Clinical trial NCT04994483
Conditions: Alzheimer Disease
Sponsor: Cassava Sciences, Inc.
Start date: 2021-11-03; Completion date: 2024-10-02
Enrollment: 804 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A 52-week safety and efficacy study of simufilam (PTI-125) given twice daily to participants with mild-to-moderate Alzheimer's disease (AD) for 52 weeks. Approximately 750 participants will be randomized (1:1) to receive either placebo or 100 mg tablets of simufilam, twice daily, for 52 weeks. Clinic visits will occur 4 weeks after the baseline visit, and then every 12 weeks until the end of the study. The safety of simufilam, and its efficacy in enhancing cognition and slowing cognitive and functional decline will be evaluated.

Detailed description:
The primary objective of this study is to investigate the safety and efficacy of simufilam (PTI-125) in enhancing cognition and slowing cognitive and functional decline following 52-week, repeat-dose oral administration in participants with mild-to-moderate AD. Secondary objectives include the assessment of simufilam's effect on neuropsychiatric symptoms and caregiver burden. A third objective is to investigate the effect of simufilam treatment on plasma biomarkers. A limited number of research sites will be invited to participate in the pharmacokinetic (PK) and plasma biomarker sub-study. Collection of PK samples will enable an exposure-response analysis. Approximately 100 subjects will participate (50 per group). Plasma samples will be collected during the Screening Visit and again at Weeks 28 and 52. Change from Baseline for plasma biomarkers represent additional secondary endpoints.

Safety will be evaluated by adverse event monitoring, vital signs, clinical labs, and the Columbia Suicide Severity Rating Scale at every visit. Subjects will undergo magnetic resonance imaging (MRI) during screening to ensure entry criteria are met (unless recent MRI confirms entry criteria). Resting electrocardiograms will be conducted at Baseline (Study Day 1) and Weeks 4, 28, and 52. A complete physical and neurological examination will be performed at screening, and brief examinations will be performed at all other visits. Weight will be measured during the Screening Period, at Baseline (Study Day 1), and at all other visits.

An independent Data Safety Monitoring Board (DSMB) will meet periodically to review subject safety assessments and determine if dosing may continue. A charter will be developed with specific guidance for the DSMB.

Arms: arm 1: Matching placebo, supplied by Cassava as coated tablets, and taken twice daily (b.i.d.) for 52 weeks arm 2: Simufilam 100 mg, supplied by Cassava as coated tablets, and taken b.i.d. for 52 weeks
Interventions: intervention 1: Simufilam intervention 2: Placebo
Intervention descriptions: intervention 1: Simufilam is a novel drug candidate designed to treat and slow the progression of AD. Simufilam binds with femtomolar affinity to an altered conformation of filamin A that is present in the brain of patients with AD and critical to the toxicity of Aβ42. In this study, simufilam will be given b.i.d. for 52 weeks at a dose of 100 mg. intervention 2: Matching placebo given b.i.d. for 52 weeks.

Protocol documents:
Prot_000.pdf: 
Study Title: A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel-group, 
52-week Study Evaluating the Safety and Efficacy of Simufilam 100 mg Tablets in Subjects 
with Mild-to-Moderate Alzheimer’s Disease 
ClinicalTrials.gov ID: NCT04994483 
 
Protocol Clarification Letter, dated 07-Jun-2024 
Final Protocol, Version 3.0, dated 15-Feb-2023 
Final Protocol, Version 2.0, dated 20-Jul-2021 
Final Protocol, Version 1.0, dated 30-Jun-2021 
Page 1 of 141


 
MMO-125-314 
 
  
 
6801 N Capital of Texas Highway, Bldg. 1, Suite 300, Austin, TX  78731 
Phone:  512-501-2444  Fax:  512-614-0414 
Page 1 of 2 
 
 
 
To: 
PTI-125-07 Study file 
From: 
, Chief Medical Officer 
CC: 
Premier Research 
Date: 07-JUN-2024 
Re: 
Protocol Clarification Letter for Study PTI-125-07, A PHASE 3, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, PARALLEL-GROUP, 52-WEEK STUDY EVALUATING THE SAFETY AND 
EFFICACY OF SIMUFILAM 100 MG TABLETS IN SUBJECTS WITH MILD-TO-MODERATE 
ALZHEIMER’S DISEASE 
 
The purpose of this memo for Protocol PTI-125-07, Version 3.0, February 15, 2023, is to 
clarify the requirement of reporting Serious Adverse Events (SAEs) to an Institutional 
Review Board (IRB) or Ethics Committee (EC).  
 
Regarding the protocol text below, the original intent was for this to refer only to SAEs/AEs 
for which the relevant authorities require reporting.  
 
Protocol section 10.5 Serious Adverse Event Reporting  
 “SAEs must be immediately reported to the responsible IRB” (Section 10.5 was 
intended to refer only to SAEs for which the relevant authorities require 
reporting). 
 
Protocol section 13.5.1 Institutional Review Board 
 “The Investigator is responsible for: 
o Notifying the IRB within 15 calendar days of all SAEs and unexpected 
AEs related to study medications.”  (Section 13.5.1 was intended to 
refer only to SAEs/AEs for which the relevant authorities require 
reporting). 
  
Sites are to follow their IRB/EC requirements for reporting SAEs/AEs. For sites that utilize 
the central WCG IRB, they have provided the following reporting guidance:   
 
WCG IRB Guide for Researchers, Rev 1.21:  
“Please note, only adverse events or IND safety reports that prompt a change to 
the protocol or consent document are required to be reported to the IRB.” 
 
The WCG IRB based their guidance on the most current FDA recommendations which 
state the following: 
 
CASSAVA 
sciences 
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MMO-125-314 
 
  
 
6801 N Capital of Texas Highway, Bldg. 1, Suite 300, Austin, TX  78731 
Phone:  512-501-2444  Fax:  512-614-0414 
Page 2 of 2 
 
 
 
“In general, an AE observed during the conduct of a study should be considered 
an unanticipated problem involving risk to human subjects, and reported to the 
IRB, only if it were unexpected, serious, and would have implications for the 
conduct of the study”.  
 
FDA then described “implications” as significant changes to the protocol, monitoring 
requirements, informed consent, or Investigator’s Brochure. 
    
SAEs that do not meet the definition as described above are not required to be 
immediately reported to the study Central IRB, WCG. For those SAEs that do require 
reporting, WCG IRB has provided the following reporting guidance: 
 
“Promptly reportable information should be submitted within five (5) days of 
becoming aware of the event.” 
 
If your site utilizes a local IRB/EC, and/or has site SOPs regarding the reporting of SAEs to 
the IRB/EC and/or other relevant authorities, please follow the relevant guidance.  
 
Please remember:  
 
All SAEs, regardless of IRB reportable status, are to be reported via email to Premier 
Pharmacovigilance within 24 hours of learning of the event, consistent with the protocol.  
 
Protocol section 10.5, Serious Adverse Event Reporting:   
“All SAEs must be reported immediately (within 24 hours of learning of the 
event) by e-mail to: 
Premier Research Global Pharmacovigilance 
” 
 
 
 
 
_____________________________________________    ___________ 
  
 
 
 
 
Date 
Chief Medical Officer 
Cassava Sciences, Inc. 
07-Jun-2024 | 12:55 CDT
CASSAVA 
sciences 
1
oocuSigned by: 
I 
 
L
Signing Reason
approve h s document 
Signing Time: 07-Jun-2024 I 12:55 CDT 
9D60F9221 DE944859AD2EE06ADD9083E 
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Cassava Sciences, Inc. 
Clinical Protocol PTI-125-07 
Simufilam (PTI-125) 
FINAL Version 3.0, FEBRUARY 15, 2023 
Page 1 of 52 
 
 
 
 
CONFIDENTIAL 
 
 
 
 
CLINICAL RESEARCH PROTOCOL 
PROTOCOL PTI-125-07 
 
A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
PARALLEL-GROUP, 52-WEEK STUDY EVALUATING THE SAFETY AND 
EFFICACY OF SIMUFILAM 100 MG TABLETS IN SUBJECTS WITH MILD-TO-
MODERATE ALZHEIMER’S DISEASE 
 
 
 
SPONSOR: 
 
CASSAVA SCIENCES, INC. 
6801 N. Capital of Texas Highway 
Building 1, Suite 300 
Austin, TX 78731 
Phone: 512-501-2444 
 
 
 
Confidentiality 
The information contained in this document and all information provided to you related to 
simufilam ("Drug") are the confidential and proprietary information of Cassava Sciences, Inc. 
and, except as may be required by federal, state, or local laws or regulations, may not be 
disclosed to others without prior written permission of Cassava. The Principal Investigator 
may, however, disclose such information to supervised individuals working on the Drug, 
provided such individuals agree to be bound to maintain the confidentiality of such Drug 
information. 
 
 
CASSAVA 
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Cassava Sciences, Inc. 
Clinical Protocol PTI-125-07 
Simufilam (PTI-125) 
FINAL Version 3.0, FEBRUARY 15, 2023 
Page 2 of 52 
 
 
 
 
CONFIDENTIAL 
 
  
Cassava Sciences, Inc. 
CLINICAL RESEARCH PROTOCOL 
 
 
 
A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
PARALLEL-GROUP, 52-WEEK STUDY EVALUATING THE SAFETY AND 
EFFICACY OF SIMUFILAM 100 MG TABLETS IN SUBJECTS WITH MILD-TO-
MODERATE ALZHEIMER’S DISEASE  
 
 
 
Approvals: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SVP, Neu o
nc
Cassava Sciences, Inc.  
 
 
 
 
 
 
 
 
 
 
 
Date 
Chief Med ca Development Officer  
Cassava Sciences, Inc. 
 
 
 
15-Feb-2023 | 15:12 CST
15-Feb-2023 | 15:14 CST
(
DocuSigned by: 
I 
 
38C3BD2216AF4FDEBBA 7B22B883DB 178 
(
DocuSigned by: 
I 
 
 
L
Signing Reason: approve this document 
Signing Time: 15-Feb-2023 I1 5:12 CST 
9D60F9221 DE944859AD2EE06ADD9083E 
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Cassava Sciences, Inc. 
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Simufilam (PTI-125) 
FINAL Version 3.0, FEBRUARY 15, 2023 
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CONFIDENTIAL 
 
SUMMARY OF PROTOCOL AMENDMENT #1 
(New text is underlined; omitted text is struck through) 
 
Title page: Address is updated 
 
2.2 SAFETY PHARMACOLOGY AND TOXICOLOGY 
The last sentence of the following was omitted: 
 
“A second 6-month repeat dose oral toxicity study in rats determined the 6-month NOAEL in 
the rat to be < 125 mg/kg/day, based on hepatocellular vacuolation in both sexes and 
hepatocellular hypertrophy in females at 125 and 250 mg/kg. We are evaluating whether these 
liver effects are rat specific.” 
 
2.3 CLINICAL STUDIES 
The summary of the Phase 2b study was updated to note that treatment effects were seen on 
plasma p-tau181 that were consistent with treatment effects on CSF biomarkers. The figure of 
CSF biomarker data from the phase 2b study was replaced by a figure of improvements from 
baseline to 6 months in 25 subjects in the 1-year open-label safety study. In the discussion of 
cognitive tests for the Phase 2b study, it was clarified that the episodic memory test analysis 
was a sensitivity analysis, effect size notation was removed from the figure, and the following 
clarification was added: 
 
Subjects who showed no detectable simufilam in plasma or >25% noncompliance by pill 
counts were excluded from cognitive data (5 subjects). For the sensitivity analysis for episodic 
memory, the most and least impaired subjects were removed by baseline score. This sensitivity 
analysis removed subjects who performed so poorly they may not have understood the task and 
those who were at a ceiling of very few errors at baseline. 
 
4. SUMMARY OF STUDY DESIGN   
Changed: All subjects will undergo MRI during screening to ensure entry criteria are met 
Changed to: Subjects will undergo MRI during screening to ensure entry criteria are met 
(unless recent MRI confirms entry criteria) 
 
Clarified that ECGs are resting ECGs, and Study Day 1 is Baseline. 
 
 
5.2 INCLUSION CRITERIA 
# 3. Clarified as follows:  Meets National Institute on Aging and Alzheimer's Association 
(NIA-AA) Research Framework criteria (2018) for individuals in clinical Stage 4 or Stage 5 of 
the Alzheimer’s continuum (per Table 6 in the corresponding 2018 publication5) 
 
#5. Clarified as follows: Evidence for AD pathophysiology, confirmed either prior to or during 
the screening period prior to randomization, as follows: 
a. Prior to screening, confirmed with appropriate documentation by either: 1) CSF 
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total tau/Aβ42 ratio (must be ≥ 0.28), or 2) an abnormal qualitative amyloid 
positron emission tomography (PET) scan consistent with AD (Note – FDG PET, 
tau PET or amyloid SUVR values are not acceptable); or 
b. During screening, subjects must demonstrate an elevated plasma P-tau181 or 
plasma P-tau217 level (research biomarkers that identify AD pathophysiology 
with high accuracy; see lab manual for details). 
#12. Deleted: antidepressants 
Added: Chronic medications for conditions other than AD (such as depression) must be 
prescribed at a stable dose for at least 4 weeks prior to screening. Medications that might 
have a potential confounding effect on cognitive testing (either prescription or non-
prescription medications) should not be modified during the Screening Period (see 
Section 6.3 for additional details). 
#13. Clarified that smoker means cigarette smoker. 
 
Added: (occasional pipe or cigar smoking is permitted, but vaping is not). 
 
#14. Clarified as follows: Availability of a person (a study partner) who, in the Investigator’s 
opinion, has frequent and sufficient contact with the study subject (defined as ≥10 hours per 
week), and can: 
a. provide accurate information regarding the study subject's cognitive and 
functional abilities in the opinion of the Investigator,  
 
#16. Added: Completed a COVID-19 vaccine primary series (“fully vaccinated”) at least two 
weeks prior to Study Day 1 (randomization) or had an unambiguous COVID-19 infection 
diagnosed more than 3 months before the start of the screening period (to minimize or 
eliminate any effect on cognition that might confound a proper assessment during screening). 
(Note – subjects having a symptomatic COVID-19 infection [or its variants] within 3 months of 
the screening period should have their screening assessment delayed; vaccinated, asymptomatic 
subjects that test positive for COVID-19 within three months of the screening period require 
Medical Monitor approval to not delay screening). 
5.3 EXCLUSION CRITERIA 
#2. Clarified that pacemakers are excluded only if not “MRI friendly” 
 
#3. Clarified that upper exclusion for BMI is > 37.5, not 35.0. 
 
#6. Changed as follows: Geriatric Depression Scale (15-item) score > 8.  (Note – a subject 
with a score > 8 may continue in screening if, in the judgment of the Investigator, the elevated 
score is not attributed to a major depressive episode). 
#9. Clarified as follows: MRI presence of cerebral vascular pathology (including, but not 
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limited to, intracerebral hemorrhage, infarct > 1 cm3, > 3 lacunar infarcts, > 10 
microhemorrhages, cortical superficial siderosis, diffuse confluent deep white matter 
hypertense lesions [Fazekas scale 3]), cerebral contusion, symptomatic subdural hematoma, or 
aneurysm.   
Changed: or space-occupying lesion deemed clinically significant in the opinion of the 
Investigator.  
Changed to: (Note – a space-occupying lesion deemed clinically insignificant by the 
Investigator and confirmed by the Medical Monitor may continue screening). 
#16. Added cancer exclusion: stage 0 melanoma in situ, 
  Added: Other potential exceptions must be discussed with the Medical Monitor.  
#21. Added: Subjects with borderline hypothyroidism may be considered for rescreening after 
consultation with the Medical Monitor.  
#24. Clarified as follows: Clinically History of or current clinically significant cardiac 
arrhythmia or heart block as evidenced by ECG in the judgment of the Investigator. 
#25. Added: (Note: borderline elevations in QTcF intervals due to bundle branch block must be 
approved by the Medical Monitor) 
#26. Changed as follows: The systolic BP for insufficiently controlled hypertension is now 
defined, at rest, as > 170 mmHg, not 160 mm Hg. 
#30. Added memantine: Discontinued AChEI or memantine < 12 weeks prior to 
randomization. 
#31. Clarified as follows: Currently or previously prescribed/administered aducanumab, 
lecanemab or any anti-amyloid monoclonal antibody, more than two doses. either currently or 
previously prescribed (Note – administration of aducanumab at any point during this clinical 
study is prohibited).  
#32. Changed as follows: Antipsychotics (Note – low doses are allowed only if given for sleep 
disturbances, agitation, aggression or dementia-related psychosis, and only if the dose has been 
stable for at least 12 weeks prior to the Baseline Visit (Study Day 1) 4 weeks prior to 
screening). 
#33. Added SSRIs and clarified as follows: Tricyclic or SSRI antidepressants and 
monoamine oxidase inhibitors if prescribed for depression less than within 4 weeks prior to 
screening; or the Investigator believes the dose of such medication must be modified during the 
Screening Period; or the Investigator believes the subject must be started on such medication 
during the Screening Period. Monoamine oxidase inhibitors are not permitted. ; all other 
antidepressants are allowed only if the dose has been stable for at least 4 weeks prior to 
screening. 
#35. Added clarification: Use of antiepileptic medications if taken for control of seizures 
(Note – use of antiepileptic medications are allowed if used for mood stabilization or 
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indications other than seizures). 
#36. Added clarification: Chronic intake of opioid-containing analgesics at standard doses 
(use of intermittent or low-dose opioids must be approved by the Medical Monitor). 
#37. Added clarification: Use of prescribed sedating H1 antihistamines (Note – fexofenadine 
is the preferred non-sedating antihistamine for subjects requiring such medication). 
#40. Removed (re: COVID) and vaccination/exposure requirements added to inclusion criteria. 
Final (now #42) added example to other: Any other medical or neurological condition (other 
than Alzheimer’s disease), that, in the opinion of the Investigator, might represent a 
contributing cause to the subject’s cognitive impairment, or affect cognitive assessment, 
subject safety, ability to comply with study assessments, drug compliance and completion of 
the study. This could include, for example, excessive marijuana or cannabinoid use. 
 
6.1.2 Storage 
Added: The Pharmacy Manual should be referenced for additional information about handling 
temperature excursions and record keeping requirements. 
 
6.3 CONCOMITTANT MEDICATIONS 
Clarified that “medications” are prescription medications for conditions other than AD. 
Added: Chronic prescription medications for conditions other than AD must be stable for at least 4 
weeks prior to screening. Medications that might have a potential confounding effect on 
cognitive testing, either prescription or non-prescription medications, should not be modified 
during the Screening Period. Medications that do not have a potential confounding effect on 
cognitive testing may be modified during the Screening Period if necessary, but the 
Investigator may wish to confer with the Medical Monitor in such a situation. After 
randomization to Study Drug at the Baseline Visit (Study Day 1), the Investigator should strive 
to maintain concomitant medications at currently prescribed doses whenever possible. Dose 
modification, addition or discontinuation of medications that might have a potential 
confounding effect on cognitive testing (e.g., cholinesterase inhibitors and memantine) after 
randomization should be reviewed by the Medical Monitor. 
7.1.1 Screening visit Period (No greater than a 60-day duration prior to Study Day 1) 
Changed: Education demographic information collected changed from years to level of 
education. 
Changed “in the 4 weeks prior to screening” to “recently” as follows: 
• Review concomitant medications and any recently discontinued medications, in 
the 4 weeks prior to screening 
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CONFIDENTIAL 
 
Clarification in eCOA order of administration at screening as follows: 
o Note:  it is a study requirement to first administer the MMSE (and then the 
other assessments if the MMSE criterion is met) 
 MMSE  
 CDR (study partner is interviewed first in the absence of the study 
subject and then the subject is interviewed, by the same rater, in the 
absence of the study partner) 
Clarified that ECG is resting ECG. 
Added “or P-tau217” to lab assessments and clarified capture requirement of unexpected 
results: 
• Laboratory assessments, including: routine serum chemistry, TSH, free T4, 
Vitamin B12 levels, HBsAg, HCV-Ab, hematology, urinalysis and urine screen 
for drugs of abuse. Plasma for P-tau181 or P-tau217 assessment will also be 
collected unless there is documented evidence of AD pathophysiology prior to 
screening. For subjects with diabetes, collect a blood sample for HbA1C. 
Unexpected, abnormal laboratory results observed during the Screening Period 
should be captured as Medical History and not as an AE (see Section 10.1 – 
Adverse Events – Definition). 
Clarified that amphetamines for psychiatric symptoms acceptable if stable as follows: 
o Note – amphetamines, prescribed to treat neuropsychiatric symptoms 
associated with progressive AD, are acceptable if prescribed for at least 12 
weeks prior to the Baseline Visit (Study Day 1); the Investigator should 
document in the subject’s file the rationale and timeframe for such use, noting 
that the expected positive drug screen for amphetamine does not reflect abuse 
of such drug. 
Clarified that previous MRI results need to be approved by the Medical Monitor and that 
Baseline visit is Study Day 1. 
o Note: previous brain MRI results, with appropriate documentation and 
approved by the Medical Monitor, will be accepted for up to 6 months prior 
to the Baseline Visit (Study Day 1) unless a recent clinical event warrants a 
repeat scan. 
Added:  
• To remain in the study, subjects who develop COVID-19 (or its variants) or manifest a 
positive COVID-19 test during the screening period will need approval from the 
Medical Monitor. 
 
