MB], distolingual [DL], lingual [L], mesiolingual 
[ML]), gingival margin (GM) position, and assessment of Bleeding on Probing (BOP).  CAL is 
defined as PD minus GM. Subjects enrolled in the study who did not have at least 8 teeth were 
exempt from the oral examination sub-study.  
Measurements of PD and gingival margin GM and calculated attachment levels (AL) will be 
used to determine the presence of periodontitis according to the Centers for Disease 
Control/American Academy of Periodontology (CDC/AAP) criteria: 
 
No periodontitis  
No evidence of mild, moderate or severe periodontitis 
Mild periodontitis 
≥ 2 interproximal sites with clinical attachment level (CAL) ≥ 3 mm, and 
≥ 2 interproximal sites with pocket depth (PD) ≥ 4 mm (not on same 
tooth), Or  
one site with PD ≥ 5 mm 
Moderate Periodontitis 
≥ 2 interproximal sites with CAL ≥ 4 mm (not on same tooth), Or  
≥ 2 interproximal sites with PD ≥ 5 mm (not on same tooth) 
Severe Periodontitis  
≥ 2 interproximal sites with CAL ≥ 6 mm (not on same tooth), And 
≥ 1 interproximal site with PD ≥ 5 mm 
The severity of periodontitis (none, mild, moderate, and severe) will be summarized (n, %) by 
treatment group at each visit for the ITT population. 
 


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Pocket Depths 
For all pocket depth analyses only sites with depth => 4mm at any time in the study will be 
included.  
For each subject at each visit, the mean pocket depth will be calculated for all 4 interproximal 
sites (e.g., DB, MB, DL, and ML). 
For mean pocket depth within each subject, summary statistics (n, mean, standard deviation, 
minimum, median, and maximum) will be presented for the observed values at each time point 
by treatment group for the ITT population.  Summary statistics will also be presented for the 
change-from-baseline values to each postbaseline time point.  Baseline will be defined as the last 
non-missing value (either scheduled, unscheduled or repeat) before or at the day the subject 
receives the first dose of study drug.   
Mean pocket depth will be analyzed using a mixed-effects model for repeated measures 
(MMRM) with SAS PROC MIXED to compare change from baseline for COR388 HCl vs 
placebo.  The MMRM model will include treatment group, visit, site_country, treatment group 
by visit interaction as fixed effects, with baseline mean pocket depth as a covariate using the ITT 
population.  The analysis will be based on an unstructured covariance matrix to model the 
within-subject errors. A Kenward-Roger approximation will be used for the denominator degrees 
of freedom. 
Following is the SAS code which will be used for the MMRM analysis: 
 
Proc Mixed; 
 
Class trtgrp subj visit site_country; 
Model cfb = trtgrp visit trtgrp*visit site_country baseline_score /CL solution  
   ddfm=kenwardroger residual outp=testresid covb; 
 
Repeated visit / subject = subj(trtgrp) type=UN rcorr; 
 
Lsmeans trtgrp*visit / pdiff cl slice=visit; 
Run; 
where cfb is the change from baseline for that endpoint.  Baseline will be defined as the last non-
missing value (either scheduled, unscheduled or repeat) before or at the day the subject receives 
the first dose of study drug. 
The same teeth will be used in the above analyses (i.e., if any tooth is missing after the first dose 
of study drug, all data for this tooth will be excluded from the analyses).  
No adjustment for multiplicity will be done. 
Shifts from baseline based on predefined categories will be tabulated (n, %) by treatment group 
at each post-baseline visit for the mean pocket depth.  The predefined categories will be <=3mm, 
4-6mm, and >=7mm. 
Clinical Attachment Level 
For all clinical attachment level (CAL) analyses only sites with depth => 3mm at any time in the 
study and for only subjects with a detectable Porphyromonas gingivalis DNA concentration at 
baseline will be included.  
For each subject at each visit, the clinical attachment score will be calculated for all 4 
interproximal sites (e.g., DB, MB, DL, and ML). 


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For mean clinical attachment score within each subject, summary statistics (n, mean, standard 
deviation, minimum, median, and maximum) will be presented for the observed values at each 
time point by treatment group for the ITT population.  Summary statistics will also be presented 
for the change-from-baseline values to each postbaseline time point.  Baseline will be defined as 
the last non-missing value (either scheduled, unscheduled or repeat) before or at the day the 
subject receives the first dose of study drug.   
The change from baseline in mean clinical attachment score at Week 48 will use the same 
methodology as that for the mean pocket depth endpoint analysis but adjusting for corresponding 
baseline value as a covariate for the ITT population.   
The same teeth will be used in the above analyses (i.e., if any tooth is missing after the first dose 
of study drug, all data from this tooth will be excluded from the analyses). No adjustment for 
multiplicity will be done. 
Shifts from baseline based on predefined categories will be tabulated (n, %) by treatment group 
at each post-baseline visit for the mean clinical attachment.  The predefined categories will be 
<=2mm, 3-5mm, and >=6mm. 
Bleeding on Probing 
For each subject at each visit, the percentage of sites with bleeding on probing will be calculated 
for all 6 sites (e.g., DB, MB, DL, B, L, and ML) across all teeth present. 
For percentage of sites with bleeding on probing, summary statistics (n, mean, standard 
deviation, minimum, median, and maximum) will be presented for the observed values at each 
time point by treatment group for the ITT population.  Summary statistics will also be presented 
for the change-from-baseline values to each postbaseline time point.  Baseline will be defined as 
the last non-missing value (either scheduled, unscheduled or repeat) before or at the day the 
subject receives the first dose of study drug.   
The change from baseline in percentage of bleeding on probing at Week 48 will use the same 
methodology as that for the mean pocket depth endpoint analysis but adjusting for corresponding 
baseline value as a covariate for the ITT population.   
The same teeth will be used in the above analyses (i.e., if any tooth is missing after the first dose 
of study drug, this tooth will be excluded from the analyses).  
No adjustment for multiplicity will be done. 
Subgroup Analyses 
To assess the effect of Porphyromonas gingivalis DNA status at baseline (not detected, detected) 
from oral samples (saliva in oral rinse, buccal swab, or subgingival plague) on treatment 
outcome, subgroup analyses for the mean change from baseline in pocket depths, clinical 
attachment levels and percentage of sites with bleeding on probing will be analyzed using the 
MMRM. 
Following is the SAS code which will be used for the MMRM analysis of subgroups: 
 