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7.1.2 Rescreening of a Subject 
Deleted “181” from p-tau181 to capture either p-tau181 or p-tau217.  
Added:  
• Clinical hypothyroidism (can rescreen 3 months after being placed on supplemental 
thyroid replacement and manifesting a normal [or low] TSH level and a normal free T4 
level) 
Clarified as follows: Other reasons for screen failure will require Medical Monitor approval to 
rescreen.  Subjects undergoing rescreen, who had an inclusionary P-tau elevation and/or an 
acceptable screening MRI, should utilize these results during the rescreening process and not 
repeat these procedures.  
7.1.3 Baseline Visit (Study Day 1) (Dosing Initiation) 
Clarified that Study Day 1 is Baseline Visit. 
Added to eCOA order of administration (also added to 7.1.4, 7.1.5 and 7.1.6):  
• Note: it is acceptable to simultaneously administer the study partner assessments in 
parallel with subject assessments (separate, qualified raters in separate rooms). When 
administered in parallel, the eCOA order of administration should be maintained (ADAS-
cog12 and then C-SSRS for the subject; ADCS-ADL, NPI and then ZBI for the study 
partner). 
Clarified details of ECG (for 7.1.3, Baseline Visit only): 
• A 12-lead resting ECG (5-min supine; triplicate format) 
Clarified details of ECG in 7.1.4, 7.1.5 and 7.1.6 (all other Visits): 
• A 12-lead resting ECG (5-min supine) 
7.1.7 End-of-Study / Early Termination Safety Follow-up 
Added:  This phone call will thus occur Week 53 to 54 for those subjects who complete all 
study visits, or 1 to 2 weeks after Early Termination. If the subject reports an adverse event, the 
subject should be followed and treated by the Investigator until the AE has resolved or 
stabilized (see Section 10.1 – Adverse Events). 
7.1.10 Stopping Criteria 
Clarified as follows: Bodyweight loss (compared to weight at Baseline Visit [Study Day 1]) of 
≥ 2 kg resulting in a BMI < 18.5 is an additional stopping criterion. 
 
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7.2.1 Clinical Laboratory Tests 
Added: or P-tau217 
Added: The plasma P-tau181 test is a validated assay using ADX antibodies, which shows a 
wide dynamic range and an AUC of 0.92 during validation without any algorithms. Validation 
of a P-tau217 assay is pending. 
 
7.2.3 Preparation of Plasma Biomarker and PK Samples from PET Sub-study Participants  
Changed as follows: At each blood collection for biomarkers and PK, blood samples will be 
drawn into two Vacutainer® tubes (10 mL per tube) containing K2EDTA. The tubes will be 
placed immediately on ice upon collection. Following the instructions within the Laboratory 
Manual, the plasma samples will be centrifuged, frozen (within 30 minutes of centrifuging), 
and shipped to the central laboratory. Within 30 min of collection, the blood will be centrifuged 
at approximately 1000 X G for 15 min, preferably 4-5°C. Within 30 min of centrifuging, 
plasma will be transferred to polypropylene tubes and stored at -70°C until shipped to the 
central lab (complete instructions as per lab manual). 
8.2 CLINICAL DEMENTIA RATING (CDR) 
Clarified as follows: The study partner is interviewed first by a qualified rater who assesses all 
six domains in the absence of the study subject. The subject is then interviewed by the same 
rater in the absence of the study partner. caregiver. 
8.8 GERIATRIC DEPRESSION SCALE (GDS) 
Added: The GDS scale score should be clinically interpreted to evaluate the potential for a 
major depressive episode by a clinician who has been trained on the scale and is familiar with 
the diagnosis of major depression. 
8.9 ELECTRONIC CAPTURE OF RATING SCALES 
Added: The electronic capture of the rating scales will include an audio recording for the 
purpose of monitoring site staff performance during scale questionnaire administration and 
providing constructive feedback to the raters.  Subject data captured on recordings will not be 
analyzed as part of the trial outcomes. The Investigator or rater will read the questions out loud 
to study participants who will then respond. The process of questions and answers will be 
recorded using an audio-recording device.  These highly secured recordings will not be made 
public at any time and will be destroyed after the Study Drug has been either approved or 
disapproved for use by the FDA or other pertinent regulatory bodies. 
9. EARLY DISCONTINUATION 
Clarified that ECG is 12-lead resting and 5 min supine. 
 
10.1 ADVERSE EVENTS -- DEFINITION 
Changed: Monitoring for AEs will start after informed consent has been obtained. at dosing.  
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Added: Adverse events reported during the screening period or AEs secondary to study-related 
procedures should always be captured as not having a reasonable possibility the AE was caused 
by the Study Drug. Unexpected, abnormal laboratory results observed during the Screening 
Period should be captured as Medical History and not as an AE.  
10.3 ADVERSE EVENTS – RELATIONSHIP TO STUDY DRUG 
Changed as follows: The relationship of each AE to the Study Drug will be based on the 
Investigator’s assessment as to whether there is a reasonable possibility the AE 
was caused by the Study Drug. This assessment will be based on the Investigator's 
clinical judgment, which in turn depends on consideration of various factors such as the 
subject's report, the timing of the AE in relationship to Study Drug 
administration/discontinuation, the Investigator’s observations, and the Investigator’s prior 
experience. The Investigator’s assessment of the relationship of the AE to the Study Drug 
will be recorded in the appropriate section of the EDC. The relationship of each AE to the 
study drug will be classified into one of three defined categories as follows:  
• Unlikely – a causal relationship between the AE and the study drug is unlikely.  
• Possible –  a causal relationship between the AE and the study drug is possible.  
• Probably –  a causal relationship between the AE and the study drug is probably. 
For example, the AE is a common adverse event known to occur with the 
pharmacological class of the study drug; or the AE abated on study drug 
discontinuation and reappeared upon rechallenge with the study drug.  
These three categories are based on the Investigator’s clinical judgment, which in turn depends 
on consideration of various factors such as the subject’s report, the timing of the AE in 
relationship to study drug administration/discontinuation, the physician’s observations and the 
physician’s prior experience. The relationship of the AE to the study drug will be recorded in 
the appropriate section of the EDC.  
11.3.2  Secondary Analyses 
Clarified that p-tau181 may be p-tau181 and/or p-tau217. 
 
 
 
 
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TABLE OF CONTENTS 
SUMMARY OF PROTOCOL AMENDMENT #1 .............................................................3 
1. 
LIST OF ABBREVIATIONS ..................................................................................14 
2. 
INTRODUCTION ....................................................................................................16 
2.1. Mechanism of Action ............................................................................................................... 16 
2.2. Safety pharmacology and toxicology ....................................................................................... 16 
2.3. Clinical Studies ........................................................................................................................ 17 
3. 
STUDY OBJECTIVES ............................................................................................20 
4. 
SUMMARY OF STUDY DESIGN .........................................................................20 
5. 
SUBJECT SELECTION ..........................................................................................21 
5.1. Study Population ...................................................................................................................... 21 
5.2. Inclusion Criteria ..................................................................................................................... 21 
5.3. Exclusion Criteria .................................................................................................................... 24 
6. 
STUDY DRUG .........................................................................................................27 
6.1. Simufilam Physical Description and Preparation ..................................................................... 27 
6.1.1. Packaging and Labelling ................................................................................................27 
6.1.2. Storage ............................................................................................................................28 
6.1.3. Drug Accountability ........................................................................................................28 
6.2. Administration and Dosing Regimen ....................................................................................... 28 
6.3. Concomitant Medications ........................................................................................................ 28 
7. 
STUDY PROCEDURES .........................................................................................29 
7.1. Evaluations by Visit ................................................................................................................. 29 
7.1.1. Screening Period (No greater than a 60-day duration prior to Study Day 1) .................29 
7.1.2. Rescreening of a Subject .................................................................................................31 
7.1.3. Baseline Visit (Study Day 1) (Dosing Initiation) ............................................................31 
7.1.4. Weeks 4, 16 and 40 Follow-up Visits ..............................................................................33 
7.1.5. Weeks 28 Follow-up Visit................................................................................................33 
7.1.6. Week 52 End-of-Treatment Visit / Early Termination (ET) Visit ....................................34 
7.1.7. End-of-study / Early Termination Safety Follow-up .......................................................35 
7.1.8. Treatment after Study Completion ..................................................................................36 
7.1.9. Unscheduled Visits and Discontinuation due to AEs ......................................................36 
7.1.10    Stopping Criteria ...........................................................................................................36 
7.2. Laboratory Assessments .......................................................................................................... 37 
7.2.1. Clinical Laboratory Tests ................................................................................................37 
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7.2.2. Collection of Whole Blood Samples for ApoE Genotyping .............................................37 
7.2.3. Preparation of Samples from PK and Plasma Biomarker Sub-study Participants ..........38 
8. 
COGNITIVE AND FUNCTIONAL ASSESSMENTS ...........................................38 
8.1. Mini-Mental State Exam (MMSE) ........................................................................................... 38 
8.2. Clinical Dementia Rating (CDR) ............................................................................................. 38 
8.3. Alzheimer’s Disease Assessment Scale – Cognitive Subscale 12 (ADAS-Cog12) ................. 38 
8.4. Neuropsychiatric Inventory (NPI) ............................................................................................ 38 
8.5. Alzheimer’s Disease Cooperative Study – Activities of Daily Living (ADCS-ADL-AD) ...... 39 
8.6. Columbia-Suicide Severity Rating Scale (C-SSRS) ................................................................ 39 
8.7. Zarit Burden Interview (ZBI) ................................................................................................... 39 
8.8. Geriatric Depression Scale (GDS) ........................................................................................... 39 
8.9. Electronic Capture of Rating Scales......................................................................................... 39 
9. 
EARLY DISCONTINUATION ...............................................................................40 
10. 
ADVERSE EVENTS/SERIOUS ADVERSE EVENTS ..........................................41 
10.1. Adverse Events - Definition ...................................................................................................... 41 
10.2. Adverse Events - Severity Rating ............................................................................................ 42 
10.3. Adverse Events – Relationship to Study   Drug ....................................................................... 42 
10.4. Serious Adverse Events and Unexpected Adverse Events - Definitions .................................. 42 
10.5. Serious Adverse Events Reporting ........................................................................................... 43 
11. 
STATISTICAL CONSIDERATIONS .....................................................................44 
11.1. Randomization ......................................................................................................................... 44 
11.2. Analysis Populations ................................................................................................................ 44 
11.3. Statistical Analysis ................................................................................................................... 44 
11.3.1 Primary Efficacy Analysis ...............................................................................................44 
11.3.2 Secondary Analyses .........................................................................................................45 
11.4. Safety Analysis ......................................................................................................................... 45 
11.5. Sample Size .............................................................................................................................. 45 
12. 
STUDY TERMINATION ........................................................................................46 
13. 
DATA COLLECTION, RETENTION AND MONITORING .................................46 
13.1. Case Report Forms ................................................................................................................... 46 
13.2. Availability and Retention of Investigational Records ............................................................ 46 
13.3. Subject Confidentiality ............................................................................................................ 47 
13.4. Liability .................................................................................................................................... 47 
13.5. Ethical and Legal Issues ........................................................................................................... 47 
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13.5.1. Institutional Review Board...............................................................................................47 
13.6. Informed Consent Form ........................................................................................................... 48 
14. 
INVESTIGATOR RESPONSIBILITIES ................................................................48 
15. 
REFERENCES .........................................................................................................49 
16. 
APPENDIX A – SCHEDULE OF ACTIVITIES ....................................................51 
 
LIST OF FIGURES 
 
Figure 1  Phase 2a Mean Change from Baseline to Day 28 in CSF biomarkers (±SEM) ...... 18 
Figure 2  Percent Change from Baseline in CSF Biomarkers at 6 Months (±SD) ................. 19 
Figure 3  Phase 2b Mean Change from Baseline to Day 28 in Total Errors in Memory Test 20 
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1. LIST OF ABBREVIATIONS 
3xTg  
 
 
triple transgenic 
α7nAChR  
 
 
α7 nicotinic acetylcholine receptor 
Aβ42 
 
 
 
amyloid beta1-42 
AChEI  
 
 
acetylcholinesterase inhibitor 
AD 
 
 
 
Alzheimer’s disease 
ADAS-Cog 
 
 
Alzheimer’s Disease Assessment Scale – Cognitive Subscale 
ADCS-ADL 
Alzheimer’s Disease Cooperative Study – Activities of Daily 
Living 
ADME 
 
 
absorption, distribution, metabolism, excretion 
AE 
 
 
 
Adverse Event 
ALT   
 
 
alanine transaminase 
ALP 
 
 
 
alkaline phosphatase 
ANOVA 
 
 
analysis of variance 
AST   
 
 
aspartate transaminase 
AUC  
 
 
area under the curve 
BMI 
 
 
 
Body Mass Index 
BUN  
 
 
blood urea nitrogen 
CDR-GS 
 
 
Clinical Dementia Rating – Global Score 
CDR-SB 
 
 
Clinical Dementia Rating – Sum of Boxes 
CFR 
 
 
 
Code of Federal Regulations 
Cmax  
 
 
maximum plasma concentration 
CRF 
 
 
 
Case Report Form 
CRO  
 
 
Contract Research Organization 
CSF 
 
 
 
cerebrospinal fluid 
CSI 
 
 
 
Cassava Sciences, Inc. 
C-SSRS 
 
 
Columbia-Suicide Severity Rating Scale 
CT 
 
 
 
computerized tomography 
DSM-V 
 
 
Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition 
DSMB  
 
 
Data Safety Monitoring Board 
ECG  
 
 
electrocardiogram 
eCOA  
 
 
electronic Clinical Outcome Assessment 
eCRF  
 
 
electronic Case Report Form 
EDC  
 
 
Electronic Data Capture 
EDTA  
 
 
ethylenediaminetetraacetic acid 
ELISA  
 
 
enzyme-linked immunosorbent assay 
FDA  
 
 
Food and Drug Administration 
FLNA  
 
 
filamin A 
GCP  
 
 
good clinical practice 
GDS  
 
 
Geriatric Depression Scale 
GGT   
 
 
gamma glutamyl transpeptidase 
GLP 
 
 
 
good laboratory practice 
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hERG  
 
 
human ether-a-go-go-related gene 
iADRS 
 
 
integrated Alzheimer’s Disease Rating Scale 
IB 
 
 
 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human 
Use 
IR 
 
 
 
insulin receptor 
IRB 
 
 
 
independent review board 
iADRS 
 
 
Integrated Alzheimer’s Disease Rating Scale 
ISLT  
 
 
International Shopping List Test 
LDH   
 
 
lactose dehydrogenase 
LOQ  
 
 
limit of quantitation 
MCI 
 
 
 
mild cognitive impairment 
MEMS 
 
 
Medication Event Monitoring System 
MMSE 
 
 
Mini-Mental State Examination 
MRI 
 
 
 
magnetic resonance imaging 
mTOR  
 
 
mammalian target of rapamycin 
NIA - AA 
 
 
National Institute on Aging - Alzheimer’s Association 
NMDAR 
 
 
N-methyl D-aspartate receptor 
NOAEL 
 
 
no observable adverse effect level 
NOEL  
 
 
no observable effect level 
NPI 
 
 
 
Neuropsychiatric Inventory 
PAL 
 
 
 
Paired Associate Learning 
PET 
 
 
 
positron emission tomography 
PK 
 
 
 
pharmacokinetics 
PTI-125 
 
 
former name of simufilam 
SavaDx 
 
 
blood-based diagnostic/biomarker candidate 
RBC  
 
 
red blood cell 
SAE 
 
 
 
serious adverse event 
SOP 
 
 
 
standard operating procedure 
Tmax  
 
 
time to Cmax 
ULN  
 
 
upper limit of normal 
WBC  
 
 
white blood cell 
YKL40 
chitinase-like protein 1, a secreted glycoprotein associated with 
inflammation and tissue remodeling 
ZBI 
Zarit Burden Interview  
 
 
 
 
 
 
 
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2. INTRODUCTION 
2.1. MECHANISM OF ACTION 
Cassava Sciences, Inc. is developing simufilam, a novel drug candidate designed to treat 
and slow the progression of Alzheimer’s disease (AD). Simufilam binds with femtomolar 
affinity to an altered conformation of filamin A (FLNA) that is induced by beta amyloid1-
42 (Aβ42), present in AD brain and critical to the toxicity of Aβ42.1-3 Simufilam binding 
reverses the altered FLNA conformation and restores FLNA’s native shape, preventing 
two toxic signaling cascades of Aβ42. Aβ42, in monomer or small oligomer form, hijacks 
the α7-nicotinic acetylcholine receptor (α7nAChR) and signals via this receptor to 
hyperphosphorylate tau. This signaling requires the recruitment of altered FLNA to this 
receptor. In addition, altered FLNA also links to toll-like receptor 4 (TLR4) to allow Aβ42 
to persistently activate this receptor, leading to inflammatory cytokine release and 
neuroinflammation. Normal FLNA does not associate with either α7nAChR or TLR4. In 
addition to disrupting the normal functions of α7nAChR and tau protein, Aβ42’s toxic 
signaling to hyperphosphorylate tau leads to the signature tangles in AD brain. In two AD 
mouse models and in postmortem human AD brain tissue, simufilam restored function of 
three receptors that are impaired in AD: the α7nAChR, the N-methyl-D-aspartate receptor 
(NMDAR), and the insulin receptor (IR).2,3 Simufilam also improved synaptic plasticity 
and reduced tau hyperphosphorylation, amyloid deposits, neurofibrillary tangles and 
inflammatory cytokine release.2,3 We therefore expect simufilam both to improve 
cognition and to slow AD progression. Both mouse models used a dose of 20 mg/kg/day 
(equivalent to 60 mg/m2/day).  
2.2. SAFETY PHARMACOLOGY AND TOXICOLOGY 
A robust nonclinical ADME, safety pharmacology, and general and genetic toxicology 
program has been conducted with simufilam. In vitro metabolic profiling showed minimal 
metabolism across several species including humans. Simufilam was rapidly absorbed and 
eliminated in in vivo studies in rat and dog with nearly 100% oral bioavailability, a 2.67-h 
half-life in dog, dose-proportional PK and no accumulation. Simufilam does not inhibit or 
induce major CYP450 enzymes, nor is a substrate or inhibitor of major human drug 
transporters at clinically relevant concentrations. Safety pharmacology studies showed no 
adverse effects on gross behavioral and physiological parameters in the Irwin test of CNS 
toxicity in rats, no adverse effects on respiratory rate, tidal volume or minute volume in the 
rat respiratory test, and no adverse effects on arterial blood pressure, heart rate and ECG 
parameters in the dog cardiovascular study. The in vitro hERG test for cardiotoxicity also 
indicated no adverse effect. A full battery of genotoxicity studies was conducted (in vitro 
bacterial Ames, in vitro chromosomal aberration, and in vivo rat micronucleus test) and all 
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were negative. An in vitro specificity screen showed no significant activation or inhibition 
of a panel of 68 receptors, channels and transporters. 
Simufilam was tested in single dose and repeat dose oral toxicity studies of up to 6 months 
in rats and 9 months in dogs. A 6-month repeat dose oral toxicity study in rats (PTI-125-
NC-049) used the same doses as a 28-day study (50, 500 and 1000 mg/kg/day), which 
found 500 mg/kg/day to be the no-adverse-effect-level (NOAEL). In the 6-month study, 
the toxicological response was characterized by decreased body weights and adverse 
structural and functional alterations in the liver of 500 and 1000 mg/kg/day animals, 
including increased hepatic weight, hepatocellular hypertrophy and vacuolation, 
single/multiple basophilic/ eosinophilic/clear cell focus, hepatocellular degeneration, 
pigmentation, and oval cell hyperplasia. The presence of bile pigment was consistent with 
cholestasis. These findings correlated with changes to the clinical chemistry profile, 
including increased ALP and total/direct bilirubin. Over the 1-month recovery period, there 
was complete recovery of the hepatocellular degeneration and partial recovery of 
hepatocellular hypertrophy; other microscopic findings in the liver remained. The NOAEL 
in this 6-month study was 50 mg/kg/day (equivalent to 300 mg/m2), corresponding to a 
safety margin of 6- and 1.6-fold based on Cmax and AUC over the 100 mg b.i.d. dose in 
human subjects. A second 6-month repeat dose oral toxicity study in rats determined the 
6-month NOAEL in the rat to be < 125 mg/kg/day, based on hepatocellular vacuolation in 
both sexes and hepatocellular hypertrophy in females at 125 and 250 mg/kg.  
In a 9-month toxicity study in dogs (PTI-125-NC-050), the no-effect-level (NOEL) of 
simufilam was 25 mg/kg. The high dose of 200 mg/kg/day was decreased to 150 mg/kg/day 
after 1 month due to bodyweight loss considered unsustainable for 9 months. Clinical signs 
were slight hypoactivity and incidences of slight muscle fasciculations early in the study, 
and salivation. There were no pathology findings, but the high dose was considered adverse 
due to two unexplained deaths. The 75 mg/kg/day NOAEL (equivalent to 1500 mg/m2) 
provides 38- and 19-fold safety margins based on Cmax and AUC over the 100 mg b.i.d. 
dose in subjects. 
Simufilam showed no mutagenic or clastogenic responses in a standard battery of 
genotoxicity assays. 
2.3. 
CLINICAL STUDIES 
A first-in-human, double-blind, single ascending dose clinical study (PTI-125-01) was 
conducted in healthy normal volunteers, age 18-45 with oral dosing solution. Doses were 
placebo, 50, 100 and 200 mg (equivalent to 31, 62, and 123 mg/m2, respectively) 
administered to three different groups of volunteers. The study showed dose proportional 
PK, a half-life ranging from 4.5 to 6 h, and there were no drug-related adverse events (AEs). 
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In a 28-day phase 2a study (PTI-125-03), 13 subjects with mild-to-moderate AD received 
simufilam 100 mg b.i.d. as oral tablets. Subjects had Mini-Mental State Exam (MMSE) 
scores ≥ 16 and ≤ 24, and were age 50-85 with a CSF total tau/Aβ42 ratio ≥ 0.30. A second 
CSF sample was collected on Day 28, allowing assessment of change from baseline in 
biomarkers using commercial ELISA kits. All 8 biomarkers that are elevated in AD were 
significantly reduced from baseline (Figure 1).4 Aβ42, which is low in AD, was increased 
slightly but non-significantly. Reduced inflammatory cytokines and YKL-40 indicated 
reduced neuroinflammation. A reduced neurodegenerative drive was suggested by 
reductions in neurogranin, neurofilament light chain, and total tau. The robust reduction in 
phospho-tau (P-Tau181) confirms the mechanism of action of simufilam. Simufilam was 
safe and well tolerated in all subjects. 
Figure 1  Phase 2a Mean Change from Baseline to Day 28 in CSF biomarkers (±SEM) 
 
 
 
A phase 2b randomized, placebo-controlled clinical study (PTI-125-02) of simufilam 50 or 
100 mg tablets or placebo (1:1:1) enrolled 64 mild-to-moderate AD subjects with MMSE 
16-26. CSF biomarker analyses were conducted blind to treatment and timepoint by an 
outside lab, and screening and Day 28 samples for each subject were measured in triplicate 
in the same ELISA plates. Albumin and immunoglobulin G (IgG) were measured by 
immunoblotting and quantified by densitometric quantitation. Plasma p-tau181, measured 
by Quanterix Corporation using their Simoa platform, was significantly reduced versus 
placebo. The treatment effect on plasma p-tau181 was consistent with treatment effects in 
CSF biomarkers, suggesting disease modification and replicating Phase 2a results in a well-
controlled study. An open-label safety study of simufilam 100 mg showed larger 
improvements from baseline at 6 months (n=25) (Figure 2). 
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Figure 2  Percent Change from Baseline in CSF Biomarkers at 6 Months (±SD)  
 
 
The secondary endpoints in the Phase 2b study were two cognitive measures using the 
Cambridge Neuropsychological Test Automated Battery. Subjects were assessed on the 
Paired Associate Learning (PAL) test, measuring episodic memory, and a test of spatial 
working memory. The primary outcome measure for each was total errors, with errors 
imputed for more difficult levels not reached in the PAL test. Simufilam produced 
encouraging mean improvements from baseline in spatial working memory and in a 
sensitivity analysis for episodic memory for both doses, suggesting cognitive enhancement 
(Figure 3). Without the sensitivity analysis, the PAL test did not show a clear treatment 
effect. Subjects who showed no detectable simufilam in plasma or >25% noncompliance 
by pill counts were excluded from cognitive data (5 subjects). For the sensitivity analysis 
for episodic memory, the most and least impaired subjects were removed by baseline score. 
This sensitivity analysis removed subjects who performed so poorly they may not have 
understood the task and those who were at a ceiling of very few errors at baseline. 
Cognitive enhancement by simufilam is supported by preclinical data showing improved 
function of α7nAChR, NMDAR and insulin receptors and improved synaptic plasticity in 
3xTg AD mice and in postmortem human AD brain tissue.  
In both Phase 2 clinical studies, simufilam was well tolerated and no subjects discontinued 
due to AEs.  
 
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Figure 3  Phase 2b Mean Change from Baseline to Day 28 in Total Errors in Memory 
Test 
 
3. STUDY OBJECTIVES 
The primary objective of this study is to investigate the safety and efficacy of simufilam 
in slowing cognitive and functional decline following 52-week, repeat-dose oral 
administration in mild-to-moderate AD subjects, 50-87 years of age. Secondary objectives 
include the assessment of simufilam’s effect on neuropsychiatric symptoms and caregiver 
burden. A third objective is to investigate the effect of simufilam treatment on plasma 
biomarkers. 
4. SUMMARY OF STUDY DESIGN 
In this Phase 3 clinical study, approximately 750 subjects with mild-to-moderate AD will 
receive placebo or 100 mg tablets of simufilam, twice daily, for 52 weeks. Randomization 
(1:1) will be stratified by low or high MMSE (16-20 and 21-27). 
 
Subjects, 50-87 years of age, will be selected for screening based on a diagnosis of AD 
consistent with Stages 4 or 5 on the Alzheimer’s continuum (National Institute on Aging – 
Alzheimer’s Association 20185). Subjects must have MMSE ≥ 16 and ≤ 27, and a Clinical 
Dementia Rating Global Score (CDR-GS) of 0.5, 1 or 2. Finally, subjects must have 
confirmed PET or fluid biomarker evidence of AD pathophysiology prior to randomization 
(see Section 5.2 – Inclusion Criteria for details). 
 
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Once subjects have been satisfactorily screened for study participation, visits to the 
research clinic will occur on Study Day 1 and at Weeks 4, 16, 28, 40 and 52.   
 
The co-primary endpoints include the 12-item Alzheimer’s Disease Assessment Scale – 
Cognitive Subscale (ADAS-Cog12) and the Alzheimer’s Disease Cooperative Study – 
Activities of Daily Living (ADCS-ADL), both assessed as the change from baseline to the 
end of the double-blind treatment period (Week 52). 
 
Secondary endpoints include the integrated Alzheimer’s Disease Rating Scale (iADRS), 
Neuropsychiatric Inventory (NPI), MMSE, and Clinical Dementia Rating Sum of Boxes 
(CDR-SB). A brief questionnaire assessing caregiver burden, the Zarit Burden Interview 
(ZBI), will be collected as an additional secondary endpoint.  
 
Safety will be evaluated by adverse event monitoring, vital signs, clinical labs, and the 
Columbia Suicide Severity Rating Scale (C-SSRS) at every visit. Subjects will undergo 
MRI during screening to ensure entry criteria are met (unless recent MRI confirms entry 
criteria). Resting ECGs will be conducted at Baseline (Study Day 1) and Weeks 4, 28 and 
52. A complete physical and neurological examination will be performed at screening, and 
brief examinations will be performed at all other visits. Weight will be measured during 
the Screening Period, at Baseline (Study Day 1) and at all other visits.  
 
A limited number of research sites will be invited to participate in the PK and plasma 
biomarker sub-study. Collection of PK samples will enable an exposure-response analysis. 
Approximately 100 subjects will participate (50 per group). Plasma samples will be 
collected during the Screening Visit and again at Weeks 28 and 52. Change from baseline 
for plasma biomarkers represent additional secondary endpoints. 
 
An independent Data Safety Monitoring Board (DSMB) will meet periodically to review 
subject safety assessments and determine if dosing may continue. A charter will be 
developed with specific guidance for the DSMB. 
 
5. SUBJECT SELECTION 
5.1. STUDY POPULATION 
Approximately 750 subjects will be enrolled in the study. 
5.2. INCLUSION CRITERIA 
Each subject must meet the following Inclusion Criteria:  
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1. Capable of providing either written informed consent or, if incapable of written 
consent, permission to participate can be obtained from a legally authorized 
representative. Verbal assent to the study procedures and schedule is required of all 
participants. Genotyping for apolipoprotein E (ApoE) will be included in the informed 
consent, and participants must consent to this to be included in the study. If, in the 
Investigator’s judgment, a subject loses capacity to consent during the duration of the 
study, a legally authorized representative must consent on behalf of the subject. All 
consent processes must be undertaken prior to any study procedures. 
2. Age ≥ 50 and ≤ 87 years at the time of the informed consent, male or female. 
3. Meets National Institute on Aging and Alzheimer's Association (NIA-AA) Research 
Framework criteria for individuals in clinical Stage 4 or Stage 5 of the Alzheimer’s 
continuum (per Table 6 in the corresponding 2018 publication5).   
4. The subject and/or study partner report a gradual and progressive change in memory 
for ≥ 6 months. 
5. Evidence for AD pathophysiology, confirmed either prior to or during the screening 
period prior to randomization, as follows: 
a. Prior to screening, confirmed with appropriate documentation by either: 1) CSF 
total tau/Aβ42 ratio (must be ≥ 0.28), or 2) an abnormal qualitative amyloid 
positron emission tomography (PET) scan consistent with AD (Note – FDG 
PET, tau PET or amyloid SUVR values are not acceptable); or 
b. During screening, subjects must demonstrate an elevated plasma P-tau181 or 
plasma P-tau217 level (research biomarkers that identify AD pathophysiology 
with high accuracy; see lab manual for details). 
6. MMSE score ≥ 16 and ≤ 27 at screening. 
7. CDR-GS must be 0.5, 1 or 2.  
8. If female, either surgically sterile or postmenopausal for at least 1 year. 
9. Male subjects must be willing to use contraception during the study. With female 
partners of childbearing potential, male subjects, regardless of their fertility status, must 
agree to either remain abstinent or use condoms in combination with one additional 
highly effective method of contraception (e.g., oral or implanted contraceptives, or 
intrauterine devices) or an effective method of contraception (e.g., diaphragms with 
spermicide or cervical sponges) during the study and for 14 days after study drug dosing 
has been completed. 
10. Fluency in a language of the research site and the utilized assessment materials. 
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11. Has adequate visual and auditory acuity (in the Investigator’s judgment) that is 
sufficient to complete all scheduled assessments (eyeglasses and hearing aids are 
permitted). 
12. If receiving background AD medications, including cholinesterase inhibitors, 
memantine, neuroleptics, anxiolytics, or sleep medications, the dosing regimen must 
be stable for at least 12 weeks prior to Study Day 1 (randomization) and should be 
expected to remain stable during the study (Note – barbiturates, meprobamate, and high 
dose benzodiazepines are not allowed, while low dose benzodiazepines, zolpidem, 
zaleplon and suvorexant are permitted). Chronic medications for conditions other than 
AD (such as depression) must be prescribed at a stable dose for at least 4 weeks prior 
to screening. Medications that might have a potential confounding effect on cognitive 
testing (either prescription or non-prescription medications) should not be modified 
during the Screening Period (see Section 6.3 for additional details). 
13. The subject has not been a cigarette smoker or chewed tobacco for at least 3 years 
(occasional pipe or cigar smoking is permitted, but vaping is not).  
14. Availability of a person (a study partner) who has frequent and sufficient contact with 
the study subject (defined as ≥ 10 hours per week), and can: 
a. provide accurate information regarding the study subject's cognitive and 
functional abilities in the opinion of the Investigator,  
b. agree to comply with and participate at all scheduled visits and study 
procedures,  
c. sign the necessary consent form,  
d. maintain the same level of interaction with the study subject throughout the 
study duration. 
15. Individuals who have participated in a clinical study with an investigational drug 
targeting the underlying AD process are permitted to participate in this study on a case-
by-case basis after consultation between the Principal Investigator and the Sponsor. 
Subjects known to have been randomized to placebo do not require such consultation 
and are permitted to participate. 
16. Completed a COVID-19 vaccine primary series (“fully vaccinated”) at least two weeks 
prior to Study Day 1 (randomization) or had an unambiguous COVID-19 infection 
diagnosed more than 3 months before the start of the screening period (to minimize or 
eliminate any effect on cognition that might confound a proper assessment during 
screening). (Note – subjects having a symptomatic COVID-19 infection [or its variants] 
within 3 months of the screening period should have their screening assessment 
delayed; vaccinated, asymptomatic subjects that test positive for COVID-19 within 
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three months of the screening period require Medical Monitor approval to not delay 
screening). 
5.3. EXCLUSION CRITERIA 
Subjects meeting any of the following criteria will be excluded from the study: 
1. Residence in a skilled nursing facility requiring 24-hour care (Note – subjects may 
reside in an assisted living facility if they do not need 24-hour care). 
2. Any contraindications to study procedures (e.g., potential subjects with a pacemaker 
that is not “MRI friendly”). 
3. BMI < 18.5 or > 37.5  
4. Evidence of a neurologic condition other than AD that, in the judgment of the 
Investigator, significantly contributes to the subject’s dementia, including, but not 
limited to, frontotemporal dementia, dementia with Lewy bodies, Parkinson's disease, 
corticobasal degeneration, Creutzfeldt-Jakob disease, progressive supranuclear palsy, 
Huntington's disease, or normal pressure hydrocephalus. 
5. Subjects with any current primary psychiatric diagnosis other than AD if, in the 
judgment of the Investigator, the psychiatric disorder or symptom is likely to confound 
interpretation of drug effect, affect cognitive assessment, or affect the subject’s ability 
either to comply with study procedures or to complete the study.  Patients with a history 
of schizophrenia or chronic psychosis are excluded.  
6. Geriatric Depression Scale (15-item) score > 8 (Note – a subject with a score > 8 may 
continue in screening if, in the judgment of the Investigator, the elevated score is not 
attributed to a major depressive episode). 
7. Affirms suicidal ideation in response to questions number 4 or 5 in the C-SSRS during 
the past 3 months (i.e., “active suicidal ideation with some intent to act, without specific 
plan,” or “active suicidal ideation with specific plan and intent”) or affirms any of the 
questions contained in the Suicidal Behavior section of the C-SSRS as applicable 
during the past 12 months.  
8. Meets DSM-V criteria for alcohol or substance use disorder within 2 years before the 
Screening Period. 
9. MRI presence of cerebral vascular pathology (including, but not limited to, 
intracerebral hemorrhage, infarct > 1 cm3, > 3 lacunar infarcts, > 10 microhemorrhages, 
cortical superficial siderosis, diffuse confluent deep white matter hypertense lesions 
[Fazekas scale 3]), cerebral contusion, symptomatic subdural hematoma, or aneurysm. 
(Note – a space-occupying lesion deemed clinically insignificant by the Investigator 
and confirmed by the Medical Monitor may continue screening). 
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10. History of transient ischemic attack (TIA) or stroke within 12 months of screening, or 
history of a stroke concurrent with the onset of dementia. 
11. History of seizure within 12 months of screening. 
12. History of severe head trauma; history of head trauma with loss of consciousness > 10 
min within 12 months of screening; history of head trauma concurrent with the onset 
of dementia; history of head trauma likely to be contributing to the subject’s cognitive 
impairment in the Investigator’s judgment. 
13. Onset of dementia secondary to cardiac arrest, surgery with general anesthesia, or 
resuscitation. 
14. Clinically significant, untreated or inadequately treated sleep apnea that is likely to be 
contributing to the subject’s cognitive impairment in the Investigator’s judgment. 
15. Insufficiently controlled diabetes mellitus, defined as: 
a. requiring insulin treatment (unless subject has been stable for at least 4 weeks 
prior to screening on a once-daily dose of long-acting insulin), or 
b. HbA1C > 8.0% during the Screening Period. 
16. Malignant tumor within 3 years before screening (except definitively treated squamous 
or basal cell carcinoma, stage 0 melanoma in situ, cervical carcinoma in situ, localized 
non-progressive prostate cancer, localized stage 1 bladder cancer or colon polyp 
resolved by excision, per judgment of the Investigator). Other potential exceptions must 
be discussed with the Medical Monitor. 
17. Known positive HIV status. 
18. Positive HBsAg or HCV-Ab during screen. 
19. Positive urine drug screen for substances of abuse. 
20. Vitamin B12 level lower than the normal limit at the time of screening (and that remains 
below on repeat testing).  Subjects may be enrolled following initiation of B12 therapy 
for at least 4 weeks prior to randomization with confirmation of a normal level upon 
repeat testing. 
21. Thyroid-stimulating hormone (TSH) levels greater than the upper limit of normal and 
a free thyroxine (free T4) lower than the lower limit of normal; subjects on thyroid 
supplementation for hypothyroidism must be on a stable dose for ≥ 3 months before 
screening. Subjects with borderline hypothyroidism may be considered for rescreening 
after consultation with the Medical Monitor. 
22. Alanine transaminase (ALT) or aspartate transaminase (AST) ≥2x the upper limit of 
normal (ULN), total bilirubin ≥1.5x ULN, or alkaline phosphatase (ALP) ≥1.5 ULN at 
screening (Note – subjects with elevated total bilirubin are not excluded if they meet 
criteria for Gilbert’s syndrome, including: bilirubin is predominantly indirect [with 
normal direct bilirubin level]; and ALT, AST and ALP ≤1x ULN). 
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23. History or diagnosis of clinically significant ischemic heart disease (e.g., myocardial 
infarction or unstable angina within 1 year of screening), moderate to severe congestive 
heart failure, cardiomyopathy, myocarditis or valvular heart disease of clinical 
significance in the Investigator’s judgment. 
24. Clinically significant cardiac arrhythmia or heart block as evidenced by ECG in the 
judgment of the Investigator. 
25. Clinically significant abnormality on screening electrocardiogram (ECG), including, 
but not necessarily limited to, a confirmed QT interval by the Fridericia correction 
formula (QTcF) > 470 msec (females) or > 450 msec (males) based on WHO 2016 
guidelines (Note – borderline elevations in QTcF intervals due to bundle branch block 
must be approved by the Medical Monitor). 
26. Insufficiently controlled hypertension (defined, at rest, as systolic BP > 170 mmHg or 
diastolic BP > 100 mmHg; if an initial BP reading is elevated, an additional 
measurement during the Screening Period could be used before excluding a potential 
subject for insufficiently controlled hypertension). 
27. Hypotension (systolic BP < 90 mmHg) or bradycardia with a heart rate less than 50 
beats per minute during screening (out of range values may be repeated once for 
confirmation). 
28. Use of medications that in the Investigator’s opinion will contribute to cognitive 
impairment, put the subject at higher risk for AEs, or impair the subject’s ability to 
perform cognitive testing or other study procedures. 
29. Donepezil > 10 mg/day, currently or within 12 weeks of Study Day 1 (randomization).  
30. Discontinued AchEI or memantine < 12 weeks prior to randomization. 
31. Currently or previously prescribed/administered aducanumab, lecanemab, or any anti-
amyloid monoclonal antibody, more than two doses. 
32. Antipsychotics (Note – low doses are allowed only if given for sleep disturbances, 
agitation, aggression or dementia-related psychosis, and only if the dose has been stable 
for at least 12 weeks prior to the Baseline Visit (Study Day 1)). 
33. Tricyclic or SSRI antidepressants if prescribed for depression less than 4 weeks prior 
to screening; or the Investigator believes the dose of such medication must be modified 
during the Screening Period; or the Investigator believes the subject must be started on 
such medication during the Screening Period. Monoamine oxidase inhibitors are not 
permitted.  
34. Immunosuppressants, including systemic corticosteroids, if taken in clinically 
immunosuppressive doses (steroid use for allergy or inflammation is permitted). 
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35. Use of antiepileptic medications if taken for control of seizures (Note – use of 
antiepileptic medications are allowed if used for mood stabilization or indications other 
than seizures). 
36. Chronic intake of opioid-containing analgesics at standard doses (use of intermittent or 
low-dose opioids must be approved by the Medical Monitor). 
37. Use of prescribed sedating H1 antihistamines (Note – fexofenadine is the preferred 
non-sedating antihistamine for subjects requiring such medication). 
38. Use of nicotine therapy (all dosage forms including a patch), varenicline (Chantix), or 
similar therapeutic agent within 4 weeks prior to screening. 
39. Loss of a significant volume of blood (> 450 mL) within 4 weeks of randomization. 
40. Clinically significant abnormalities on screening laboratory tests in the judgment of the 
Investigator. 
41. Unstable medical condition that is clinically significant in the judgment of the 
Investigator, including significant neurologic, hepatic, renal, endocrinologic, 
cardiovascular, gastrointestinal, pulmonary, hematologic, immunologic or metabolic 
disease.  
42. Any other medical or neurological condition (other than Alzheimer’s disease), that, in 
the opinion of the Investigator, might represent a contributing cause to the subject’s 
cognitive impairment, or affect cognitive assessment, subject safety, ability to comply 
with study assessments, drug compliance and completion of the study. This could 
include, for example, excessive marijuana or cannabinoid use.  
6. STUDY DRUG 
6.1. SIMUFILAM PHYSICAL DESCRIPTION AND PREPARATION 
Investigational simufilam (100 milligram active strength) and matching placebo will 
be supplied by Cassava as coated tablets.   
All remaining unused Study Drug will be returned to the Sponsor or designee. 
6.1.1. Packaging and Labelling 
Simufilam or placebo tablets in plastic bottles will be supplied in 70-count bottles for 
a 4-week supply or 188-count bottles for a 12-week supply. Bottles include a desiccant 
canister and are closed with a foil seal and child-resistant (CR) cap. Each bottle contains 
7 or 10 days of extra medication to accommodate scheduling flexibility with clinic 
visits.   
 