Proc Mixed; 
Class trtgrp subj visit subgroup_factor site_country; 


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      Model cfb = trtgrp visit subgroup_factor trtgrp*visit 
          subgroup_factor*trtgroup trtgrp*visit*subgroup_factor 
          site_country baseline_score/CL solution ddfm=kenwardroger residual outp=testresid 
          covb; 
       Repeated visit / subject = subj(trtgrp) type=UN rcorr; 
       Lsmeans trtgrp *subgroup_factor / diff pdiff cl  
Run; 
 
where cfb is the change from baseline for that endpoint.  Baseline will be defined as the last non-
missing value (either scheduled, unscheduled or repeat) before or at the day the subject receives 
the first dose of study drug. 
The oral examination information for the ITT population will be displayed in subject listings. 
Porphyromonas Gingivalis DNA Concentrations from Saliva in Oral Rinse 
Saliva will be collected in an oral rinse with a preservative.   
Summary statistics (n, mean, standard deviation, minimum, median, and maximum) will be 
presented for the observed values for Porphyromonas gingivalis DNA concentrations at each 
time point for the ITT population for only subjects with a detectable Porphyromonas gingivalis 
DNA concentration at any point in the study. Summary statistics will also be presented for the 
change-from-baseline values to each postbaseline time point for only patients with a detectable 
Porphyromonas gingivalis DNA concentration at any point in the study. Baseline will be defined 
as the average of the last two non-missing values (either scheduled, unscheduled or repeat) 
before or at the day the subject receives the first dose of study drug. 
Porphyromonas gingivalis DNA concentration will be analyzed using a mixed-effects model for 
repeated measures (MMRM) with SAS PROC MIXED to compare change from baseline for 
COR388 HCl vs placebo for only subjects with a detectable Porphyromonas gingivalis DNA 
concentration at any point in the study.  The MMRM model will include treatment group, visit, 
site_country, treatment group by visit interaction as fixed effects, with baseline mean 
Porphyromonas gingivalis DNA concentration as a covariate. The analysis will be based on an 
unstructured covariance matrix to model the within-subject errors. A Kenward-Roger 
approximation will be used for the denominator degrees of freedom.  
 
Following is the SAS code which will be used for the MMRM analysis: 
 
Proc Mixed; 
 
Class trtgrp subj visit site_country; 
Model cfb = trtgrp visit trtgrp*visit site_country baseline_score/CL solution 
  ddfm=kenwardroger residual outp=testresid covb; 
 
Repeated visit / subject = subj(trtgrp) type=UN rcorr; 
 
Lsmeans trtgrp*visit / pdiff cl slice=visit; 
Run; 
where cfb is the change from baseline for that endpoint.  Baseline will be defined as the average 
of the last two non-missing values (either scheduled, unscheduled or repeat) before or at the day 
the subject receives the first dose of study drug. 


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Correlation analyses of Porphyromonas gingivalis concentrations at Week 48 and ADAS-Cog 11 
at average of Weeks 40 and 48 will be conducted for only subjects with a detectable 
Porphyromonas gingivalis DNA concentration at any point of the study. 
Porphyromonas gingivalis concentrations for the ITT population will be displayed in subject 
listings. 
Porphyromonas Gingivalis DNA Concentrations from Buccal Swab 
Porphyromonas gingivalis concentrations will be collected from buccal cells at selected sites.   
Summary statistics (n, mean, standard deviation, minimum, median, and maximum) will be 
presented for the observed values for Porphyromonas gingivalis concentrations at each time 
point for the ITT population for only subjects with a detectable Porphyromonas gingivalis DNA 
concentration at any point in the study.  Summary statistics will also be presented for the 
change-from-baseline values to each postbaseline time point for only subjects with a detectable 
Porphyromonas gingivalis DNA concentration at any point in the study.  Baseline will be 
defined as the last non-missing values (either scheduled, unscheduled or repeat) before or at the 
day the subject receives the first dose of study drug. 
Porphyromonas gingivalis DNA concentration will be analyzed using a mixed-effects model for 
repeated measures (MMRM) with SAS PROC MIXED to compare change from baseline for 
COR388 HCl vs placebo for only subjects with a detectable Porphyromonas gingivalis DNA 
concentration at any point in the study.  The MMRM model will include treatment group, visit, 
site_country, treatment group by visit interaction as fixed effects, with baseline mean 
Porphyromonas gingivalis DNA concentration as a covariate. The analysis will be based on an 
unstructured covariance matrix to model the within-subject errors. A Kenward-Roger 
approximation will be used for the denominator degrees of freedom. Following is the SAS code 
which will be used for the MMRM analysis: 
 
 
Proc Mixed; 
 
 
Class trtgrp subj visit site_country;  
Model cfb = trtgrp visit trtgrp*visit site_country baseline_score /CL solution 
   
   ddfm=kenwardroger residual outp=testresid covb; 
 
 
Repeated visit / subject = subj(trtgrp) type=UN rcorr; 
 
 
Lsmeans trtgrp*visit / pdiff cl slice=visit; 
Run; 
where cfb is the change from baseline for that endpoint.  Baseline will be defined as the last non-
missing value (either scheduled, unscheduled or repeat) before or at the day the subject receives 
the first dose of study drug. 
Correlation analyses of Porphyromonas gingivalis concentrations at Week 48 and ADAS-Cog 11 
at average of Weeks 40 and 48 will be conducted for only subjects with a detectable 
Porphyromonas gingivalis DNA concentration at any point in the study. 
Porphyromonas gingivalis concentrations for the ITT population will be displayed in subject 
listings. 
 