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A Medication Event Monitoring System (MEMS®) that is 21 CFR Part 11 compliant 
will be used to track adherence to the b.i.d. dosing schedule. MEMS® caps will be 
supplied to replace the conventional CR cap on each bottle. One (1) MEMS® cap will 
be assigned to each subject for use throughout the study. Each MEMS® cap has an LCD 
display that provides immediate visual indication of the number of doses taken that day 
and the number of hours since the prior dose that day, resetting to zero each night. 
Instructions on management and use of MEMS® caps will be provided in the Pharmacy 
manual and during site training. 
 
Each bottle is labeled with a unique double-blind ID number that is randomly assigned 
to a treatment. A computer-based clinical study management system will specify the 
bottle ID number to be dispensed according to the subject’s treatment randomization. 
 
6.1.2. Storage 
The investigational drug supplies must be stored in a locked cabinet or room with 
limited access at controlled room temperature, 20-25º C (68-77º F) and protected from 
moisture. The Pharmacy Manual should be referenced for additional information about 
handling temperature excursions and record keeping requirements. 
6.1.3. Drug Accountability 
The Investigator will be responsible for monitoring the receipt, storage, dispensing 
and accounting of all study medications according to site standard operating 
procedures (SOPs). All records documenting the chain of custody for the study 
medication must be retained in the site study file. Accurate, original site records 
must be maintained of drug inventory and dispensing. All records must be made 
available to the Sponsor (or designee) and appropriate regulatory agencies upon 
request. 
6.2. ADMINISTRATION AND DOSING REGIMEN 
Subjects will be randomized to receive placebo or 100 mg simufilam twice daily 
(b.i.d.). Study Drug can be taken with or without food.  
6.3. CONCOMITANT MEDICATIONS 
Use of prescription or non-prescription medications will be recorded during the study. 
Chronic prescription medications for conditions other than AD must be stable for at 
least 4 weeks prior to screening. Medications that might have a potential confounding 
effect on cognitive testing, either prescription or non-prescription medications, should 
not be modified during the Screening Period. Medications that do not have a potential 
confounding effect on cognitive testing may be modified during the Screening Period, 
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if necessary, but the Investigator may wish to confer with the Medical Monitor in such 
a situation. After randomization to Study Drug at the Baseline Visit (Study Day 1), the 
Investigator should strive to maintain concomitant medications at currently prescribed 
doses whenever possible. Dose modification, addition or discontinuation of 
medications that might have a potential confounding effect on cognitive testing (e.g., 
cholinesterase inhibitors and memantine) after randomization should be reviewed by 
the Medical Monitor. [Note – see Inclusion Criterion #12 and Exclusion Criteria #29 
and #30 for additional details regarding background medications frequently prescribed 
to patients with AD].   
7. STUDY PROCEDURES 
Appendix A presents the Schedule of Activities. 
Prior to any study-related activities, the Informed Consent Form (ICF) must be signed 
and dated by the subject (or a legally authorized representative) and the study partner.  
The format and content of the ICF must be agreed upon by the Principal 
Investigator(s), the appropriate IRB and the Sponsor. The signed and dated ICF must 
be retained by the Investigator in the subject's file. 
 
7.1. 
EVALUATIONS BY VISIT 
Follow-up visits can be scheduled +/- five (5) days from the targeted Study Visit date.  
 
7.1.1. Screening Period (No greater than a 60-day duration prior to Study Day 1) 
The Sponsor recognizes the Screening Period assessments and procedures may not 
necessarily be completed in a single visit. A subject is permitted to be screened over 
more than one calendar day if, in the Investigator’s judgment, such scheduling will 
optimize the accuracy of Screening Period assessments and procedures.  The following 
will be completed during the Screening Period: 
• Informed Consent.  
• Review of Inclusion and Exclusion Criteria 
• Collect demographic information (e.g., sex, date of birth, race/ethnicity, level 
of education) 
• Medical and surgical history  
• Review concomitant medications and any recently discontinued medications. 
• To the extent such information is available, review and record any 
investigational drugs administered during past clinical study participation 
regardless of the date of such participation. 
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• History of drug, alcohol and tobacco use  
• eCOA order of administration at screening: 
o Note – it is a study requirement to first administer the MMSE (and then 
the other assessments if the MMSE criterion is met) 
• 
MMSE 
• 
CDR (study partner is interviewed first in the absence of 
the study subject and then the subject is interviewed, by 
the same rater, in the absence of the study partner) 
• 
Geriatric Depression Scale 
• 
C-SSRS – Baseline/screening version  
• Complete physical and neurologic examination; including measurement of 
key vital signs (blood pressure [supine], temperature, pulse rate), height and 
weight (to calculate BMI) 
• A 12-lead resting ECG (5-min supine) 
• Laboratory assessments, including routine serum chemistry, TSH, free T4, 
Vitamin B12 levels, HBsAg, HCV-Ab, hematology, urinalysis and urine screen 
for drugs of abuse. Plasma for P-tau181 or P-tau217 assessment will also be 
collected unless there is documented evidence of AD pathophysiology prior to 
screening. For subjects with diabetes, collect a blood sample for HbA1C. 
Unexpected, abnormal laboratory results observed during the Screening Period 
should be captured as Medical History and not as an AE (see Section 10.1 – 
Adverse Events – Definition). 
o Note – amphetamines, prescribed to treat neuropsychiatric symptoms 
associated with progressive AD, are acceptable if prescribed for at least 12 
weeks prior to the Baseline Visit (Study Day 1); the Investigator should 
document in the subject’s file the rationale and timeframe for such use, 
noting that the expected positive drug screen for amphetamine does not 
reflect abuse of such drug. 
• Once the clinical and laboratory assessments above have been completed and 
verified to be consistent with study participation, schedule brain MRI to 
confirm subject meets MRI-specific entry criteria. 
o Note – previous brain MRI results, with appropriate documentation and 
approved by the Medical Monitor, will be accepted for up to 6 months prior 
to the Baseline Visit (Study Day 1) unless a recent clinical event warrants a 
repeat scan. 
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• Subjects participating in the PK and plasma biomarker sub-study (100 total; 50 
subjects/treatment group) will have, in addition to the blood collection during 
the Screening Period, subsequent blood collections at Weeks 28 and 52. 
To remain in the study, subjects who develop COVID-19 (or its variants) or manifest a 
positive COVID-19 test during the screening period will need approval from the 
Medical Monitor. 
7.1.2. Rescreening of a Subject 
Individuals who have given informed consent and fail to meet the Inclusion and/or 
Exclusion criteria (screen failure) may not be rescreened if the screen failure is due to 
non-eligible MMSE (<16), MRI or P-tau results.  If screen failure occurs for the 
following reasons, then the subject is allowed one rescreen:  
• Low vitamin B12 requiring supplemental therapy (can retest after 4 weeks) 
• MMSE of 28 (can rescreen after 8 weeks) 
• Clinical hypothyroidism (can rescreen 3 months after being placed on 
supplemental thyroid replacement and manifesting a normal [or low] TSH level 
and a normal free T4 level) 
Other reasons for screen failure will require Medical Monitor approval to rescreen. 
Subjects undergoing rescreen, who had an inclusionary P-tau elevation and/or an 
acceptable screening MRI, should utilize these results during the rescreening process 
and not repeat these procedures.   
7.1.3. Baseline Visit (Study Day 1) (Dosing Initiation) 
Subjects will come to the clinic in the morning. Prior to dosing, the following 
assessments will be conducted: 
• Confirmation of Inclusion/Exclusion criteria 
• Confirm subject has been fully vaccinated for COVID-19 for at least two weeks 
if there is no history of a prior COVID-19 infection 
• Review of concomitant medications 
• Adverse event monitoring 
• Vital signs (blood pressure [supine], temperature, pulse). 
• Weight 
• Brief physical and neurologic examination 
o Note – the brief physical and neurologic examination performed on Study 
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Day 1 and at all subsequent visits will include an assessment of the 
following: general appearance; cardiovascular, pulmonary, and abdominal 
examination, as well as an examination of any other system in response to 
subject-reported symptoms; cranial nerves [II-XII], tone, power, deep 
tendon reflexes, coordination and gait. 
• Clinical laboratory tests (blood and urine) 
• eCOA order of administration: 
o Note – it is acceptable to simultaneously administer the study partner 
assessments in parallel with subject assessments (separate, qualified raters 
in separate rooms). When administered in parallel, the eCOA order of 
administration should be maintained (ADAS-cog12 and then C-SSRS for 
the subject; ADCS-ADL, NPI and then ZBI for the study partner). 
• 
ADAS-Cog12  
• 
ADCS-ADL 
• 
NPI 
• 
ZBI  
• 
C-SSRS – Since Last Visit version 
• A 12-lead resting ECG (5 min supine; triplicate format) 
• Genotyping for ApoE 
  
Once all Baseline Visit (Study Day 1) procedures and assessments have been 
completed, the subject is randomized to a treatment and the bottle of Study Drug to be 
dispensed is assigned by the computer-based study management system. A Medication 
Event Monitoring System (MEMS®) cap is drawn from stock for permanent assignment 
to the subject and initialized via the computer interface. Before removing Study Drug 
from the bottle, remove the original closure and apply the MEMS® cap as a 
replacement. Just prior to administering the first dose of Study Drug, remove the 
MEMS® cap and remove one (1) tablet. 
Subjects will be administered Study Drug at least 1 hour before leaving the clinic. The 
subject will be discharged with their supply of Study Drug. The study partner will be 
trained on the features and proper use of the MEMS® cap and instructed to administer 
Study Drug twice daily with or without food. The study partner should be advised that 
a dose can be up to 4 hours late, but, if a dose is missed, the next dose should NOT be 
doubled. 
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Information and instruction for the computer-based study management system, and the 
MEMS® cap will be covered during site training, and written reference information will 
be included in the Pharmacy Manual.   
For all follow-up visits, subjects will be instructed to bring their Study Drug bottle to 
the clinic. At each visit, the MEMS® cap will be read into the computer-based study 
management system to inform the site about the subject’s Study Drug adherence. The 
MEMS® cap will be removed from the returned bottle and applied to the newly 
dispensed bottle of Study Drug.  
7.1.4. Weeks 4, 16 and 40 Follow-up Visits 
Subjects will return to clinic for these scheduled visits within a ± 5-day “window.” 
• Vital signs (blood pressure [supine], temperature and pulse) 
• Weight  
• Brief physical and neurologic examination  
• Adverse event monitoring 
• Use of concomitant medications 
• eCOA order of administration: 
o Note – it is acceptable to simultaneously administer the study partner 
assessments in parallel with subject assessments (separate, qualified raters 
in separate rooms). When administered in parallel, the eCOA order of 
administration should be maintained (ADAS-cog12 and then C-SSRS for 
the subject; ADCS-ADL and then ZBI for the study partner). 
• 
ADAS-Cog12 (whenever possible, within 1 hour of the time of 
day administered at the Baseline Visit [Study Day 1], and by 
the same rater) 
• 
ADCS-ADL 
• 
ZBI 
• 
C-SSRS – Since Last Visit version 
• Clinical laboratory tests (blood and urine) 
• A 12-lead resting ECG (5 min supine; only at Week 4) 
7.1.5. Weeks 28 Follow-up Visit 
Subjects will return to clinic for these scheduled visits within a ± 5-day “window.” 
Subjects in the PK and plasma biomarker sub-study should come to the clinic before 
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taking their a.m. dose and have their blood sample collected prior to their dose. 
• Vital signs (blood pressure [supine], temperature and pulse) 
• Weight 
• Brief physical and neurologic examination 
• Adverse event monitoring 
• Use of concomitant medications 
• eCOA order of administration:  
o Note – it is acceptable to simultaneously administer the study partner 
assessments in parallel with subject assessments (separate, qualified raters 
in separate rooms). When administered in parallel, the eCOA order of 
administration should be maintained (ADAS-cog12, MMSE and then C-
SSRS for the subject; ADCS-ADL, NPI and then ZBI for the study partner). 
• 
ADAS-Cog12 (whenever possible, within 1 hour of the time of 
day administered at the Baseline Visit [Study Day 1], and by 
the same rater) 
• 
ADCS-ADL 
• 
MMSE 
• 
NPI 
• 
ZBI 
• 
C-SSRS – Since Last Visit version 
• Clinical laboratory tests (blood and urine) 
• For those 100 subjects participating in the PK and Plasma Biomarker sub-study, 
collect their Week 28 blood samples before administering their a.m. dose of 
study drug. 
• A 12-lead resting ECG (5 min supine) 
7.1.6. Week 52 End-of-Treatment Visit / Early Termination (ET) Visit 
Subjects will return to clinic for this scheduled visit within a ± 5-day “window.” Subjects in 
the PK and plasma biomarker sub-study should not take an a.m. dose prior to their blood 
draw. 
• Vital signs (blood pressure [supine], temperature and pulse) 
• Weight 
• Brief physical and neurologic examination 
• Adverse Event monitoring 
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• Use of concomitant medications 
• eCOA order of administration:  
o Note – it is acceptable to simultaneously administer the study partner 
assessments in parallel with subject assessments (separate, qualified raters 
in separate rooms except for CDR). When administered in parallel, the 
eCOA order of administration should be maintained (ADAS-cog12 and 
then MMSE for the subject, and ADCS-ADL, for the study partner; for the 
CDR, the study partner is interviewed first in the absence of the study 
subject and then the subject is interviewed, by the same rater, in the absence 
of the study partner; the C-SSRS is then administered to the subject, and the 
NPI and ZBI are then administered to the study partner). 
• 
ADAS-Cog12 (whenever possible, within 1 hour of the time of 
day administered at the Baseline Visit [Study Day 1], and by 
the same rater) 
• 
ADCS-ADL 
• 
MMSE 
• 
CDR 
• 
NPI 
• 
ZBI 
• 
C-SSRS – Since Last Visit version 
• Clinical laboratory tests (blood and urine) 
• For those 100 subjects participating in the PK and Plasma Biomarker sub-study, 
collect their Week 52 blood samples.  
• A 12-lead resting ECG (5 min supine) 
Note: Early Termination subjects do not need to complete the eCOA if performed 
within 30 days of the ET Visit (see Section 9 – Early Discontinuation) 
7.1.7. End-of-study / Early Termination Safety Follow-up  
The subject and/or study partner will receive a follow-up phone call 7-14 days after the 
last dose of Study Drug for adverse event monitoring. If needed, a follow-up clinic visit 
will be scheduled. This phone call will thus occur Week 53 to 54 for those subjects who 
complete all study visits, or 1 to 2 weeks after Early Termination. If the subject reports 
an adverse event, the subject should be followed and treated by the Investigator until 
the AE has resolved or stabilized (see Section 10.1 – Adverse Events). 
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7.1.8. Treatment after Study Completion 
The Sponsor plans to initiate an open-label extension study for subjects who have 
completed participation in Study PTI-125-07. Should a subject elect to participate in 
the open-label extension study, the End-of-Study Follow-up (Section 7.1.7) will not be 
conducted. 
7.1.9. Unscheduled Visits and Discontinuation due to AEs 
For unscheduled visits due to AEs, any assessments conducted will be at the discretion 
of the Investigator and pertinent to the AE. If a decision is made to discontinue the 
subject from Study Drug, the Sponsor will be notified immediately. The subject should 
be followed and treated by the Investigator until the AE has resolved or stabilized (see 
Section 10.1 – Adverse Events).  Restarting the subject on Study Drug will be a mutual 
decision by the Investigator and the Sponsor. See also Section 9.0 – Early 
Discontinuation. 
7.1.10    Stopping Criteria 
Liver chemistry threshold stopping criteria have been designed to ensure subject safety 
and to evaluate liver event etiology during administration of Study Drug. Potential 
discontinuation of Study Drug for abnormal liver function tests should be considered 
by the Investigator in consultation with the designated medical monitor if the study 
subject meets one or more of the following criteria: 
• ALT or AST ≥ 4x ULN; 
• ALT or AST ≥ 3x ULN and total bilirubin ≥ 2x ULN; 
• ALT or AST ≥ 3x ULN if associated with the appearance or worsening of 
fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash 
and/or eosinophilia; or 
• ALP elevations, if deemed of liver origin and drug-related as follows: 
o ALP > 3x ULN; 
o ALP > 2.5x ULN and total bilirubin > 2x ULN; or 
o ALP > 2.5x ULN if associated with the appearance or worsening of 
fatigue, nausea, vomiting, right upper quadrant pain or tenderness, 
fever, rash and/or eosinophilia. 
 
In the event of discontinuation due to abnormal liver function tests, the subject will be 
appropriately investigated to determine the potential cause and referred to a physician 
experienced in the treatment of hepatic disorders. 
 
Study drug should be discontinued if a subject: (1) positively affirms suicidal ideation in 
response to questions number 4 or 5 in the suicidal ideation section of the C-SSRS, or (2) 
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reports any suicidal behavior or non-suicidal self-injurious behavior since their last visit in 
response to the C-SSRS Suicidal Behavior questions. The subject should be referred to a 
psychiatrist or an appropriate health care professional for further evaluation and 
management. 
 
Bodyweight loss (compared to weight at Baseline Visit [Study Day 1]) of ≥ 2 kg resulting 
in a BMI < 18.5 is an additional stopping criterion. 
 
7.2. 
LABORATORY ASSESSMENTS 
7.2.1. Clinical Laboratory Tests 
The following clinical laboratory tests will be performed during the Screening Period, 
Baseline (Study Day 1) pre-dose, and at all follow-up visits: 
 
• Hematology:  white blood cell (WBC) count with differential, red blood cell 
(RBC) count, hemoglobin, hematocrit, platelet count. 
• Serum Chemistry:  glucose, sodium, potassium, chloride, bicarbonate, calcium, 
phosphate, blood urea nitrogen (BUN), total bilirubin, creatinine,  albumin, 
globulin, total protein, uric acid, alkaline phosphatase (ALP), 
alanine 
transaminase 
(ALT), 
aspartate transaminase 
(AST), 
gamma 
glutamyl 
transpeptidase (GGT), lactose dehydrogenase (LDH). 
• Urinalysis: color, specific gravity, pH, protein, glucose, ketones, occult blood, 
nitrites and leukocyte esterase.  A “reflex” microscopic examination will be 
performed if protein, occult blood, nitrites or leukocyte esterase is present on the 
basic analysis. 
• Screening Period:  During the Screening Period only, bloods will be drawn for TSH, 
free T4, Vitamin B12, HepBsAg, HCV-Ab, HbA1C (diabetic subjects only) and 
plasma P-tau181 or P-tau217 (Note – plasma collection for P-tau181 or P-tau217 
not required if subject has documented evidence of AD pathophysiology prior to 
screening). The plasma P-tau181 test is a validated assay using ADX antibodies, 
which shows a wide dynamic range and an AUC of 0.92 during validation without 
any algorithms. Validation of a P-tau217 assay is pending. Urine to screen for drugs 
of abuse (amphetamines, cocaine, opiates and phencyclindine) will also be 
collected during the Screening Period. 
7.2.2. Collection of Whole Blood Samples for ApoE Genotyping   
Whole blood samples for genotyping ApoE will be collected at the Baseline Visit 
(Study Day 1); please review instructions as per lab manual. 
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7.2.3. Preparation of Samples from PK and Plasma Biomarker Sub-study Participants  
At each blood collection for PK and biomarkers, blood samples will be drawn into a 
Vacutainer® tube (10 mL per tube) containing K2EDTA. The tubes will be placed 
immediately on ice upon collection. Following the instructions within the Laboratory 
Manual, the plasma samples will be centrifuged, frozen (within 30 minutes of 
centrifuging), and shipped to the central laboratory.  
8. COGNITIVE AND FUNCTIONAL ASSESSMENTS 
8.1. 
MINI-MENTAL STATE EXAM (MMSE) 
The MMSE6 is a set of standardized questions covering several target areas: orientation, 
registration, attention and calculation, short-term verbal recall, naming, repetition, 3-
step command, reading, writing, and visuospatial cognitive assessment. Administration 
of the MMSE is estimated to take approximately 10 minutes. 
8.2. 
CLINICAL DEMENTIA RATING (CDR) 
Washington University’s CDR7 characterizes six domains of cognitive and functional 
performance applicable to AD and related dementias: memory, orientation, judgment 
and problem solving, community affairs, home and hobbies, and personal care. The 
study partner is interviewed first by a qualified rater who assesses all six domains in 
the absence of the study subject. The subject is then interviewed by the same rater in 
the absence of the study partner. A CDR global score can be calculated by accessing 
Washington 
University’s 
online 
algorithm 
(https://biostat.wustl.edu/~adrc/cdrpgm/index.html) where 0 = no dementia, and scores 
of 0.5, 1, 2, or 3 = questionable, mild, moderate, or severe dementia, respectively.  The 
sum of boxes (i.e., CDR-SB)8 can also be calculated by summing the six individual 
domain scores. This detailed quantitative general index may provide more information 
than the CDR-GS in patients with mild dementia.  
8.3. 
ALZHEIMER’S DISEASE ASSESSMENT SCALE – COGNITIVE SUBSCALE 12 (ADAS-
COG12) 
The ADAS-Cog9,10 is a psychometrician-administered battery comprised of several 
cognitive domains including memory, comprehension, praxis, orientation, and 
spontaneous speech. The ADAS-Cog12 (which includes Delayed Word Recall) will be 
administered to all subjects at various key visits throughout the study. 
8.4. 
NEUROPSYCHIATRIC INVENTORY (NPI)  
A study partner interview, the 12-item NPI11 records frequency and severity of common 
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neuropsychiatric 
symptoms 
in 
dementia 
(Hallucinations, 
Delusions, 
Agitation/aggression, Dysphoria/depression, Anxiety, Irritability, Disinhibition, 
Euphoria, Apathy, Aberrant motor behavior, Sleep, and nighttime behavior change, 
Appetite and eating change). The study partner is then asked to rate their own distress 
for the subject’s behavioral symptoms occurring in the past 4 weeks.  
8.5. 
ALZHEIMER’S DISEASE COOPERATIVE STUDY – ACTIVITIES OF DAILY LIVING 
(ADCS-ADL-AD) 
The ADCS-ADL12 is a 23-item study partner questionnaire that covers both basic 
activities of daily living (ADL) (e.g., eating and toileting) and more complex ADL or 
instrumental ADL (e.g., using the telephone, managing finances, preparing a meal). 
8.6. 
COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS) 
The C-SSRS13 is an assessment tool used to assess the lifetime suicidality of a subject 
(C-SSRS at baseline) as well as any new instances of suicidality (C-SSRS since last 
visit). 
8.7. 
ZARIT BURDEN INTERVIEW (ZBI) 
The ZBI14,15 is a 22-item scale designed to assess the stress or burden experienced by 
caregivers of people with dementia. The ZBI will be administered as an interview with 
the caregiver. The scale consists of 22 statements reflecting how people can feel when 
taking care of another person. The statements are phrased as questions for the caregiver 
to indicate how often they feel the way described in the statement. The 5 possible 
responses for each item are Never, Rarely, Sometimes, Quite Frequently, and Nearly 
Always.  
8.8. 
GERIATRIC DEPRESSION SCALE (GDS) 
The GDS16 is a 30-item yes/no question test designed to screen for depression in elderly 
persons. The GDS short form (15-items)17 version utilized in this study will be clinician 
administered with caregiver input. Subjects will be evaluated for symptoms of 
depression during the Screening Period. The GDS scale score should be clinically 
interpreted to evaluate the potential for a major depressive episode by a clinician who 
has been trained on the scale and is familiar with the diagnosis of major depression. 
8.9. 
ELECTRONIC CAPTURE OF RATING SCALES 
The assessments MMSE, CDR, ADAS-Cog12, GDS, NPI, ADCS-ADL, C-SSRS, and 
ZBI will be captured electronically by an eCOA platform that is 21 CFR Part 11 
compliant. Data collected by eCOA will be transferred directly to the EDC vendor’s 
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database.   
The electronic capture of the rating scales will include an audio recording for the 
purpose of monitoring site staff performance during scale questionnaire administration 
and providing constructive feedback to the raters. Subject data captured on recordings 
will not be analyzed as part of the trial outcomes. The Investigator or rater will read the 
questions out loud to study participants who will then respond. The process of questions 
and answers will be recorded using an audio-recording device. These highly secured 
recordings will not be made public at any time and will be destroyed after the Study 
Drug has been either approved or disapproved for use by the FDA or other pertinent 
regulatory bodies. 
9. EARLY DISCONTINUATION 
Subjects may choose to discontinue Study Drug or study participation at any time, 
for any reason, and without prejudice. Moreover, a subject may be withdrawn at any 
time at the discretion of the Investigator or Sponsor for safety, behavioral or 
administrative reasons. Discontinued subjects should be followed according to medical 
practice standards, and the outcome documented. Follow-up is required if the subject 
is discontinued due to an adverse event (AE). Any comments (spontaneous or elicited) 
or complaints made by the subject and the reason for termination and the date of 
stopping the drug must be recorded in the Case Report Form (CRF) and source 
documents.  
The following must be completed and documented in the source documents and 
CRFs for all subjects who discontinue the study early: 
• The reason for early study discontinuation.  If the subject is withdrawn for more than 
one reason, each reason should be documented in the source documents and the 
most clinically relevant reason should be entered on the CRF. 
• Vital signs (blood pressure, temperature and pulse), brief physical and neurologic 
examination, weight, clinical laboratory tests, 12-lead resting ECG (5 min 
supine), use of concomitant medications and adverse events should be obtained 
at discharge prior to release. 
• Blood draw for plasma biomarkers 
• ADAS-Cog12, MMSE, CDR, ADCS-ADL, NPI, ZBI and C-SSRS (as detailed in 
Section 7.1.6 – Early Termination Visit), if not performed within the last 30 days. 
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10. ADVERSE EVENTS/SERIOUS ADVERSE EVENTS  
10.1. ADVERSE EVENTS - DEFINITION 
An Adverse Event (AE) is any undesirable event that occurs to a subject during a study, 
whether or not that event is considered related to Study Drug. Monitoring for AEs will 
start after informed consent has been obtained. Examples include: 
• Any treatment-emergent signs and symptoms (events that are marked by a change 
from the subject's baseline/entry status [e.g., an increase in severity or frequency of 
pre-existing abnormality or disorder]) 
• All reactions from Study Drug, an overdose, abuse of drug, withdrawal phenomena, 
sensitivity or toxicity to Study Drug 
• Apparently unrelated illnesses 
• Injury or accidents (Note: if a medical condition is known to have caused the injury 
or accident, the medical condition and the accident should be reported as two separate 
medical events [e.g., for a fall secondary to dizziness, both "dizziness" and "fall" 
should be recorded separately]) 
• Extensions or exacerbations of symptoms, subjective subject-reported events, new 
clinically significant abnormalities in clinical laboratory, physiological testing or 
physical examination 
 
All AEs, whether or not related to Study Drug, must be fully documented on the AE 
page of the CRF and in the subject's clinical chart. Adverse events reported during the 
screening period or AEs secondary to study-related procedures should always be captured 
as not having a reasonable possibility the AE was caused by the Study Drug. Unexpected, 
abnormal laboratory results observed during the Screening Period should be captured as 
Medical History and not as an AE. 
In the event that a subject is withdrawn from the study because of an AE, it must be 
recorded on the CRF as such. The subject should be followed and treated by the 
Investigator until the abnormal parameter or symptom has resolved or stabilized. 
The Investigator must report all directly observed AEs and all spontaneously reported 
AEs. The Investigator will ask the subject a non-specific question (e.g., "Have you 
noticed anything different since your dose of the study medication?") to assess whether 
any AEs have been experienced since the last assessment. AEs will be identified and 
documented in the Electronic Data Capture (EDC) system in appropriate medical 
terminology. The severity and the relationship to the Study Drug will be determined 
and reported in EDC (see below). 
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10.2. ADVERSE EVENTS - SEVERITY RATING 
The severity of each AE should be characterized and then classified into one of three 
clearly defined categories as follows: 
• Mild – the AE does not interfere in a significant manner with the subject's normal 
functioning level. It may be an annoyance. 
• Moderate – the AE produces some impairment of functioning but is not hazardous 
to health. It is uncomfortable or an embarrassment. 
• Severe – the AE produces significant impairment of functioning or incapacitation 
and is a definite hazard to the subject's health. 
These three categories are based on the Investigator's clinical judgment, which in turn 
depends on consideration of various factors such as the subject's report and the physician's 
observations. The severity of the AE should be recorded in the appropriate section of the 
EDC. 
10.3. ADVERSE EVENTS – RELATIONSHIP TO STUDY   DRUG 
The relationship of each AE to the Study Drug will be based on the Investigator’s 
assessment as to whether there is a reasonable possibility the AE was caused by the Study 
Drug. This assessment will be based on the Investigator’s clinical judgment, which in 
turn depends on consideration of various factors such as the subject’s report, the timing 
of the AE in relationship to Study Drug administration/discontinuation, the Investigator’s 
observations, and the Investigator’s prior experience. The Investigator’s assessment of 
the relationship of the AE to the Study Drug will be recorded in the appropriate section 
of the EDC. 
10.4. SERIOUS ADVERSE EVENTS AND UNEXPECTED ADVERSE EVENTS - DEFINITIONS 
A Serious Adverse Event (SAE) includes (but is not limited to) an experience occurring 
at any dose that results in any of the following outcomes: 
• Death 
• A life-threatening event (i.e., the subject is at immediate risk of death from the 
reaction as it occurs). "Life-threatening" does not include an event that, had it 
occurred in a more serious form, might have caused death. For example, drug­ 
induced hepatitis that resolved without evidence of hepatic failure would not be 
considered life-threatening even though drug-induced hepatitis can be fatal. 
• In-patient hospitalization (hospital admission, not an emergency room visit) or 
prolongation of existing hospitalization. 
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• A persistent or significant disability/incapacity (i.e., a substantial disruption of 
the subject's ability to carry out normal life functions). 
• A congenital anomaly/birth defect. 
 
In addition, medical and scientific judgment should be exercised in deciding whether 
other situations should be considered an SAE (i.e., important medical events that may 
not be immediately life-threatening or result in death but may jeopardize the subject or 
may require medical or surgical intervention to prevent one of the other outcomes listed 
in the definition above). Examples of such medical events include (but are not limited 
to): allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in in-patient hospitalization, or 
the development of drug dependency or drug abuse. 
An unexpected AE is one for which the specificity or severity is not consistent with the 
current Investigator's Brochure. For example, hepatic necrosis would be unexpected (by 
virtue of greater severity) if the Investigator's Brochure listed only elevated hepatic 
enzymes or hepatitis. 
Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by 
virtue of greater specificity) if the Investigator's Brochure listed only cerebral vascular 
accidents. 
10.5. SERIOUS ADVERSE EVENTS REPORTING 
The reporting of SAEs by the Sponsor to regulatory authorities (e.g., FDA) is a 
regulatory requirement. Each regulatory agency has established a timetable for 
reporting SAEs based upon established criteria.  Likewise, it is the responsibility of 
the Principal Investigator to report SAEs to the IRB. 
All SAEs must be reported immediately (within 24 hours of learning of the event) 
by e-mail to: 
Premier Research Global Pharmacovigilance 
 
 
Do not delay reporting a suspected SAE to obtain additional information.  Any 
additional information, if collected, can be reported to the Sponsor as a follow-up to 
the initial report. 
SAEs must be immediately reported to the responsible IRB. 
In the case of a death or other SAE that has occurred within 30 days after receiving 
Study Drug, the Principal Investigator must also report such an event within 24 hours 
of being notified. Your local IRB may also require these reports. 
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In the event of any SAE (other than death), the subject will be instructed to contact the 
study physician (Principal Investigator or designee) using the phone number provided 
in the Informed Consent Form. All subjects experiencing an SAE will be seen by a 
Principal Investigator or designee as soon as feasible following the report of an SAE. 
11. STATISTICAL CONSIDERATIONS 
11.1. RANDOMIZATION 
Randomized treatments will be assigned by subject numbers in a randomly generated 
numeric sequence. 
The randomization code will not be revealed to study subjects, Investigators, clinical 
staff, study monitors or the Sponsor until all subjects have completed therapy and the 
database has been finalized and locked.  
Under normal circumstances, the blind should not be broken. The blind may be broken 
only if specific emergency treatment is indicated. The date, time and reason for the 
unblinding must be documented in the CRFs, and the Medical Monitor must be informed 
as soon as possible. 
11.2. ANALYSIS POPULATIONS 
The Intent-To-Treat (ITT) analysis set includes all randomized subjects. All efficacy 
analyses will be conducted in this analysis set and subjects will be included in the group 
to which they were randomized. 
The Safety analysis set includes all subjects who receive study treatment. All safety 
analyses will be completed in the Safety analysis set and subjects will be included in the 
group based on the treatment actually received.  
11.3. STATISTICAL ANALYSIS 
 
11.3.1 Primary Efficacy Analysis 
Each of the two co-primary endpoints will be analyzed using a linear mixed model for 
repeated measurements. The dependent variable is the change from baseline and the 
model will include fixed effects for treatment group (two levels), week (5 levels, 
corresponding to Weeks 4, 16, 28, 40 and 52), the treatment group-by-week interaction, 
and the randomization stratification variable. The baseline value of the corresponding 
endpoint will be included as a covariate and the unstructured covariance model will be 
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used. The Baseline Visit (Study Day 1) ADAS-Cog12 and ADCS-ADL assessments will 
represent the baseline value for these variables. 
 
For each of the two co-primary endpoints, the primary analysis will compare the 100 mg 
group and the placebo group at Week 52 using a two-sided test at the alpha = 0.05 level 
of significance. Study success requires that both co-primary comparisons are statistically 
significant. 
 
11.3.2 Secondary Analyses 
The iADRS18,19 is a linear combination of scores from two well-established, widely 
accepted, therapeutically sensitive measures of AD: the ADAS-Cog and ADCS-iADL 
(the instrumental component of the ADCS-ADL). The iADRS has been validated and 
statistical properties of the composite performance have been described20. All items of 
the ADAS-Cog12 and the ADCS-iADL will be included to generate this primary efficacy 
composite measurement without additional weighting. 
 
Secondary clinical endpoint data (iADRS, NPI, MMSE, and ZBI) measured repeatedly will 
be analyzed using the same types of linear mixed models as described for the primary 
analysis.  
Plasma assays may include P-tau181 and/or P-tau217, SavaDx and neurofilament light 
chain, and additional plasma biomarkers may be measured. All plasma biomarker data 
involving repeated measures will also be analyzed using the same types of linear mixed 
models as described for the primary analysis.  
CDR-SB data will be analyzed using ANCOVA models with treatment group as a factor 
and the baseline value as a covariate.  
All secondary analyses will be conducted using two-sided tests at the alpha = 0.05 level 
of significance, with no adjustments for multiplicity. 
11.4. SAFETY ANALYSIS 
Adverse events reported on case report forms will be mapped to preferred terms and 
organ systems using the MedDRA mapping system. Vital signs and clinical laboratory 
results will be descriptively summarized in terms of change from screening values. 
11.5. SAMPLE SIZE 
Approximately seven hundred fifty (750) subjects will be enrolled in this study. The 
sample size was determined by a power analysis of ADAS-Cog in a similar population 
over 52 weeks. This analysis determined that group sizes of 300 are powered to show a 
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45% difference from placebo at 52 weeks with 90% power and a two-sided significance 
level of 0.05.  The power calculation assumes a true mean change from baseline for 
placebo of 5.0 points and a standard deviation of 8.5 points.  Assuming a drop-out of 
20%, each treatment group should enroll 375 subjects. 
12. STUDY TERMINATION 
The study will be terminated following completion of the study or at any time at the 
discretion of the Sponsor. 
13. DATA COLLECTION, RETENTION AND MONITORING 
13.1. CASE REPORT FORMS 
The CRF will be provided as an Electronic Data Capture (EDC) system that will serve as 
the collection method for subject data. The subjects in the study will not be identified by 
name on any study documents to be collected by the Sponsor (or CRO designee) but will 
be identified by a unique subject number. 
All clinical information requested in this protocol will be recorded in the EDC 
system.  It is strongly recommended that data entry be completed within 48 hours of a 
subject’s visit. In case of error noted on paper source documents, the correction will be 
noted, initialed and dated. 
EDC data must be reviewed and verified for accuracy and signed-off by the staff 
personnel before database lock. Paper source documents, if used, will remain at the 
Investigator's site at the completion of the study. 
13.2. AVAILABILITY AND RETENTION OF INVESTIGATIONAL RECORDS 
The Investigator must make study data accessible to the monitor, other authorized 
representatives of the Sponsor (or designee) and Regulatory Agency (e.g., FDA) 
inspectors upon request. To assure accuracy of data collected in the EDC, it is 
mandatory that Sponsor representatives have access to original source documents (e.g., 
subject records, subject charts, and laboratory reports). During review of these 
documents, the subject's anonymity will be maintained with adherence to professional 
standards of confidentiality and applicable laws. A file for each subject must be 
maintained that includes the signed ICF and all source documentation related to that 
subject. The Investigator must ensure the reliability and availability of source 
documents for the EDC. 
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Investigators are required to maintain all study documentation until notification by the 
Sponsor that any records may be discarded. 
The Investigator is responsible for maintaining adequate case histories in each 
subject's source records.  
13.3. SUBJECT CONFIDENTIALITY 
All reports and subject samples will be identified only by the assigned subject number 
and initials, as applicable by local law, to maintain subject confidentiality. Additional 
subject confidentiality measures (as required by region) will be covered within the 
Clinical Trial Agreement for each site as applicable. 
13.4. LIABILITY 
In the event of a side effect or injury, appropriate medical care as determined by the 
Investigator or his/her designated alternate will be provided. 
If a bodily injury is sustained resulting directly from the Study Drug, the Sponsor will 
reimburse for reasonable physician fees and medical expenses necessary for treatment of 
only the bodily injury that is not covered by the subject's medical or hospital insurance, 
provided that the injury is not due to a negligent or wrongful act or omission by the study 
doctor and his/her staff. No other compensation of any type will be provided by the 
Sponsor. Compensation for lost wages, disability, or discomfort due to the study is not 
available. 
13.5. ETHICAL AND LEGAL ISSUES 
The Investigator and site personnel are responsible for conducting this study in 
accordance with the ICH, GCP, and all other applicable laws and regulations. 
13.5.1. Institutional Review Board 
The protocol,  ICF, clinical sites and Investigators must be approved by an IRB before 
the study is initiated. The IRB must comply with U.S. CFR 21 Part 56 and local laws. 
Documentation of approval by the designated central IRB will be provided to the 
Investigators. The Sponsor will:  
• Obtain IRB approval of the protocol, ICF, advertisements to recruit subjects and 
IRB approval of any protocol amendments and ICF revisions before implementing 
the changes. 
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• Provide the IRB with any required information before or during the study. 
• Submit progress reports to the IRB, as required, requesting additional review and 
approval, as needed; and provide copies of all relevant IRB communications to the 
Investigator. 
 