 


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Porphyromonas Gingivalis DNA Concentrations from Subgingival Plague 
Porphyromonas gingivalis DNA copy number concentrations were collected from subgingival 
plague at selected sites.   
Porphyromonas gingivalis concentrations for the ITT population will be displayed in subject 
listings. 
Porphyromonas Gingivalis Antibody Levels from Serum 
Porphyromonas gingivalis antibody levels will be analyzed from serum.   
Porphyromonas gingivalis antibody levels for the ITT population will be displayed in subject 
listings. 
Evidence of Porphyromonas Gingivalis Infection in CSF Samples 
Evidence of anti-Porphyromonas gingivalis antibody levels will be analyzed in CSF and 
normalized to albumin levels using an exploratory assay.  
Results for the ITT population will be displayed in subject listings. 
Ab40, Ab42, and Ab42/Ab40 Ratio Concentrations from Cerebrospinal Fluid (CSF)  
Ab40 and Ab42 will be analyzed in CSF.   
Summary statistics (n, mean, standard deviation, minimum, median, and maximum) will be 
presented for the observed values for Ab42/Ab40 ratio concentrations at each time point for the 
ITT population.  Summary statistics will also be presented for the change-from-baseline values 
to each postbaseline time point.  Baseline will be defined as the last non-missing value (either 
scheduled, unscheduled or repeat) before or at the day the subject receives the first dose of study 
drug.  
For Ab42/Ab40 ratio, the change from baseline at the Week 48 will be analyzed using ANCOVA 
with fixed effects of treatment group, APOE4 status, acetylcholinesterase inhibitor and/or 
memantine usage, site_country, and baseline Ab42/Ab40 ratio as a covariate for the ITT 
population.  
Following is the SAS code which will be used for the ANCOVA analysis: 
Proc GLM; 
Class trtgrp site_country APOE4_status    
   acetylcholinesterase_inhibitor_memantine_usage; 
Model cfb = trtgrp site_country APOE4_status acetylcholinesterase   
   inhibitor_memantine_usage baseline_score; 
 
Lsmeans trtgrp / pdiff cl; 
Run; 
where cfb is the change from baseline for that endpoint.  Baseline will be defined as the last non-
missing value (either scheduled, unscheduled or repeat) before or at the day the subject receives 
the first dose of study drug. 
Ab42 and Ab42/Ab40 ratio concentrations for the ITT population will be displayed in subject 
listings. 
 


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Total Tau and p181 Tau from Cerebrospinal Fluid (CSF)  
Total Tau and p181 Tau will be analyzed in CSF.   
Summary statistics (n, mean, standard deviation, minimum, median, and maximum) will be 
presented for the observed values for total Tau and p181 Tau at each time point for the ITT 
population.  Summary statistics will also be presented for the change-from-baseline values to 
each postbaseline time point.  Baseline will be defined as the last non-missing value (either 
scheduled, unscheduled or repeat) before or at the day the subject receives the first dose of study 
drug. 
For total Tau and p181 Tau, the change from baseline at the Week 48 will be analyzed separately 
using ANCOVA with fixed effects of treatment group, ApoE4 status, acetylcholinesterase 
inhibitor and/or memantine usage, and site_country and the corresponding baseline value as a 
covariate for the ITT population.  
Following is the SAS code which will be used for the ANCOVA analysis: 
 
Proc GLM; 
Class trtgrp site_country APOE4_status   
   acetylcholinesterase_inhibitor_memantine_usage; 
Model cfb = trtgrp site_country APOE4_status acetylcholinesterase_   
    inhibitor_memantine_usage baseline_score; 
 
Lsmeans trtgrp / pdiff cl; 
Run; 
where cfb is the change from baseline for that endpoint.  Baseline will be defined as the last non-
missing value (either scheduled, unscheduled or repeat) before or at the day the subject receives 
the first dose of study drug. 
Total Tau and p181 Tau for the ITT population will be displayed in subject listings. 
Biomarkers from Serum and Plasma 
Available biomarkers of inflammation and neuroinflammation, in serum and plasma, will be 
analyzed. 
 
 