The Investigator is responsible for: 
• Notifying the IRB within 15 calendar days of all SAEs and unexpected AEs related 
to study medications. 
• Obtaining approval by their institution’s own IRB if the Investigator’s institution 
has its own IRB. 
13.6. INFORMED CONSENT FORM 
The Sponsor will submit the ICF to the central IRB for approval. An IRB-approved 
copy of the ICF will be forwarded to the Investigator or site staff. 
The ICF documents study-specific information the Investigator provides to the subject 
and the subject's agreement to participate. The Investigator explains in plain terms the 
nature of the study along with the aims, methods, anticipated benefits, potential risks, 
and any discomfort that participation may entail. The ICF must be signed and dated 
before the subject enters the study. The original ICF and any amended ICF, signed and 
dated, must be retained in the subject's file at the study site and a copy must be given 
to the subject. 
14.  INVESTIGATOR RESPONSIBILITIES 
The Investigator agrees to: 
• Conduct the study in accordance with the protocol, except to protect the safety, rights, 
or welfare of subjects. 
• Personally conduct or supervise the study. 
• Ensure that requirements for obtaining informed consent and IRB review 
and approval comply with ICH, CFR 21 Parts 50 and 56 and local laws. 
• Report to the Sponsor any AEs that occur during the study in accordance with 
ICH, CFR 21 Part 312.64 and local laws. 
• Read and understand the Investigator's Brochure including potential risks and 
side effects of the drug. 
• Ensure that all associates, colleagues, and employees assisting in the conduct of 
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the study are informed about their obligations in meeting the above commitments. 
• Maintain adequate records in accordance with ICH, 21 CFR Part 312.62, and 
local laws and have records available for inspection by the Sponsor, FDA, or 
other authorized agency. 
• Promptly report to the IRB and the Sponsor all changes in research activity and 
unanticipated problems involving risks to subjects or others (including 
amendments and expedited safety reports). 
• Comply with all other requirements regarding obligations of Clinical 
Investigators and all other pertinent requirements listed in ICH, 21 CFR Part 
312 and local laws. 
15. REFERENCES 
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an altered conformation of filamin A to reduce Alzheimer's disease pathogenesis. 
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3. Wang H-Y, Bakshi K, Frankfurt M, et al. Reducing amyloid-related Alzheimer’s 
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4. Wang H-Y, Pei Z, Lee K-C, et al. PTI-125 reduces biomarkers of Alzheimer’s disease 
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biological definition of Alzheimer's disease; Alzheimer’s and Dementia 14(4):535-562 
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7. Morris JC. The Clinical Dementia Rating (CDR): current version and scoring rules. 
Neurology 1993;43:2412- 4. 
8. O'Bryant SE, Lacritz LH, Hall J, et al. Validation of the new interpretive guidelines for 
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9. Mohs R, Knopman D, Petersen R, Ferris S, Ernesto C, Grundman M, Sano M, 
Bieliauskas L, Geldmacher D, Clark C, Thal L and the ADCS. Development of 
Cognitive Instruments for Use in Clinical Trials of Antidementia Drugs: Additions to 
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10. Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer’s disease. 
American Journal of Psychiatry 1984; 141(11): 1356-1364. 
11. Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. The 
Neuropsychiatric Inventory: comprehensive assessment of psychopathology in 
dementia, 1994;44(12):2308-14. 
12. Galasko D, Bennett D, Sano M, et al. An inventory to assess activities of daily living 
for clinical trials in Alzheimer’s disease. The Alzheimer's Disease Cooperative Study. 
Alzheimer Disease and Associated Disorders 1997;11(Suppl 2):S33-9. 
13. Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. The 
Columbia-Suicide Severity Rating Scale: initial validity and internal consistency 
findings from three multisite studies with adolescents and adults. American  Journal of  
Psychiatry 2011;168(12):1266-77. 
14. Zarit SH, Reever KE and Bach-Peterson J. (1980) Relatives of the impaired elderly: 
correlates of feelings of burden. Gerontologist Dec; 20: 649-655. 
15. Zarit SH, Zarit JM. The memory and behavior problems checklist and the burden 
interview. Gerontology Center, The Pennsylvania State University, 1990. 
16. Yesavage, J.A., Brink, T.L., Rose, T.L., Lum, O., Huang, V., Adey, M.B., & Leirer, 
V.O. (1983). Development and validation of a geriatric depression screening scale: A 
preliminary report. Journal of Psychiatric Research, 17, 37-49. 
17. Sheikh JI, Yesavage JA: Geriatric Depression Scale (GDS): Recent evidence and 
development of a shorter version. Clinical Gerontology: A Guide to Assessment and 
Intervention; 165-173, NY: The Haworth Press, 1986. 
18. Wessels AM, Siemers ER, Yu P, Andersen SW, Holdridge KC, Sims JR, Sundell K, 
Stern Y, Rentz DM, Dubois B, Jones RW, Cummings J, Aisen PS; A combined 
measure of cognition and function for clinical trials: the integrated Alzheimer’s Disease 
Rating Scale (iADRS). Journal of Prevention of Alzheimer’s Disease, 2 (4) 2015, 227-
241. 
19. Wessels AM, Andersen SW, Dowsett SA, Siemers ER; The integrated Alzheimer’s 
Disease Rating Scale (iADRS) findings from the EXPEDITION3 trial. Journal of 
Prevention of Alzheimer’s Disease, 5 (2) 2018, 134-136. 
20. Liu-Seifert H, Andersen SW, Case M, Sparks JD, Holdridge KC, Wessels AM, Hendrix 
S, Aisen P, Siemers E; Statistical properties of continuous composite scales and 
implications for drug development. Journal of Biopharmaceutical Statistics 27 (6) 
2017, 1104-1114. 
 
 
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Clinical Protocol PTI-125-07 
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 FINAL Version 3.0, FEBRUARY 15, 2023 
 
Page 51 of 52 
 
 
 
 
CONFIDENTIAL 
 
16.  APPENDIX A – SCHEDULE OF ACTIVITIES 
Procedures 
Screening 
Period (-60 
Days to 0) 
Baseline 
Visit 
(Study 
Day 1) 
Week 
4 
Week 
16 
Week 
28 
Week 
40 
Week 52 
ET/ED3 
Safety 
Follow-
up8 
Informed Consent 
X 
 
 
 
 
 
 
 
I/E Criteria 
X 
X 
 
 
 
 
 
 
Medical & Surgical 
History 
X 
 
 
 
 
 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Meds 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
 
Physical 
Examination  
X1 
X 
X 
X 
X 
X 
X 
 
Neurologic 
Examination 
X1 
X 
X 
X 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
 
Resting ECG 
X 
X9 
X 
 
X 
 
X 
 
Biochemistry, 
Hematology, 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
 
Urine Drug Screen 
X 
 
 
 
 
 
 
 
TSH, free T4, B12, 
HBsAg, HCV-Ab 
X 
 
 
 
 
 
 
 
HbA1c (diabetic 
subjects only) 
X 
 
 
 
 
 
 
 
Plasma P-tau181 or 
P-tau217 
X7 
 
 
 
 
 
 
 
Genotyping sample 
 
X 
 
 
 
 
 
 
MRI 
X 
 
 
 
 
 
 
 
PK and Plasma 
Biomarkers 
X2 
 
 
 
X2 
 
X2 
 
MMSE 
X 
 
 
 
X 
 
X 
 
CDR 
X 
 
 
 
 
 
X 
 
Geriatric Depression 
Scale 
X 
 
 
 
 
 
 
 
ADAS-Cog12 
 
X 
X 
X 
X 
X 
X 
 
ADCS-ADL 
 
X 
X 
X 
X 
X 
X 
 
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 FINAL Version 3.0, FEBRUARY 15, 2023 
 
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CONFIDENTIAL 
 
Procedures 
Screening 
Period (-60 
Days to 0) 
Baseline 
Visit 
(Study 
Day 1) 
Week 
4 
Week 
16 
Week 
28 
Week 
40 
Week 52 
ET/ED3 
Safety 
Follow-
up8 
NPI 
 
X 
 
 
X 
 
X 
 
ZBI 
 
X 
X 
X 
X 
X 
X 
 
C-SSRS 
X4 
X5 
X5 
X5 
X5 
X5 
X5 
 
Drug Dispensation 
 
X6 
X 
X 
X6 
X 
 
 
Drug Accountability 
 
 
X 
X 
X 
X 
X 
 
End of Study 
Follow-up Phone 
Call 
 
 
 
 
 
 
 
X 
 
 
1. Complete Physical and Neurologic Examinations during the Screening Period only, 
brief examinations thereafter 
2. PK and plasma biomarker sub-study subjects only (100 subjects total; 50 
subjects/group) 
3. Early Termination / Early Discontinuation subjects do not need to complete the 
electronic clinical outcome assessments if performed within 30 days of the ET/ED 
Visit 
4. During the Screening Period, the C-SSRS Baseline/Screening version will be 
administered 
5. At Study Day 1, as well as all remaining visits, the C-SSRS Since Last Visit version 
will be administered 
6. The first dose of Study Drug is administered at the clinic to all subjects on Study Day 
1; for plasma PK and biomarker sub-study subjects only at the Week 28 visit, 
administer Study Drug after blood samples are collected 
7. Plasma P-tau181 or plasma P-tau217 not required if the subject has evidence for AD 
pathophysiology prior to screening 
8. This phone call will occur Week 53 to 54 for those subjects who complete all study 
visits, or 1 to 2 weeks after Early Termination. If the subject reports an adverse event, 
the subject should be followed and treated by the Investigator until the AE has 
resolved or stabilized. 
9. ECG on Study Day 1 collected in triplicate 
 
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Cassava Sciences, Inc. 
Clinical Protocol PTI-125-07 
Simufilam (PTI-125) 
FINAL Version 2.0, JULY 20, 2021 
 
Page 1 of 43 
 
 
 
 
CONFIDENTIAL 
 
 
 
CLINICAL RESEARCH PROTOCOL 
PROTOCOL PTl-125-07 
 
A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
PARALLEL-GROUP, 52-WEEK STUDY EVALUATING THE SAFETY AND 
EFFICACY OF SIMUFILAM 100 MG TABLETS IN SUBJECTS WITH MILD-TO-
MODERATE ALZHEIMER’S DISEASE 
 
 
 
SPONSOR: 
 
CASSAVA SCIENCES, INC. 
7801 N. Capital of Texas Highway, Suite 260 
Austin, TX 78731 
Phone: 512-501-2444 
 
 
 
Confidentiality 
The information contained in this document and all information provided to you related to 
simufilam ("Drug") are the confidential and proprietary information of Cassava Sciences, Inc. 
and, except as may be required by federal, state, or local laws or regulations, may not be 
disclosed to others without prior written permission of Cassava. The Principal Investigator 
may, however, disclose such information to supervised individuals working on the Drug, 
provided such individuals agree to be bound to maintain the confidentiality of such Drug 
information. 
 
 
CASSAVA 
sciences 
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20 July 2021
Cassava Sciences, Inc. 
Simufilam (PTI-125) 
Clinical Protocol PTI-125-07 
FINAL Version 2.0, JULY 20, 2021 
Cassava Sciences, Inc. 
CLINICAL RESEARCH PROTOCOL 
A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
PARALLEL-GROUP, 52-WEEK STUDY EVALUATING THE SAFETY AND 
EFFICACY OF SIMUFILAM 100 MG TABLETSINSURJECTSWITHMILD-TO-
MODERATE ALZHEIMER'S DISEASE 
Approvals: 
 
SVP, Neuroscience 
Cassava Sciences, Inc. 
 
Chief Clinical Development Officer 
Cassava Sciences, Inc. 
Page 2 of 43 
Date 
CONFIDENTIAL 
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Cassava Sciences, Inc. 
Simufilam (PTI-125) 
Clinical Protocol PTI-125-07 
FINAL Version 2.0, JULY 20, 2021 
Cassava Sciences, Inc. 
CLINICAL RESEARCH PROTOCOL 
A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
PARALLEL-GROUP, 52-WEEK STUDY EVALUATING THE SAFETY AND 
EFFICACY OF SIMUFILAM 100 MG TABLETS IN SUBJECTS WITHMILD-TO-
MODERATE ALZHEIMER'S DISEASE 
Signature of Agreement for Protocol PTI-125-07 
I have read this protocol and agree to conduct the study as outlined herein, in accordance 
with Good Clinical Practice (GCP) and complying with the obligations and requirements of 
clinical investigators and all other requirements listed in 21 CFR Part 312. 
Date 
Print Coordinating Principal Investigator Name 
Page 3 of 43 
CONFIDENTIAL 
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Cassava Sciences, Inc. 
Clinical Protocol PTI-125-07 
Simufilam (PTI-125) 
FINAL Version 2.0, JULY 20, 2021 
 
Page 4 of 43 
 
 
 
 
CONFIDENTIAL 
 
TABLE OF CONTENTS 
1. 
LIST OF ABBREVIATIONS ....................................................................................7 
2. 
INTRODUCTION ......................................................................................................9 
2.1. Mechanism of Action ................................................................................................................. 9 
2.2. Safety pharmacology and toxicology ......................................................................................... 9 
2.3. Clinical Studies ........................................................................................................................ 10 
3. 
STUDY OBJECTIVES ............................................................................................13 
4. 
SUMMARY OF STUDY DESIGN .........................................................................13 
5. 
SUBJECT SELECTION ..........................................................................................14 
5.1. Study Population ...................................................................................................................... 14 
5.2. Inclusion Criteria ..................................................................................................................... 14 
5.3. Exclusion Criteria .................................................................................................................... 16 
6. 
STUDY DRUG .........................................................................................................20 
6.1. Simufilam Physical Description and Preparation ..................................................................... 20 
6.1.1. Packaging and Labelling ................................................................................................20 
6.1.2. Storage ............................................................................................................................20 
6.1.3. Drug Accountability ........................................................................................................20 
6.2. Administration and Dosing Regimen ....................................................................................... 21 
6.3. Concomitant Medications ........................................................................................................ 21 
7. 
STUDY PROCEDURES .........................................................................................21 
7.1. Evaluations by Visit ................................................................................................................. 21 
7.1.1. Screening Period (No greater than a 60-day duration prior to Study Day 1) .................21 
7.1.2. Rescreening of a Subject .................................................................................................22 
7.1.3. Study Day 1 (Dosing Initiation) ......................................................................................23 
7.1.4. Weeks 4, 16 and 40 Follow-up Visits ..............................................................................24 
7.1.5. Weeks 28 Follow-up Visit................................................................................................25 
7.1.6. Week 52 End-of-Treatment Visit / Early Termination (ET) Visit ....................................25 
7.1.7. Week 53-54 End-of-study Follow-up ...............................................................................26 
7.1.8. Treatment after Study Completion ..................................................................................26 
7.1.9. Unscheduled Visits and Discontinuation due to AEs ......................................................26 
7.1.10    Stopping Criteria ...........................................................................................................27 
7.2. Laboratory Assessments .......................................................................................................... 27 
7.2.1. Clinical Laboratory Tests ................................................................................................27 
7.2.2. Collection of Whole Blood Samples for ApoE Genotyping .............................................28 
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7.2.3. Preparation of Samples from PK and Plasma Biomarker Sub-study Participants ..........28 
8. 
COGNITIVE AND FUNCTIONAL ASSESSMENTS ...........................................28 
8.1. Mini-Mental State Exam (MMSE) ........................................................................................... 28 
8.2. Clinical Dementia Rating (CDR) ............................................................................................. 29 
8.3. Alzheimer’s Disease Assessment Scale – Cognitive Subscale 12 (ADAS-Cog12) ................. 29 
8.4. Neuropsychiatric Inventory (NPI) ............................................................................................ 29 
8.5. Alzheimer’s Disease Cooperative Study – Activities of Daily Living (ADCS-ADL-AD) ...... 29 
8.6. Columbia-Suicide Severity Rating Scale (C-SSRS) ................................................................ 29 
8.7. Zarit Burden Interview (ZBI) ................................................................................................... 30 
8.8. Geriatric Depression Scale (GDS) ........................................................................................... 30 
8.9. Electronic Capture of Rating Scales......................................................................................... 30 
9. 
EARLY DISCONTINUATION ...............................................................................30 
10. 
ADVERSE EVENTS/SERIOUS ADVERSE EVENTS ..........................................31 
10.1. Adverse Events - Definition ...................................................................................................... 31 
10.2. Adverse Events - Severity Rating ............................................................................................ 32 
10.3. Adverse Events – Relationship to Study   Drug ....................................................................... 32 
10.4. Serious Adverse Events and Unexpected Adverse Events - Definitions .................................. 33 
10.5. Serious Adverse Events Reporting ........................................................................................... 33 
11. 
STATISTICAL CONSIDERATIONS .....................................................................34 
11.1. Randomization ......................................................................................................................... 34 
11.2. Analysis Populations ................................................................................................................ 34 
11.3. Statistical Analysis ................................................................................................................... 35 
11.3.1 Primary Efficacy Analysis ...............................................................................................35 
11.3.2 Secondary Analyses .........................................................................................................35 
11.4. Safety Analysis ......................................................................................................................... 36 
11.5. Sample Size .............................................................................................................................. 36 
12. 
STUDY TERMINATION ........................................................................................36 
13. 
DATA COLLECTION, RETENTION AND MONITORING .................................36 
13.1. Case Report Forms ................................................................................................................... 36 
13.2. Availability and Retention of Investigational Records ............................................................ 37 
13.3. Subject Confidentiality ............................................................................................................ 37 
13.4. Liability .................................................................................................................................... 37 
13.5. Ethical and Legal Issues ........................................................................................................... 38 
13.5.1. Institutional Review Board...............................................................................................38 
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13.6. Informed Consent Form ........................................................................................................... 38 
14. 
INVESTIGATOR RESPONSIBILITIES ................................................................39 
15. 
REFERENCES .........................................................................................................39 
16. 
APPENDIX A – SCHEDULE OF ACTIVITIES ....................................................42 
 
LIST OF FIGURES 
 
Figure 1.  Phase 2a Mean Change from Baseline to Day 28 in CSF biomarkers (±SEM)      11 
Figure 2.  Phase 2b Mean Change from Baseline to Day 28 in CSF biomarkers (±SEM)      12 
Figure 3.  Phase 2b Mean Change from Baseline to Day 28 in Total Errors in Memory Test13 
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Clinical Protocol PTI-125-07 
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CONFIDENTIAL 
 
1. LIST OF ABBREVIATIONS 
3xTg  
 
 
triple transgenic 
α7nAChR  
 
 
α7 nicotinic acetylcholine receptor 
Aβ42 
 
 
 
amyloid beta1-42 
AChEI  
 
 
acetylcholinesterase inhibitor 
AD 
 
 
 
Alzheimer’s disease 
ADAS-Cog 
 
 
Alzheimer’s Disease Assessment Scale – Cognitive Subscale 
ADCS-ADL 
Alzheimer’s Disease Cooperative Study – Activities of Daily 
Living 
ADME 
 
 
absorption, distribution, metabolism, excretion 
AE 
 
 
 
Adverse Event 
ALT   
 
 
alanine transaminase 
ALP 
 
 
 
alkaline phosphatase 
ANOVA 
 
 
analysis of variance 
AST   
 
 
aspartate transaminase 
AUC  
 
 
area under the curve 
BMI 
 
 
 
Body Mass Index 
BUN  
 
 
blood urea nitrogen 
CDR-GS 
 
 
Clinical Dementia Rating – Global Score 
CDR-SB 
 
 
Clinical Dementia Rating – Sum of Boxes 
CFR 
 
 
 
Code of Federal Regulations 
Cmax  
 
 
maximum plasma concentration 
CRF 
 
 
 
Case Report Form 
CRO  
 
 
Contract Research Organization 
CSF 
 
 
 
cerebrospinal fluid 
CSI 
 
 
 
Cassava Sciences, Inc. 
C-SSRS 
 
 
Columbia-Suicide Severity Rating Scale 
CT 
 
 
 
computerized tomography 
DSM-V 
 
 
Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition 
DSMB  
 
 
Data Safety Monitoring Board 
ECG  
 
 
electrocardiogram 
eCOA  
 
 
electronic Clinical Outcome Assessment 
eCRF  
 
 
electronic Case Report Form 
EDC  
 
 
Electronic Data Capture 
EDTA  
 
 
ethylenediaminetetraacetic acid 
ELISA  
 
 
enzyme-linked immunosorbent assay 
FDA  
 
 
Food and Drug Administration 
FLNA  
 
 
filamin A 
GCP  
 
 
good clinical practice 
GDS  
 
 
Geriatric Depression Scale 
GGT   
 
 
gamma glutamyl transpeptidase 
GLP 
 
 
 
good laboratory practice 
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Clinical Protocol PTI-125-07 
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FINAL Version 2.0, JULY 20, 2021 
 
Page 8 of 43 
 
 
 
 
CONFIDENTIAL 
 
hERG  
 
 
human ether-a-go-go-related gene 
iADRS 
 
 
integrated Alzheimer’s Disease Rating Scale 
IB 
 
 
 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human 
Use 
IR 
 
 
 
insulin receptor 
IRB 
 
 
 
independent review board 
iADRS 
 
 
Integrated Alzheimer’s Disease Rating Scale 
ISLT  
 
 
International Shopping List Test 
LDH   
 
 
lactose dehydrogenase 
LOQ  
 
 
limit of quantitation 
MCI 
 
 
 
mild cognitive impairment 
MEMS 
 
 
Medication Event Monitoring System 
MMSE 
 
 
Mini-Mental State Examination 
MRI 
 
 
 
magnetic resonance imaging 
mTOR  
 
 
mammalian target of rapamycin 
NIA - AA 
 
 
National Institute on Aging - Alzheimer’s Association 
NMDAR 
 
 
N-methyl D-aspartate receptor 
NOAEL 
 
 
no observable adverse effect level 
NOEL  
 
 
no observable effect level 
NPI 
 
 
 