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13 SAFETY ANALYSES 
13.1 Adverse Events 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
coding system (using MedDRA Version stated in Data Management Plan).  An overall summary 
table will be presented to summarize all treatment-emergent adverse events, all 
treatment-emergent study drug-related adverse events, deaths, all serious treatment-emergent 
adverse events, all treatment-related serious treatment-emergent adverse events, all treatment-
emergent adverse events leading to study drug withdrawal, and all treatment-emergent adverse 
events leading to study drug interruption by treatment group for the safety population.  In 
addition, frequency tables will present all treatment-emergent adverse events by System Organ 
Class and Preferred Term, treatment-related treatment-emergent adverse events by System Organ 
Class and Preferred Term, all serious treatment-emergent adverse events by System Organ Class 
and Preferred Term, all treatment-related serious treatment-emergent adverse events by System 
Organ Class and Preferred Term, all treatment-emergent adverse events leading to study drug 
withdrawal by System Organ Class and Preferred Term, all treatment-emergent adverse events 
leading to study drug interruption by System Organ Class and Preferred Term, all treatment-
emergent adverse events by System Organ Class, Preferred Term and maximum severity, and all 
treatment-emergent adverse events by System Organ Class, Preferred Term and relationship by 
treatment group for the safety population. 
Any adverse events occurring before the start of treatment (i.e., before the first dose of the 
investigational product) will be recorded in the medical history.   
In all displays, adverse events will be displayed by MedDRA System Organ Class and Preferred 
Term, with subjects who have the same adverse event counted only once for that event and 
subjects who have more than one adverse event within a System Organ Class counted only once 
in that System Organ Class. 
Treatment-emergent adverse events, fatal treatment-emergent adverse events, and serious 
treatment-emergent events will be displayed in subject listings. 
13.2 Laboratory Tests (Hematology, Serum Chemistry, Coagulation, and 
Urinalysis) 
Summary statistics (n, mean, standard deviation, minimum, median, and maximum) will be 
presented for the observed values for hematology, serum chemistry, coagulations, and urinalysis 
at each time point by treatment group for the safety population.  Summary statistics will also be 
presented for the change-from-baseline values to each postbaseline time point by treatment 
group.  In these displays, baseline will be defined as the last non-missing value (either scheduled, 
unscheduled or repeat) before the subject receives the first dose of study drug. 
Out of range values at any time post-baseline will tabulated (n, %) by treatment group for the 
hematology, serum chemistry, coagulations, and urinalysis.  Shifts from baseline based on 
normal reference ranges will be tabulated (n, %) by treatment group at each post-baseline visit 
for the hematology, serum chemistry, coagulations, and urinalysis. 
Liver function test with values satisfying Hy’s Law at any time post-baseline will be tabulated by 
treatment group. 


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Hematology, chemistry, coagulation, and urinalysis results will be listed, with values falling 
outside the laboratory reference range flagged.  Choriogonadotropin beta results will also be 
listed. 
Laboratory reference ranges will be provided by the laboratory site(s) and will be included in the 
clinical study report. 
13.3 Vital Signs 
Summary statistics (n, mean, standard deviation, minimum, median, and maximum) will be 
presented for the observed values for systolic and diastolic blood pressures, pulse rate, 
respiration rate, and temperature at each time point by treatment group for the safety population.  
Summary statistics will also be presented for the change-from-baseline values to each 
postbaseline time point by treatment group.  In these displays, baseline will be defined as the last 
non-missing value (either scheduled, unscheduled or repeat) before the subject receives the first 
dose of study drug. 
Potential vital sign values of concern at any time post-baseline will be tabulated (n, %) by 
treatment group for the following vital sign parameters: 
x Systolic blood pressure 
o Increase from baseline of ≥ 20 mm Hg 
o Post-baseline value > 160mm Hg 
o Post-baseline value > 160mm and Increase ≥ 20 mm Hg 
o Decrease from Baseline of ≥ 20 mm Hg 
o Post-baseline value <60 mm Hg 
o Post-baseline value < 60mm Hg and Decrease ≥ 20 mm Hg 
x Diastolic blood pressure 
o Increase from baseline of ≥ 20mm Hg 
o Post-baseline value > 100mm Hg 
o Post-baseline value > 100mm Hg and Increase ≥ 20mm Hg 
o Decrease from Baseline of ≥ 10 mm Hg 
o Post-baseline value < 50 mm Hg 
o Post-baseline value < 50 mm Hg and Decrease ≥ 10 mm Hg 
x Pulse 
o ≥ 30 beats/min increase or decrease from baseline and outside the range of 50-100 
beats/min 
Vital sign results will be displayed in subject listings for the safety population.  In addition, vital 
sign results where at least one value is a potential value of concern will be listed. 


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13.4 Physical Examinations 
Physical examination findings (e.g., normal; abnormal, not clinically significant; or abnormal, 
clinically significant) within each body system for each subject will be assessed at each visit.  
For each body system, the most severe (worst case) any time post-baseline will be tabulated (n, 
%) by treatment group for the safety population.   For each body system, shifts from baseline to 
each post-baseline visit will be tabulated (n, %) by treatment group for the safety population.  In 
these displays, baseline will be defined as the last non-missing value (either scheduled, 
unscheduled or repeat) before the subject receives the first dose of study drug. 
Physical examination abnormalities will be listed for the safety population. 
13.5 Electrocardiograms 
Summary statistics (n, mean, standard deviation, minimum, median, and maximum) will be 
presented for the observed values for each ECG interval (e.g., PR, QRS, QT, QTcB, QTcF, and 
RR) and heart rate, at each time point, by treatment group, for the safety population.  Summary 
statistics will also be presented for the change-from-baseline values to each postbaseline time 
point by treatment group.  In these displays, baseline will be defined as the last non-missing 
value (either scheduled, unscheduled or repeat) before the subject receives the first dose of study 
drug.   
 
The following results will be tabulated (n, %) by treatment group: 
x Abnormal ECG findings at any time post-baseline for subjects who had a normal ECG at 
baseline.   
x Abnormal ECG findings at each post-baseline visit for subjects who had a normal ECG at 
baseline. 
x Worse case (e.g., Not evaluable<Normal<Abnormal) based on ECG interpretability at 
any time post-baseline.   
x For ECG Overall Interpretation, shifts from baseline to each post-baseline visit will be 
tabulated (n, %) by treatment group for the safety population. 
x Potential ECG values of concern at any time post-baseline for each of the following ECG 
parameters: 
x QTcF and QTcB 
o Post-baseline value ≥ 500 msec 
o Increase from baseline ≥ 60 msec 
o Post-baseline value ≥ 500 msec and increase ≥ 60 msec 
x PR interval 
o Post-baseline value > 250 msec 
o Increase from baseline > 50 msec 
x QRS duration 
o Post-baseline value > 120 msec 
o Increase from baseline > 25 msec 
x Heart Rate 
o Post-baseline value < 50 bpm 
o Post-baseline value > 100 bpm 


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ECG results will be displayed in subject listings for the safety population.  In addition, ECG 
results where at least one value is a potential value of concern will be listed. 
13.6 Columbia Suicide Severity Rating Scale (C-SSRS) 
C-SSRS is composed of questions related to 1) suicidal ideation, 2) suicidal behavior, and 3) 
suicidal behavior and self-injurious behavior without suicidal intent. 
Suicidal ideation will have the following questions with binary responses (yes/no): 
x Wish to be Dead 
x Non-specific active suicidal thoughts 
x Active suicidal ideation with any methods (Not Plan) without Intent to Act 
x Active suicidal ideation with some intent, without Specific Plan 
x Active suicidal ideation with Specific Plan and Intent 
Each of the above questions will be tabulated (n, %) by treatment group.  In addition, the number 
(%) of subjects which answered one or more of the 5 above suicidal ideation items as ‘yes’ by 
treatment group. 
Suicidal behavior will have the following questions with binary responses (yes/no): 
x Preparatory acts or behavior 
x Aborted Attempt 
x Interrupted Attempt 
x Actual attempt (Non-fatal) 
x Completed Suicide 
Each of the above questions will be tabulated (n, %) by treatment group.  In addition, the number 
(%) of subjects which answered one or more of the 5 above suicidal behavior items as ‘yes’ by 
treatment group. 
The number (%) of subjects which answered one or more of the 10 above suicidal ideation or 
suicidal behavior items as ‘yes’ will be summarized by treatment group.  In addition, the number 
of ‘yes’ responses from Self-injurious Behavior without suicidal intent will be tabulated (n, %) 
by treatment group. 
C-SSRS events will be displayed in subject listings for the safety population. 
13.7 MRI Safety Readings from the Brain 
MRI safety readings from the brain collected the following:  modality, presence and severity of 
vasogenic edema, microhemorrhages information, presence of white matter, and presence of 
other clinically significant MRI/CT abnormalities. 
The results from the MRI safety readings from the brain for the safety population will be 
displayed in subject listings. 
 
 


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14 PHARMACOKINETIC ANALYSES 
Population PK will be analyzed as part of a separate pharmacokinetic analysis plan.    
 
15 SUBJECT LISTINGS  
Data that are collected and entered into the study database but not displayed in the summary 
tables that are specified in the preceding sections will be presented in subject listings.  These will 
include (but will not be limited to) data from the following modules: 
x Inclusion/Exclusion Criteria 
x Pregnancy Report 
x Obstetric History 
x Pregnancy Exposure 
x Pregnancy Illnesses and/or Medication During Pregnancy 
x Pregnancy Outcome 
x Condition of Neonates(s) 
x Neonate Medications 
 
 


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16 INTERIM ANALYSES 
16.1 Interim Analysis for Efficacy 
An unblinded interim analysis of mean change from baseline in ADAS-Cog 11 and the mean 
change from baseline in the CDR-SB is planned for when approximately 300 subjects have 
completed 24 weeks of treatment (Week-24 endpoint).  Only an independent statistician and the 
independent Data Monitoring Committee (DMC) will be unblinded.  No study personnel will 
have access to unblinded data.  For further details, refer to the DMC charter.   
Both treatment comparisons will be assessed at the interim analysis: 40 mg COR388 HCl and 80 
mg COR388 HCl vs. placebo for the co-primary endpoints mean change from baseline in 
ADAS-Cog 11 and mean change from baseline in CDR-SB at Week 24.  
These co-primary endpoints will be analyzed using MMRM to compare COR388 HCl at 40 mg 
vs. placebo and COR388 HCl at 80 mg vs placebo. The MMRM model is similar to the MMRM 
presented in section 12.1 “Final Analysis” and will include treatment group, visit, treatment 
group by visit interaction, ApoE4 status, baseline MMSE (collected within 7 days prior to the 
first dose of the IP), and country/site, and baseline co-primary endpoint (i.e., ADAS-Cog 11 
score or  CDR-SB) as covariates.  Analysis will be performed, including in the population all 
subjects randomized (i.e., ITT subject population) that had the opportunity to complete the       
24 weeks of treatment.  When change from baseline is assessed, subjects will be included in the 
ITT analysis population only if both a baseline and a postbaseline measure are available. 
Baseline will be defined as the average of the last two non-missing values (either scheduled, 
unscheduled or repeat) before or at the day the subject receives the first dose of study drug.  All 
data available for up to visit 7 (i.e., week 24) will be used for the analysis. 
The Lan-DeMets method, adjusted according to Chen et al (2004) as described earlier, will be 
used to determine the criterion of efficacy to be used at the interim analysis and final analysis. 
The two-sided significance level at the interim analysis is currently planned to be 0.005 for both 
doses.  P-values to compare each dose with placebo will be adjusted using the Benjamini-
Hochberg multiplicity adjustment procedure.  If significance is achieved for both ADAS-Cog 11 
and CDR-SB for one of the two doses, then the study may be stopped early for overwhelming 
efficacy.  Also, the study, or one of the two doses may be stopped for futility if the Placebo is 
superior to one or both doses (i.e., 40 or 80 mg) for either ADAS-Cog 11 or CDR-SB at the p-
value < 0.05 (see Figure 2) and the other endpoint is directionally favoring placebo. 
Figure 2: Decision Tree for Interim Analysis and Sample Size Re-estimation.  JCP is the joint 
conditional power for ADAS-Cog and ADCS-ADL at 48 Weeks. 