Neuropsychiatric Inventory 
PAL 
 
 
 
Paired Associate Learning 
PET 
 
 
 
positron emission tomography 
PK 
 
 
 
pharmacokinetics 
PTI-125 
 
 
former name of simufilam 
SavaDx 
 
 
blood-based diagnostic/biomarker candidate 
RBC  
 
 
red blood cell 
SAE 
 
 
 
serious adverse event 
SOP 
 
 
 
standard operating procedure 
Tmax  
 
 
time to Cmax 
ULN  
 
 
upper limit of normal 
WBC  
 
 
white blood cell 
YKL40 
chitinase-like protein 1, a secreted glycoprotein associated with 
inflammation and tissue remodeling 
ZBI 
Zarit Burden Interview  
 
 
 
 
 
 
 
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Clinical Protocol PTI-125-07 
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FINAL Version 2.0, JULY 20, 2021 
 
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CONFIDENTIAL 
 
2. INTRODUCTION 
2.1. MECHANISM OF ACTION 
Cassava Sciences, Inc. is developing simufilam, a novel drug candidate designed to treat 
and slow the progression of Alzheimer’s disease (AD). Simufilam binds with femtomolar 
affinity to an altered conformation of filamin A (FLNA) that is induced by beta amyloid1-
42 (Aβ42), present in AD brain and critical to the toxicity of Aβ42.1-3 Simufilam binding 
reverses the altered FLNA conformation and restores FLNA’s native shape, preventing 
two toxic signaling cascades of Aβ42. Aβ42, in monomer or small oligomer form, hijacks 
the α7-nicotinic acetylcholine receptor (α7nAChR) and signals via this receptor to 
hyperphosphorylate tau. This signaling requires the recruitment of altered FLNA to this 
receptor. In addition, altered FLNA also links to toll-like receptor 4 (TLR4) to allow Aβ42 
to persistently activate this receptor, leading to inflammatory cytokine release and 
neuroinflammation. Normal FLNA does not associate with either α7nAChR or TLR4. In 
addition to disrupting the normal functions of α7nAChR and tau protein, Aβ42’s toxic 
signaling to hyperphosphorylate tau leads to the signature tangles in AD brain. In two AD 
mouse models and in postmortem human AD brain tissue, simufilam restored function of 
three receptors that are impaired in AD: the α7nAChR, the N-methyl-D-aspartate receptor 
(NMDAR), and the insulin receptor (IR).2,3 Simufilam also improved synaptic plasticity 
and reduced tau hyperphosphorylation, amyloid deposits, neurofibrillary tangles and 
inflammatory cytokine release.2,3 We therefore expect simufilam both to improve 
cognition and to slow AD progression. Both mouse models used a dose of 20 mg/kg/day 
(equivalent to 60 mg/m2/day).  
2.2. SAFETY PHARMACOLOGY AND TOXICOLOGY 
A robust nonclinical ADME, safety pharmacology, and general and genetic toxicology 
program has been conducted with simufilam. In vitro metabolic profiling showed minimal 
metabolism across several species including humans. Simufilam was rapidly absorbed and 
eliminated in in vivo studies in rat and dog with nearly 100% oral bioavailability, a 2.67-h 
half-life in dog, dose-proportional PK and no accumulation. Simufilam does not inhibit or 
induce major CYP450 enzymes, nor is a substrate or inhibitor of major human drug 
transporters at clinically relevant concentrations. Safety pharmacology studies showed no 
adverse effects on gross behavioral and physiological parameters in the Irwin test of CNS 
toxicity in rats, no adverse effects on respiratory rate, tidal volume or minute volume in the 
rat respiratory test, and no adverse effects on arterial blood pressure, heart rate and ECG 
parameters in the dog cardiovascular study. The in vitro hERG test for cardiotoxicity also 
indicated no adverse effect. A full battery of genotoxicity studies was conducted (in vitro 
bacterial Ames, in vitro chromosomal aberration, and in vivo rat micronucleus test) and all 
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Cassava Sciences, Inc. 
Clinical Protocol PTI-125-07 
Simufilam (PTI-125) 
FINAL Version 2.0, JULY 20, 2021 
 
Page 10 of 43 
 
 
 
 
CONFIDENTIAL 
 
were negative. An in vitro specificity screen showed no significant activation or inhibition 
of a panel of 68 receptors, channels and transporters. 
Simufilam was tested in single dose and repeat dose oral toxicity studies of up to 6 months 
in rats and 9 months in dogs. A 6-month repeat dose oral toxicity study in rats (PTI-125-
NC-049) used the same doses as a 28-day study (50, 500 and 1000 mg/kg/day), which 
found 500 mg/kg/day to be the no-adverse-effect-level (NOAEL). In the 6-month study, 
the toxicological response was characterized by decreased body weights and adverse 
structural and functional alterations in the liver of 500 and 1000 mg/kg/day animals, 
including increased hepatic weight, hepatocellular hypertrophy and vacuolation, 
single/multiple basophilic/ eosinophilic/clear cell focus, hepatocellular degeneration, 
pigmentation, and oval cell hyperplasia. The presence of bile pigment was consistent with 
cholestasis. These findings correlated with changes to the clinical chemistry profile, 
including increased ALP and total/direct bilirubin. Over the 1-month recovery period, there 
was complete recovery of the hepatocellular degeneration and partial recovery of 
hepatocellular hypertrophy; other microscopic findings in the liver remained. The NOAEL 
in this 6-month study was 50 mg/kg/day (equivalent to 300 mg/m2), corresponding to a 
safety margin of 6- and 1.6-fold based on Cmax and AUC over the 100 mg b.i.d. dose in 
human subjects. A second 6-month repeat dose oral toxicity study in rats determined the 
6-month NOAEL in the rat to be < 125 mg/kg/day, based on hepatocellular vacuolation in 
both sexes and hepatocellular hypertrophy in females at 125 and 250 mg/kg. We are 
evaluating whether these liver effects are rat specific. 
In a 9-month toxicity study in dogs (PTI-125-NC-050), the no-effect-level (NOEL) of 
simufilam was 25 mg/kg. The high dose of 200 mg/kg/day was decreased to 150 mg/kg/day 
after 1 month due to bodyweight loss considered unsustainable for 9 months. Clinical signs 
were slight hypoactivity and incidences of slight muscle fasciculations early in the study, 
and salivation. There were no pathology findings, but the high dose was considered adverse 
due to two unexplained deaths. The 75 mg/kg/day NOAEL (equivalent to 1500 mg/m2) 
provides 38- and 19-fold safety margins based on Cmax and AUC over the 100 mg b.i.d. 
dose in subjects. 
Simufilam showed no mutagenic or clastogenic responses in a standard battery of 
genotoxicity assays. 
2.3. 
CLINICAL STUDIES 
A first-in-human, double-blind, single ascending dose clinical study (PTI-125-01) was 
conducted in healthy normal volunteers, age 18-45 with oral dosing solution. Doses were 
placebo, 50, 100 and 200 mg (equivalent to 31, 62, and 123 mg/m2, respectively) 
administered to three different groups of volunteers. The study showed dose proportional 
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Cassava Sciences, Inc. 
Clinical Protocol PTI-125-07 
Simufilam (PTI-125) 
FINAL Version 2.0, JULY 20, 2021 
 
Page 11 of 43 
 
 
 
 
CONFIDENTIAL 
 
PK, a half-life ranging from 4.5 to 6 h, and there were no drug-related adverse events (AEs). 
In a 28-day phase 2a study (PTI-125-03), 13 subjects with mild-to-moderate AD received 
simufilam 100 mg b.i.d. as oral tablets. Subjects had Mini-Mental State Exam (MMSE) 
scores ≥ 16 and ≤ 24, and were age 50-85 with a CSF total tau/Aβ42 ratio ≥ 0.30. A second 
CSF sample was collected on Day 28, allowing assessment of change from baseline in 
biomarkers using commercial ELISA kits. All 8 biomarkers that are elevated in AD were 
significantly reduced from baseline (Fig. 1).4 Aβ42, which is low in AD, was increased 
slightly but non-significantly. Reduced inflammatory cytokines and YKL-40 indicated 
reduced neuroinflammation. A reduced neurodegenerative drive was suggested by 
reductions in neurogranin, neurofilament light chain, and total tau. The robust reduction in 
phospho-tau (P-Tau181) confirms the mechanism of action of simufilam. Simufilam was 
safe and well tolerated in all subjects. 
Figure 1   Phase 2a Mean Change from Baseline to Day 28 in CSF biomarkers (±SEM) 
 
 
 
A phase 2b randomized, placebo-controlled clinical study (PTI-125-02) of simufilam 50 or 
100 mg tablets or placebo (1:1:1) enrolled 64 mild-to-moderate AD subjects with MMSE 
16-26. Both 50 and 100 mg doses significantly improved eleven CSF biomarkers of AD 
pathology, neurodegeneration, neuroinflammation and blood-brain barrier integrity (Fig. 
2). CSF biomarker analyses were conducted blind to treatment and timepoint by an outside 
lab, and screening and Day 28 samples for each subject were measured in triplicate in the 
same ELISA plates. Albumin and immunoglobulin G (IgG) were measured by 
immunoblotting and quantified by densitometric quantitation. These data suggest disease 
modification and replicate Phase 2a results in a well-controlled study. 
 
Neurogranin 
Nfl 
T-Tau 
P-tau1s1 
YKL40 
IL-6 
IL-113 
TNFa -
# 
* 
* 
* 
* 
* 
* 
* 
*p<0.00001; #p<0.001 by paired t test 
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Figure 2   Phase 2b Mean Change from Baseline to Day 28 in CSF biomarkers (±SEM) 
 
 
The secondary endpoints in the Phase 2b study were two cognitive measures using the 
Cambridge Neuropsychological Test Automated Battery. Subjects were assessed on the 
Paired Associate Learning (PAL) test, measuring episodic memory, and a test of spatial 
working memory. The primary outcome measure for each was total errors, with errors 
imputed for more difficult levels not reached in the PAL test. Simufilam produced 
encouraging effect sizes (calculated by Hedge’s g for group sizes of 20), suggesting 
cognitive enhancement (Fig. 3). Effect sizes versus placebo for the test of episodic memory 
were 0.37 and 0.23 for the 50 and 100 mg groups, respectively, after removing the most 
and least impaired subjects by baseline score. For spatial working memory, effect sizes 
were 0.25 and 0.46 for these respective dose groups. Cognitive enhancement by simufilam 
is supported by preclinical data showing improved function of α7nAChR, NMDAR and 
insulin receptors and improved synaptic plasticity in 3xTg AD mice and in postmortem 
human AD brain tissue.  
In both Phase 2 clinical studies, simufilam was well tolerated and no subjects discontinued 
due to AEs.  
 
 
 
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Cassava Sciences, Inc. 
Clinical Protocol PTI-125-07 
Simufilam (PTI-125) 
FINAL Version 2.0, JULY 20, 2021 
 
Page 13 of 43 
 
 
 
 
CONFIDENTIAL 
 
Figure 3   Phase 2b Mean Change from Baseline to Day 28 in Total Errors in Memory 
Test 
 
3. STUDY OBJECTIVES 
The primary objective of this study is to investigate the safety and efficacy of simufilam 
in slowing cognitive and functional decline following 52-week, repeat-dose oral 
administration in mild-to-moderate AD subjects, 50-87 years of age. Secondary objectives 
include the assessment of simufilam’s effect on neuropsychiatric symptoms and caregiver 
burden. A third objective is to investigate the effect of simufilam treatment on plasma 
biomarkers. 
4. SUMMARY OF STUDY DESIGN 
In this Phase 3 clinical study, approximately 750 subjects with mild-to-moderate AD will 
receive placebo or 100 mg tablets of simufilam, twice daily, for 52 weeks. Randomization 
(1:1) will be stratified by low or high MMSE (16-20 and 21-27). 
 
Subjects, 50-87 years of age, will be selected for screening based on a diagnosis of AD 
consistent with Stages 4 or 5 on the Alzheimer’s continuum (National Institute on Aging – 
Alzheimer’s Association 20185). Subjects must have MMSE ≥ 16 and ≤ 27, and a Clinical 
Dementia Rating Global Score (CDR-GS) of 0.5, 1 or 2. Finally, subjects must have 
confirmed PET or fluid biomarker evidence of AD pathophysiology prior to randomization 
(see Section 5.2 – Inclusion Criteria for details). 
 
Once subjects have been satisfactorily screened for study participation, visits to the 
research clinic will occur on Study Day 1 and at Weeks 4, 16, 28, 40 and 52.   
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Cassava Sciences, Inc. 
Clinical Protocol PTI-125-07 
Simufilam (PTI-125) 
FINAL Version 2.0, JULY 20, 2021 
 
Page 14 of 43 
 
 
 
 
CONFIDENTIAL 
 
 
The co-primary endpoints include the 12-item Alzheimer’s Disease Assessment Scale – 
Cognitive Subscale (ADAS-Cog12) and the Alzheimer’s Disease Cooperative Study – 
Activities of Daily Living (ADCS-ADL), both assessed as the change from baseline to the 
end of the double-blind treatment period (Week 52). 
 
Secondary endpoints include the integrated Alzheimer’s Disease Rating Scale (iADRS), 
Neuropsychiatric Inventory (NPI), MMSE, and Clinical Dementia Rating Sum of Boxes 
(CDR-SB). A brief questionnaire assessing caregiver burden, the Zarit Burden Interview 
(ZBI), will be collected as an additional secondary endpoint.  
 
Safety will be evaluated by adverse event monitoring, vital signs, clinical labs, and the 
Columbia Suicide Severity Rating Scale (C-SSRS) at every visit. All subjects will undergo 
MRI during screening to ensure entry criteria are met. ECGs will be conducted Day 1 and 
Weeks 4, 28 and 52. A complete physical and neurological examination will be performed 
at screening, and brief examinations will be performed at all other visits. Weight will be 
measured during the Screening Period, on Study Day 1 and at all other visits.  
 
A limited number of research sites will be invited to participate in the PK and plasma 
biomarker sub-study. Collection of PK samples will enable an exposure-response analysis. 
Approximately 100 subjects will participate (50 per group). Plasma samples will be 
collected during the Screening Visit and again at Weeks 28 and 52. Change from baseline 
for plasma biomarkers represent additional secondary endpoints. 
 
An independent Data Safety Monitoring Board (DSMB) will meet periodically to review 
subject safety assessments and determine if dosing may continue. A charter will be 
developed with specific guidance for the DSMB. 
 
5. SUBJECT SELECTION 
5.1. STUDY POPULATION 
Approximately 750 subjects will be enrolled in the study. 
5.2. INCLUSION CRITERIA 
Each subject must meet the following Inclusion Criteria:  
1. Capable of providing either written informed consent or, if incapable of written 
consent, permission to participate can be obtained from a legally authorized 
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Cassava Sciences, Inc. 
Clinical Protocol PTI-125-07 
Simufilam (PTI-125) 
FINAL Version 2.0, JULY 20, 2021 
 
Page 15 of 43 
 
 
 
 
CONFIDENTIAL 
 
representative. Verbal assent to the study procedures and schedule is required of all 
participants. Genotyping for apolipoprotein E (ApoE) will be included in the informed 
consent, and participants must consent to this to be included in the study. If, in the 
Investigator’s judgment, a subject loses capacity to consent during the duration of the 
study, a legally authorized representative must consent on behalf of the subject. All 
consent processes must be undertaken prior to any study procedures. 
2. Age ≥ 50 and ≤ 87 years at the time of the informed consent, male or female. 
3. Meets National Institute on Aging and Alzheimer's Association (NIA-AA) Research 
Framework criteria (2018) for individuals in clinical Stage 4 or Stage 5 of the 
Alzheimer’s continuum.5   
4. The subject and/or study partner report a gradual and progressive change in memory 
for ≥ 6 months. 
5. Evidence for AD pathophysiology, confirmed either prior to or during the screening 
period prior to randomization, as follows: 
a. Prior to screening, confirmed with appropriate documentation by either: 1) CSF 
total tau/Aβ42 ratio (must be ≥ 0.28), or 2) an abnormal amyloid or tau positron 
emission tomography (PET) scan consistent with AD; or 
b. During screening, subjects must demonstrate an elevated plasma P-tau181 level 
(a research biomarker that identifies AD pathophysiology with high accuracy; 
see lab manual for details). 
6. MMSE score ≥ 16 and ≤ 27 at screening. 
7. CDR-GS must be 0.5, 1 or 2.  
8. If female, either surgically sterile or postmenopausal for at least 1 year. 
9. Male subjects must be willing to use contraception during the study. With female 
partners of childbearing potential, male subjects, regardless of their fertility status, must 
agree to either remain abstinent or use condoms in combination with one additional 
highly effective method of contraception (e.g., oral or implanted contraceptives, or 
intrauterine devices) or an effective method of contraception (e.g., diaphragms with 
spermicide or cervical sponges) during the study and for 14 days after study drug dosing 
has been completed. 
10. Fluency in a language of the research site and the utilized assessment materials. 
11. Has adequate visual and auditory acuity (in the Investigator’s judgment) that is 
sufficient to complete all scheduled assessments (eyeglasses and hearing aids are 
permitted). 
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12. If receiving background AD medications, including cholinesterase inhibitors, 
memantine, neuroleptics, antidepressants, anxiolytics, or sleep medications, the dosing 
regimen must be stable for at least 12 weeks prior to Study Day 1 (randomization) and 
should be expected to remain stable during the study (Note – barbiturates, 
meprobamate, and high dose benzodiazepines are not allowed, while low dose 
benzodiazepines, zolpidem, zaleplon and suvorexant are permitted).  
13. The subject has not been a smoker or chewed tobacco for at least 3 years.  
14. Availability of a person (a study partner) who, in the Investigator's opinion, has 
frequent and sufficient contact with the study subject (defined as ≥ 10 hours per week), 
and can: 
a. provide accurate information regarding the study subject's cognitive and 
functional abilities,  
b. agree to comply with and participate at all scheduled visits and study 
procedures,  
c. sign the necessary consent form,  
d. maintain the same level of interaction with the study subject throughout the 
study duration. 
15. Individuals who have participated in a clinical study with an investigational drug 
targeting the underlying AD process are permitted to participate in this study on a case-
by-case basis after consultation between the Principal Investigator and the Sponsor 
(subjects known to have been randomized to placebo do not require such consultation 
and are permitted to participate). 
5.3. EXCLUSION CRITERIA 
Subjects meeting any of the following criteria will be excluded from the study: 
1. Residence in a skilled nursing facility requiring 24-hour care (Note – subjects may 
reside in an assisted living facility if they do not need 24-hour care). 
2. Any contraindications to study procedures (e.g., potential subjects having a pacemaker 
must be excluded due to the required MRI during screening). 
3. BMI < 18.5 or > 35.0. 
4. Evidence of a neurologic condition other than AD that, in the judgment of the 
Investigator, significantly contributes to the subject’s dementia, including, but not 
limited to, frontotemporal dementia, dementia with Lewy bodies, Parkinson's disease, 
corticobasal degeneration, Creutzfeldt-Jakob disease, progressive supranuclear palsy, 
Huntington's disease, or normal pressure hydrocephalus. 
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5. Subjects with any current primary psychiatric diagnosis other than AD if, in the 
judgment of the Investigator, the psychiatric disorder or symptom is likely to confound 
interpretation of drug effect, affect cognitive assessment, or affect the subject’s ability 
either to comply with study procedures or to complete the study.  Patients with a history 
of schizophrenia or chronic psychosis are excluded.  
6. Geriatric Depression Scale (15-item) score > 8. 
7. Affirms suicidal ideation in response to questions number 4 or 5 in the C-SSRS during 
the past 3 months (i.e., “active suicidal ideation with some intent to act, without specific 
plan,” or “active suicidal ideation with specific plan and intent”) or affirms any of the 
questions contained in the Suicidal Behavior section of the C-SSRS as applicable 
during the past 12 months.  
8. Meets DSM-V criteria for alcohol or substance use disorder within 2 years before the 
Screening Period. 
9. MRI presence of cerebral vascular pathology (including, but not limited to, 
hemorrhage, infarct > 1 cm3, or > 3 lacunar infarcts), cerebral contusion, symptomatic 
subdural hematoma, aneurysm, or space-occupying lesion deemed clinically significant 
in the opinion of the Investigator. 
10. History of transient ischemic attack (TIA) or stroke within 12 months of screening, or 
history of a stroke concurrent with the onset of dementia. 
11. History of seizure within 12 months of screening. 
12. History of severe head trauma; history of head trauma with loss of consciousness > 10 
min within 12 months of screening; history of head trauma concurrent with the onset 
of dementia; history of head trauma likely to be contributing to the subject’s cognitive 
impairment in the Investigator’s judgment. 
13. Onset of dementia secondary to cardiac arrest, surgery with general anesthesia, or 
resuscitation. 
14. Clinically significant, untreated or inadequately treated sleep apnea that is likely to be 
contributing to the subject’s cognitive impairment in the Investigator’s judgment. 
15. Insufficiently controlled diabetes mellitus, defined as: 
a. requiring insulin treatment (unless subject has been stable for at least 4 weeks 
prior to screening on a once-daily dose of long-acting insulin), or 
b. HbA1C > 8.0% during the Screening Period. 
16. Malignant tumor within 3 years before screening (except definitively treated squamous 
or basal cell carcinoma, cervical carcinoma in situ, localized non-progressive prostate 
cancer, localized stage 1 bladder cancer or colon polyp resolved by excision, per 
judgment of the Investigator). 
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CONFIDENTIAL 
 