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If the study is not stopped for overwhelming efficacy or futility, as described above, the study 
will retain its original design and the final analysis will be based on 48-week of treatment for 
ADAS-Cog 11 and ADCS-ADL. Because of the changes in co-primary endpoint at 48 weeks 
(i.e., CDR-SB 24 weeks replaced by ADCS-ADL at 48 weeks and ADAS-Cog 11 at 24 weeks 
replaced by ADAS-Cog 11 at 48 weeks), the Lan-DeMets correction for sequential analysis will 
be further adjusted as described in Chen et al. (2014). This adjustment will account for the 
correlation between the outcomes and time points. The correlations used for this adjustment were 
0.56 between ADAS-Cog 11 at 24 and 48 weeks, and -0.30 between CDR-SB at 24 weeks and 
ADCS-ADL at 48 weeks.  These correlations were estimated using a pooled data from placebo 
patients form 3 ADCS studies (i.e., NSAID, Selegiline, and Homocysteine studies) described 
in Sano et al., 1997, Aisen et al., 2003, and Aisen et al., 2008. 
Boundaries will be calculated to account for the change in timing of evaluation and endpoint and 
the more conservative boundary will be used.  Accounting for the above correlations, the final 
alpha will be 0.0456.  If both doses continue to the 48 weeks, p-values to compare each dose 
with Placebo will be adjusted using the Benjamini-Hochberg procedure.   


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16.2 Sample Size Re-estimation
Sample size re-estimation will be based on joint conditional power calculated using the 48-week 
ADAS-Cog 11 and ADCS-ADL co-primary endpoints for one or both doses.  The conditional 
power for each endpoint will be calculated using the formula from Jennison and Turnbull (2000) 
as quoted in the PASS manual in the section about conditional power for a two-sample t-test:
The joint conditional probability for ADAS-Cog 11 and ADCS-ADL will be calculated as 
follows:   
ܲ(ܣת ܤ) = ܲ஺ܲ஻+ ߩ஺஻ඥܲ஺(1 െܲ஺)ܲ஻(1 െܲ஻)
Where 
A = ADAS-Cog 11 endpoint at 48 weeks
B = ADCS-ADL endpoint at 48 weeks
ߩ= correlation between ADAS-Cog 11 and ADCS-ADL at the time of analysis
Examples of conditional power boundaries for each endpoint for the joint conditional power to 
lie between 50% and 90% are presented in Table 1.  
Table 1. Required individual conditional power to reach joint conditional power of 50% and 90% 
assuming no correlation between endpoints. The sample size increase will also take into 
consideration the correlation between outcomes present at the interim analysis.
Outcome 1
JCP = 50%
JCP = 90%
Outcome2
Outcome 2
99%
51%
91%
98%
51%
92%
97%
52%
93%


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96% 
52% 
94% 
95% 
53% 
95% 
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53% 
96% 
93% 
54% 
97% 
92% 
54% 
98% 
91% 
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58% 
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61% 
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67% 
-- 
74% 
68% 
-- 
73% 
68% 
-- 
72% 
69% 
-- 
71% 
70% 
-- 
70% 
71% 
-- 
 


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Figure 3: Combination of Conditional Power for ADAS-Cog 11 and ADCS-ADL and 
Requirement for Sample Size Adjustment  
As shown in Figure 3, if the joint conditional power for ADAS-Cog 11 and ADCS-ADL is 
between 50-90% for at least one dose level, the sample size will be increased from the originally 
planned approximately 573 (i.e., approximately 191 subjects per group) by a maximum of 100 
additional patients per group (i.e., approximately 291 patients per group) to target a joint 
conditional probability of 90%. The sample size for all remaining arms will be increased by the 
largest calculated sample size increase across the 2 doses.  If joint conditional power is >90% or 
<50% for all remaining doses the sample size will not be increased. 
If the joint conditional power for ADAS-Cog 11 and ADCS-ADL for the final analysis is 90% or 
higher or 50% or lower for a doses, the study will continue with the planned sample size until all 
patients have reached the final analysis time point of 48 weeks.  Also, as shown in Figure 3, if 
the joint conditional power for ADAS-Cog 11 and ADCS-ADL is between 50-90% for at least 
one dose level, the sample size will be increased by a maximum of 100 additional patients per 
group to target a joint conditional probability of 90%. The sample size for all remaining arms 
will be increased by the largest calculated sample size increase across the 2 doses. 
As described by Chen et al 2004, this sample size re-estimation procedure based on conditional 
power in the promising zone (i.e., 50 to 95%) will not inflate the type I error and no statistical 


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adjustment is necessary.  However, the adjusted alpha at the end of the study will be based on the 
new sample size at the final analysis. 
The DMC may recommend increasing or not increasing sample size for each active arm, using 
the guidelines above, based on an overall assessment of ADAS-Cog 11 and ADCS-ADL 48-
weeks and safety at each dose.   
To maintain data integrity during the unblinded interim analysis, the Data Monitoring Committee 
(DMC) will be used to provide recommendations on prespecified study adaptations related to 
sample size estimation and early study discontinuation due to efficacy.   
The following recommendations at the interim are possible: 
x Stopping early for overwhelming efficacy defined as p<0.005 adjusted for multiplicity 
using the Benjamini-Hochberg procedure for both ADAS-Cog 11 and CDR-SB in favor 
of either 40 mg COR388 or 80 mg COR388 HCl over placebo; 
x Stopping either or both arms (stopping both arms would mean stopping the study) early 
for futility defined as p<0.05 on either ADAS-Cog 11 or CDR-SB in favor of placebo 
over active dose(s), and the other endpoint for the same dose is directionally favoring 
placebo; 
x Continue with no sample size adjustment; or 
x Continue with an appropriate sample size adjustment 
All personnel directly involved with the trial, will remain blinded.  The Sponsor will not be 
unblinded to the data and will be notified of the DMC recommendations only, as above. The 
Sponsor will make the final decision regarding continuation with or without adjustment to 
sample size after carefully evaluating various factors including safety and enrollment rate.   
If the study is stopped early for overwhelming efficacy, the interim analysis for the co-primary 
endpoints will be considered the final primary outcome for the study, and the primary duration of 
the study will be 24 weeks.  
All study subjects that were not included in the interim analysis will be allowed to complete 24 
weeks of double-blinded randomized treatment, and if eligible, to enroll in the OLE.  This 
independent cohort of subjects will be analyzed separately for efficacy on the co-primary 
endpoints.   
If both doses are stopped early for futility, the entirety of the COR388-010 trial, including the 
OLE will be immediately concluded, and data analyzed based on the current SAP.  If a dose is 
stopped for futility, that dose will be terminated, and all eligible subjects will have the option to 
move to the OLE. 
 
 


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17 REFERENCES 
Aisen PS, Shafer KA, Grundman M, et al., Effects of Rofecoxib or Naproxen vs Placebo on 
Alzheimer Disease Progression. JAMA 2003; 289:2819-2826. 
Aisen PS; Scneider LS; Sano M et al., High-Dose B Vitamin Supplementation and Cognitive 
Decline in Alzheimer Disease. JAMA 2008; 300(15): 1774-1783 
Benjamini, Y; Hochberg, Y. "Controlling the false discovery rate: a practical and powerful 
approach to multiple testing" (PDF). Journal of the Royal Statistical Society, Series B. 1995; 57 
(1): 289–300. MR 1325392. 
Benjamini, Y; Yekutieli, D. "The control of the false discovery rate in multiple testing under 
dependency" (PDF). Annals of Statistics. 2001; 29 (4): 1165–1188. 
doi:10.1214/aos/1013699998. MR 1869245. 
Chen YH, DeMets DL, Lan KK. Increasing the sample size when the unblinded interim result is 
promising. Stat Med. 2004; 23:1023-1038. 
Chen, L.M; Ibrahim, J.G; Chu, H.  Flexible Stopping Boundaries When Changing Primary 
Endpoints after Unblinded Interim Analyses. J Biopharm Stat. 2014; 24(4): 817–833. 
Dmitrienko A, Millen BA, Brechenmacher T, Paux G. Development of gatekeeping strategies in 
confirmatory clinical trials. Biom J. 2011;53(6):875-893. 
Jennison, C; Turnbull, BW. Group Sequential Methods with Applications to Clinical Trials. 
Chapman & Hall/CRC, 2000, pp 205-208. 
Liu-Seifert H, Siemers E, Price K, et al.  Cognitive Impairment Precedes and Predicts Functional 
Impairment in Mild Alzheimer’s Disease. Journal of Alzheimer’s Disease. 2015;47:205-214. 
McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer's 
disease: recommendations from the National Institute on Aging-Alzheimer's Association 
workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011;7:263-
269. 
Ratitch, B. and O’Kelly, M, “Implementation of Pattern-Mixture Models Using Standard 
SAS/STAT Procedure,” in Proceeding of PharmaSUG 2011 (Pharmaceutical Industry SAS 
Users Group), SP04, Nashville. 2011. 
Sano M, Ernest MS, Thomas RG et al., A Controlled Trials of Selegiline, Alpha-Tocopherol or 
both as Treatment for Alzheimer’s Disease. N Engl J Med 1997; 336:1216-22 


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18 FINAL SIGN-OFF FOR CORTEXYME, INC, PROTOCOL COR388-010
STATISTICAL ANALYSIS PLAN
Sarah Horine, PhD
Sr. Director Biostatistics
Cortexyme, Inc.
South San Francisco, CA  94080
Date
Craig Mallinckrodt, PhD
VP Biostatistics 
Cortexyme, Inc.
South San Francisco, CA  94080
Date
Michael J. Detke, MD, PhD
Chief Medical Officer
Cortexyme, Inc.
South San Francisco, CA  94080
Date
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Statistical Analysis Plan-Double-Blind Phase 
Version 5.0 
Cortexyme, Inc. Protocol COR388-010 
27 August 2021 
CONFIDENTIAL 
47 
19 REVISIONS TO STATISTICAL ANALYSIS PLAN 
Date 
Revision 
Statistician’s Signature 
October 09, 2020 
Version 2 
 
October 30, 2020 
Version 3 
x 
 
April 27, 2021 
Version 4 
x 
 
August 27, 2021 
Version 5 
x 
 
 


Statistical Analysis Plan-Double-Blind Phase 
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Cortexyme, Inc. Protocol COR388-010 
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20 APPENDIX 
20.1 Conventions for Statistical Tables and Subject Listings 
The following conventions are used in the mockups for the statistical tables and subject listings: 
[Sponsor] = [Cortexyme, Inc.] 
[Protocol] = [COR388-010] 
Calculation of “Day” in Data Listings 
Study day will be calculated as the number of days from first dose of study drug. For analysis, 
study day is relative to first dose of study drug and will be deemed “Day 1”, note this differs 
from the time and events in the Protocol where the first dose of study drug is given on Day 0. 
x date of event – date of first dose of study drug + 1, for events on or after first dose 
x date of event – date of first dose of study drug, for events before first dose.  
Baseline Determination 
Baseline is defined as average of the last two non-missing value (either scheduled, unscheduled 
or repeat) before or at the day the subject receives the first dose of study drug for ADAS-Cog 11, 
CDR-SB, ADCS-ADL, and MMSE.  For all other assessments, baseline is defined as the last 
non-missing value (either scheduled, unscheduled or repeat) before or at the day the subject 
receives the first dose of study drug. 
 
Missing/Partial Start/Stop Date of Adverse Events and Concomitant Medications 
Missing and partial start and stop date will be imputed for analysis purposes as follows: 
 
1. Partial or missing stop date will be imputed as follows: 
If the stop date is completely missing and the event has resolved or the subject has 
stopped taking the concomitant medication, the stop date will be imputed as the date of 
the subject’s last clinic visit in the study. 
x If only the year is known, the stop date will be imputed as “31-Dec” of that year or as 
the date of the subject’s last clinic visit in the study if in the same year. 
x If the month and year are known, the stop date will be imputed as the last day of that 
month unless the stop date corresponds to the same month as the subject’s last clinic 
visit in which case the date of subject’s last clinic visit in the study will be used 
instead. 
2. Missing start date will be imputed as follows: 
x If the stop date occurs on or after the start of study drug or the event/concomitant 
medication is ongoing, the start date will be imputed as the date of the first dose of 
study drug. 
x If the stop date occurs before the start of study drug, the start date of the 
event/concomitant medication will be imputed as the subject’s screening date. 
3. Partial start date (year present, but month and day missing) 
x If the stop date occurs on or after the start of study drug or the event/concomitant 
medication is ongoing, and the year is the same as the year of first dosing then the 


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start date will be imputed as the date of the first dose of study drug. If the year is 
different from the year of first dosing “01-Jan” will be used. 
x If the stop date occurs before the start of study drug, the start date of the 
event/concomitant medication will be imputed as the “01-Jan” of the same year. 
4. Partial start date (month and year present, but day missing)  
x If the stop date occurs on or after the start of study drug or the event/concomitant 
medication is ongoing, the start date will be imputed as the first day of the same 
month and year unless this partial start date is in the same month as the first dose of 
study drug in which case the date of first dose of study drug will be used. 
x If the stop date occurs before the start of study drug, the start date will be imputed as 
the first day of the month and year of the partial stop date.   
 
If the start time is missing, it will be imputed only in the case where the start date of the 
concomitant medication/event corresponds to the date of the first dose of study drug. The time 
will be imputed as the same time as the first dose of study drug. In all other cases the time will 
not be imputed. 
 
Missing Values for ADAS-Cog 11 Total Score 
For ADAS-Cog11, if <30% (<4 of a total of 11) of the items are missing, the total score 
(maximum = 70) will be imputed as follows: The total from remaining items will be multiplied 
by a factor that includes the maximum score for the missing items. For example, if the first item, 
“Word-Recall Task,” which ranges from a score of 0 through 10 (maximum = 10), is missing, 
and the second item “Commands,” which ranges from a score of 0 to 5 (maximum = 5), is 
missing, then the multiplication factor = 70/(70 - [10 + 5]) = 70/55 = 1.27. Thus, the total score 
for this example, will be the sum of the remaining 9 items multiplied by 1.27. The imputed 
number will be rounded up to the nearest integer. If more than 3 items are missing, the total 
score for ADAS-Cog11 at that visit will be considered missing. 
 
Missing Values for ADCS-ADL Total Score 
For the ADCS-ADL, if <4 of the 24 items are missing, the total score will be imputed. The 
sum of the non-missing items will be prorated to the sum of total items. The imputed number 
will 
be rounded up to the nearest integer. If the nearest integer is greater than the maximum possible 
score, the imputed score will be equal to the maximum score. If more than 3 of the items are 
missing, the total score for ADCS-ADL at that visit will be considered missing.  
 
Missing Values for CDR-SB Total Score 
The same imputation technique will be applied to the Clinical Dementia Rating-Sum of Boxes 
(CDR-SB) as outlined above for the ADCS-ADL. If only 1 box (of 6) of the CDR is missing, the 
sum of the boxes will be imputed by prorating the sum from the other 5 boxes. If the score from 
more than 1 box is not available, the CDR-SB at that visit will be considered missing. 
 
Exposure to Study Drug 
Exposure to study drug will be calculated as the date of last dosing minus the date of first dosing 
+ 1. The exposure calculation will not take into account breaks in therapy. 
 


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Inexact Values 
In the case where a variable is recorded as “> x”, “≥ x”, “< x” or “≤ x”, a value of x will be taken 
for analysis purposes. 
 
Adverse Events 
x If the relationship to study medication is missing for an adverse event, it will be assumed to 
be related to study medication for analysis purposes. 
Programming Specifications 
x In general, font size will be at least 9-point and all margins will be 1 inch. 
x Tables and listings will be internally paginated (i.e., page numbers will appear sequentially 
within each display).  All output will have the SAS program name in footer at the lower left 
margin. 
x In general, data listings will be sorted by subject identification (ID) number and 
visit/assessment/collection/start dates, unless specified otherwise.   
x Dates will be displayed in SDTM (Study Data Tabulation Model) format (YYYY-MM-DD) 
on listings. 
x Continuous variables will be summarized by the number of non-missing observations, mean, 
median, standard deviation, and minimum and maximum.  
x Categorical variables will be summarized by presenting the frequency and percent.  
Percentages will be based on the number of non-missing observations or the subject 
population unless otherwise specified. For each variable, all categories will be shown.   
x Unless otherwise noted (see below), the mean and median (standard deviation) of a set of 
values should be printed out to 1 (2) more decimal place(s) than the raw value for 
demographic and safety assessments. 
eg, 
raw: 
 
 
 
 
 
xx 
 
 
mean and median 
 
 
 
xx.x 
 
 
standard deviation and standard error: 
xx.xx 
 
 
range (minimum and maximum): 
 
xx, xx 
In cases in which the raw data are reported to 2 or 3 decimal places, the mean, median, standard 
deviation, and standard error will be displayed to 1 more decimal place than the raw data (eg, in 
tables summarizing changes from baseline in laboratory parameters). 
x All percentages in tables will be reported to the precision of tenths (i.e., 0.1) unless otherwise 
noted. 
x The following specifications apply to tables that summarize categorical data unless otherwise 
noted: 
o If the categories of a parameter are ordered, then all categories between the maximum 
possible category and the minimum category will be included, even if n=0 for a given 


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category between the minimum and maximum level for that parameter unless 
specified. 
o If the categories are not ordered, then only categories for which there is at least one 
subject represented will be included.