17. Known positive HIV status. 
18. Positive HBsAg or HCV-Ab during screen. 
19. Positive urine drug screen for substances of abuse. 
20. Vitamin B12 level lower than the normal limit at the time of screening (and that remains 
below on repeat testing).  Subjects may be enrolled following initiation of B12 therapy 
for at least 4 weeks prior to randomization with confirmation of a normal level upon 
repeat testing. 
21. Thyroid-stimulating hormone (TSH) levels greater than the upper limit of normal and 
a free thyroxine (free T4) lower than the lower limit of normal; subjects on thyroid 
supplementation for hypothyroidism must be on a stable dose for ≥ 3 months before 
screening. 
22. Alanine transaminase (ALT) or aspartate transaminase (AST) ≥2x the upper limit of 
normal (ULN), total bilirubin ≥1.5x ULN, or alkaline phosphatase (ALP) ≥1.5 ULN at 
screening (Note – subjects with elevated total bilirubin are not excluded if they meet 
criteria for Gilbert’s syndrome, including: bilirubin is predominantly indirect [with 
normal direct bilirubin level]; and ALT, AST and ALP ≤1x ULN). 
23. History or diagnosis of clinically significant ischemic heart disease (e.g., myocardial 
infarction or unstable angina within 1 year of screening), moderate to severe congestive 
heart failure, cardiomyopathy, myocarditis or valvular heart disease of clinical 
significance in the Investigator’s judgment. 
24. History of or current clinically significant cardiac arrhythmia or heart block as 
evidenced by ECG in the judgment of the Investigator. 
25. Clinically significant abnormality on screening electrocardiogram (ECG), including, 
but not necessarily limited to, a confirmed QT interval by the Fridericia correction 
formula (QTcF) > 470 msec (females) or > 450 msec (males) based on WHO 2016 
guidelines. 
26. Insufficiently controlled hypertension (defined, at rest, as systolic BP > 160 mmHg or 
diastolic BP > 100 mmHg; if an initial BP reading is elevated, an additional 
measurement during the Screening Period could be used before excluding a potential 
subject for insufficiently controlled hypertension). 
27. Hypotension (systolic BP < 90 mmHg) or bradycardia with a heart rate less than 50 
beats per minute during screening (out of range values may be repeated once for 
confirmation). 
28. Use of medications that in the Investigator’s opinion will contribute to cognitive 
impairment, put the subject at higher risk for AEs, or impair the subject’s ability to 
perform cognitive testing or other study procedures. 
29. Donepezil > 10 mg/day, currently or within 12 weeks of Study Day 1 (randomization).  
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30. Discontinued AChEI < 12 weeks prior to randomization. 
31. Administration of aducanumab, either currently or previously prescribed (Note – 
administration of aducanumab at any point during this clinical study is prohibited). 
32. Antipsychotics (Note – low doses are allowed only if given for sleep disturbances, 
agitation, aggression or dementia-related psychosis, and only if the dose has been stable 
for at least 4 weeks prior to screening). 
33. Tricyclic antidepressants and monoamine oxidase inhibitors if prescribed within 4 
weeks prior to screening; all other antidepressants are allowed only if the dose has been 
stable for at least 4 weeks prior to screening. 
34. Immunosuppressants, including systemic corticosteroids, if taken in clinically 
immunosuppressive doses (steroid use for allergy or inflammation is permitted). 
35. Use of antiepileptic medications if taken for control of seizures (Note – use of 
antiepileptic medications are allowed if used for mood stabilization). 
36. Chronic intake of opioid-containing analgesics. 
37. Use of prescribed sedating H1 antihistamines. 
38. Use of nicotine therapy (all dosage forms including a patch), varenicline (Chantix), or 
similar therapeutic agent within 4 weeks prior to screening. 
39. Loss of a significant volume of blood (> 450 mL) within 4 weeks of randomization. 
40. COVID-19 infection within 3 months of screening (Note – the subject must be fully 
vaccinated for COVID-19 at least two weeks prior to Study Day 1 [randomization] if 
there is no history of a prior COVID-19 infection).  
41. Clinically significant abnormalities on screening laboratory tests in the judgment of the 
Investigator. 
42. Unstable medical condition that is clinically significant in the judgment of the 
Investigator, including significant neurologic, hepatic, renal, endocrinologic, 
cardiovascular, gastrointestinal, pulmonary, hematologic, immunologic or metabolic 
disease.  
43. Any other medical or neurological condition (other than Alzheimer’s disease), that, in 
the opinion of the Investigator, might represent a contributing cause to the subject’s 
cognitive impairment, or affect cognitive assessment, subject safety, ability to comply 
with study assessments, drug compliance and completion of the study. 
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Page 20 of 43 
 
 
 
 
CONFIDENTIAL 
 
6. STUDY DRUG 
6.1. SIMUFILAM PHYSICAL DESCRIPTION AND PREPARATION 
Investigational simufilam (100 milligram active strength) and matching placebo will 
be supplied by Cassava as coated tablets.   
All remaining unused simufilam study drug will be returned to the Sponsor or 
designee. 
6.1.1. Packaging and Labelling 
Simufilam or placebo tablets in plastic bottles will be supplied in 70-count bottles for 
a 4-week supply or 188-count bottles for a 12-week supply. Bottles include a desiccant 
canister and are closed with a foil seal and child-resistant (CR) cap. Each bottle contains 
7 or 10 days of extra medication to accommodate scheduling flexibility with clinic 
visits.   
 
A Medication Event Monitoring System (MEMS®) that is 21 CFR Part 11 compliant 
will be used to track adherence to the b.i.d. dosing schedule. MEMS® caps will be 
supplied to replace the conventional CR cap on each bottle. One (1) MEMS cap will 
be assigned to each subject for use throughout the study. Each MEMS cap has an LCD 
display that provides immediate visual indication of the number of doses taken that day 
and the number of hours since the prior dose that day, resetting to zero each night. 
Instructions on management and use of MEMS caps will be provided in the Pharmacy 
manual and during site training. 
 
Each bottle is labeled with a unique double-blind ID number that is randomly assigned 
to a treatment. A computer-based clinical study management system will specify the 
bottle ID number to be dispensed according to the subject’s treatment randomization. 
 
6.1.2. Storage 
The investigational drug supplies must be stored in a locked cabinet or room with 
limited access at controlled room temperature, 20-25º C (68-77º F) and protected from 
moisture.  
6.1.3. Drug Accountability 
The Investigator will be responsible for monitoring the receipt, storage, dispensing 
and accounting of all study medications according to site standard operating 
procedures (SOPs). All records documenting the chain of custody for the study 
medication must be retained in the site study file. Accurate, original site records 
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FINAL Version 2.0, JULY 20, 2021 
 
Page 21 of 43 
 
 
 
 
CONFIDENTIAL 
 
must be maintained of drug inventory and dispensing. All records must be made 
available to the Sponsor (or designee) and appropriate regulatory agencies upon 
request. 
6.2. ADMINISTRATION AND DOSING REGIMEN 
Subjects will be randomized to receive placebo or 100 mg simufilam twice daily 
(b.i.d.). Study drug can be taken with or without food.  
6.3. CONCOMITANT MEDICATIONS 
Use of prescription or non-prescription medications will be recorded during the study. 
Chronic medications must be stable for 4 weeks prior to screening [Note – see Inclusion 
Criterion #12 and Exclusion Criteria #29 and #30 for additional details regarding 
background medications frequently prescribed to patients with AD].   
7. STUDY PROCEDURES 
Appendix A presents the Schedule of Activities. 
Prior to any study-related activities, the Informed Consent Form (ICF) must be signed 
and dated by the subject (or a legally authorized representative) and the study partner.  
The format and content of the ICF must be agreed upon by the Principal 
Investigator(s), the appropriate IRB and the Sponsor. The signed and dated ICF must 
be retained by the Investigator in the subject's file. 
 
7.1. 
EVALUATIONS BY VISIT 
Follow-up visits can be scheduled +/- five (5) days from the targeted Study Visit date.  
 
7.1.1. Screening Period (No greater than a 60-day duration prior to Study Day 1) 
The Sponsor recognizes the Screening Period assessments and procedures may not 
necessarily be completed in a single visit. A subject is permitted to be screened over 
more than one calendar day if, in the Investigator’s judgment, such scheduling will 
optimize the accuracy of Screening Period assessments and procedures.  The following 
will be completed during the Screening Period: 
• Informed Consent.  
• Review of Inclusion and Exclusion Criteria 
• Collect demographic information (e.g., sex, date of birth, race/ethnicity, years 
of education) 
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FINAL Version 2.0, JULY 20, 2021 
 
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• Medical and surgical history  
• Review concomitant medications, and any discontinued medications, in the 4 
weeks prior to screening. 
• To the extent such information is available, review and record any 
investigational drugs administered during past clinical study participation 
regardless of the date of such participation. 
• History of drug, alcohol and tobacco use  
• eCOA order of administration at screening: 
• MMSE 
• CDR  
• Geriatric Depression Scale 
• C-SSRS – Baseline/screening version  
• Complete physical and neurologic examination; including measurement of 
key vital signs (blood pressure [supine], temperature, pulse rate), height and 
weight (to calculate BMI) 
• A 12-lead ECG (5-min supine) 
• Laboratory assessments, including routine serum chemistry, TSH, free T4, Vitamin 
B12 levels, HBsAg, HCV-Ab, hematology, urinalysis and urine screen for drugs of 
abuse. Plasma for P-tau181 assessment will also be collected unless there is 
documented evidence of AD pathophysiology prior to screening. For subjects with 
diabetes, collect a blood sample for HbA1C. 
• Once the clinical and laboratory assessments above have been completed and 
verified to be consistent with study participation, schedule brain MRI to 
confirm subject meets MRI-specific entry criteria (Note – previous brain MRI 
results, with appropriate documentation, will be accepted for up to 6 months 
prior to the Study Day 1 Visit unless a recent clinical event warrants a repeat 
scan). 
• Subjects participating in the PK and plasma biomarker sub-study (100 total; 50 
subjects/treatment group) will have, in addition to the blood collection during 
the Screening Period, subsequent blood collections at Weeks 28 and 52. 
7.1.2. Rescreening of a Subject 
Individuals who have given informed consent and fail to meet the Inclusion and/or 
Exclusion criteria (screen failure) may not be rescreened if the screen failure is due to 
non-eligible MMSE (<16), MRI or P-tau181 results.  If screen failure occurs for the 
following reasons, then the subject is allowed one rescreen:  
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• Low vitamin B12 requiring supplemental therapy (can rescreen after 4 weeks) 
• MMSE of 28 (can rescreen after 8 weeks) 
Other reasons for screen failure will require Sponsor approval to rescreen.   
7.1.3. Study Day 1 (Dosing Initiation) 
Subjects will come to the clinic in the morning. Prior to dosing, the following 
assessments will be conducted: 
• Confirmation of Inclusion/Exclusion criteria 
• Confirm subject has been fully vaccinated for COVID-19 for at least two weeks 
if there is no history of a prior COVID-19 infection 
• Review of concomitant medications 
• Adverse Event Monitoring 
• Vital signs (blood pressure [supine], temperature, pulse). 
• Weight 
• Brief physical and neurologic examination (Note: the brief physical and 
neurologic examination performed on Study Day 1 and at all subsequent visits 
will include an assessment of the following: general appearance; 
cardiovascular, pulmonary, and abdominal examination, as well as an 
examination of any other system in response to subject-reported symptoms; 
cranial nerves [II-XII], tone, power, deep tendon reflexes, coordination and 
gait) 
• Clinical laboratory tests (blood and urine) 
• eCOA order of administration: 
• 
ADAS-Cog12  
• 
ADCS-ADL 
• 
NPI 
• 
ZBI  
• 
C-SSRS – Since Last Visit version 
• ECG 
• Genotyping for ApoE 
  
Once all Study Day 1 procedures and assessments have been completed, the subject is 
randomized to a treatment and the bottle of Study Drug to be dispensed is assigned by 
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CONFIDENTIAL 
 
the computer-based study management system. A Medication Event Monitoring 
System (MEMS®) cap is drawn from stock for permanent assignment to the subject and 
initialized via the computer interface. Before removing Study Drug from the bottle, 
remove the original closure and apply the MEMS cap as a replacement. Just prior to 
administering the first dose of Study Drug, remove the MEMS cap and remove one (1) 
tablet. 
Subjects will be administered Study Drug at least 1 hour before leaving the clinic. The 
subject will be discharged with their supply of Study Drug. The study partner will be 
trained on the features and proper use of the MEMS cap and instructed to administer 
Study Drug twice daily with or without food. The study partner should be advised that 
a dose can be up to 4 h late, but, if a dose is missed, the next dose should NOT be 
doubled. 
Information and instruction for the computer-based study management system, and the 
MEMS cap will be covered during site training, and written reference information will 
be included in the pharmacy manual.   
For all follow-up visits, subjects will be instructed to bring their Study Drug bottle to 
the clinic. At each visit, the MEMS cap will be read into the computer-based study 
management system to inform the site about the subject’s Study Drug adherence. The 
MEMS cap will be removed from the returned bottle and applied to the newly dispensed 
bottle of Study Drug.  
7.1.4. Weeks 4, 16 and 40 Follow-up Visits 
Subjects will return to clinic for these scheduled visits within a ± 5-day “window.” 
• 
Vital signs (blood pressure [supine], temperature and pulse) 
• 
Weight  
• 
Brief physical and neurologic examination  
• 
Adverse event monitoring 
• 
Use of concomitant medications 
• 
eCOA order of administration:  
• 
ADAS-Cog12 (whenever possible, within 1 h of the time of day 
administered at the Study Day 1 Visit, and by the same rater) 
• 
ADCS-ADL 
• 
ZBI 
• 
C-SSRS – Since Last Visit version 
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• Clinical laboratory tests (blood and urine) 
• Resting ECG (only at Week 4) 
7.1.5. Weeks 28 Follow-up Visit 
Subjects will return to clinic for these scheduled visits within a ± 5-day “window.” 
Subjects in the PK and plasma biomarker sub-study should come to the clinic before 
taking their a.m. dose and have their blood sample collected prior to their dose. 
• 
Vital signs (blood pressure [supine], temperature and pulse) 
• 
Weight 
• 
Brief physical and neurologic examination 
• 
Adverse event monitoring 
• 
Use of concomitant medications 
• 
eCOA order of administration:  
• 
ADAS-Cog12 (whenever possible, within 1 h of the time of day 
administered at the Study Day 1 Visit, and by the same rater) 
• 
ADCS-ADL 
• 
MMSE 
• 
NPI 
• 
ZBI 
• 
C-SSRS – Since Last Visit version 
• 
Clinical laboratory tests (blood and urine) 
• 
For those 100 subjects participating in the PK and plasma biomarker sub-
study, collect their Week 28 blood samples before administering their a.m. 
dose of study drug. 
• 
Resting ECG 
7.1.6. Week 52 End-of-Treatment Visit / Early Termination (ET) Visit 
Subjects will return to clinic for this scheduled visit within a ± 5-day “window.” Subjects in 
the PK and plasma biomarker sub-study should not take an a.m. dose prior to their blood 
draw. 
• Vital signs (blood pressure [supine], temperature and pulse) 
• Weight 
• Brief physical and neurologic examination 
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• Adverse Event monitoring 
• Use of concomitant medications 
• eCOA order of administration:  
• 
ADAS-Cog12 (whenever possible, within 1 h of the time of day 
administered at the Study Day 1 Visit, and by the same rater) 
• 
ADCS-ADL 
• 
MMSE 
• 
CDR 
• 
NPI 
• 
ZBI 
• 
C-SSRS – Since Last Visit version 
• Clinical laboratory tests (blood and urine) 
• For those 100 subjects participating in the PK and plasma biomarker sub-study, 
collect their Week 52 blood samples.  
• Resting ECG 
Note: Early Termination subjects do not need to complete the electronic Clinical 
Outcome Assessments if performed within 30 days of the ET Visit (see Section 9 – 
Early Discontinuation) 
7.1.7. Week 53-54 End-of-study Follow-up  
The subject and/or study partner will receive a follow-up phone call 7-14 days after the 
last dose for adverse event monitoring. If needed, a follow-up clinic visit will be 
scheduled. 
7.1.8. Treatment after Study Completion 
The Sponsor plans to initiate an open-label extension study for subjects who have 
completed participation in Study PTI-125-07. Should a subject elect to participate in 
the open-label extension study, the End-of-Study Follow-up (Section 7.1.7) will not be 
conducted. 
7.1.9. Unscheduled Visits and Discontinuation due to AEs 
For unscheduled visits due to AEs, any assessments conducted will be at the discretion 
of the Investigator and pertinent to the AE. If a decision is made to discontinue the 
subject from study drug, the Sponsor will be notified immediately. The subject should 
be followed and treated by the Investigator until the AE has resolved or stabilized (see 
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Section 10.1 – Adverse Events).  Restarting the subject on study drug will be a mutual 
decision by the Investigator and the Sponsor. See also Section 9.0 – Early 
Discontinuation. 
7.1.10    Stopping Criteria 
Liver chemistry threshold stopping criteria have been designed to ensure subject safety 
and to evaluate liver event etiology during administration of study drug. Potential 
discontinuation of study drug for abnormal liver function tests should be considered by 
the Investigator in consultation with the designated medical monitor if the study subject 
meets one or more of the following criteria: 
• ALT or AST ≥ 4x ULN; 
• ALT or AST ≥ 3x ULN and total bilirubin ≥ 2x ULN; 
• ALT or AST ≥ 3x ULN if associated with the appearance or worsening of 
fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash 
and/or eosinophilia; or 
• ALP elevations, if deemed of liver origin and drug-related as follows: 
o ALP > 3x ULN; 
o ALP > 2.5x ULN and total bilirubin > 2x ULN; or 
o ALP > 2.5x ULN if associated with the appearance or worsening of 
fatigue, nausea, vomiting, right upper quadrant pain or tenderness, 
fever, rash and/or eosinophilia. 
 
In the event of discontinuation due to abnormal liver function tests, the subject will be 
appropriately investigated to determine the potential cause and referred to a physician 
experienced in the treatment of hepatic disorders. 
 
Study drug should be discontinued if a subject: (1) positively affirms suicidal ideation in 
response to questions number 4 or 5 in the suicidal ideation section of the C-SSRS, or (2) 
reports any suicidal behavior or non-suicidal self-injurious behavior since their last visit in 
response to the C-SSRS Suicidal Behavior questions. The subject should be referred to a 
psychiatrist or an appropriate health care professional for further evaluation and 
management. 
 
Bodyweight loss of ≥ 2 kg resulting in a BMI < 18.5 is an additional stopping criterion. 
 
7.2. 
LABORATORY ASSESSMENTS 
7.2.1. Clinical Laboratory Tests 
The following clinical laboratory tests will be performed during the Screening Period, 
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Study Day 1 pre-dose, and at all follow-up visits: 
 
• Hematology:  white blood cell (WBC) count with differential, red blood cell 
(RBC) count, hemoglobin, hematocrit, platelet count. 
• Serum Chemistry:  glucose, sodium, potassium, chloride, bicarbonate, calcium, 
phosphate, blood urea nitrogen (BUN), total bilirubin, creatinine,  albumin, 
globulin, total protein, uric acid, alkaline phosphatase (ALP), 
alanine 
transaminase 
(ALT), 
aspartate transaminase 
(AST), 
gamma 
glutamyl 
transpeptidase (GGT), lactose dehydrogenase (LDH). 
• Urinalysis: color, specific gravity, pH, protein, glucose, ketones, occult blood, 
nitrites and leukocyte esterase.  A “reflex” microscopic examination will be 
performed if protein, occult blood, nitrites or leukocyte esterase is present on the 
basic analysis. 
• Screening Period:  During the Screening Period only, bloods will be drawn for TSH, 
free T4, Vitamin B12, HepBsAg, HCV-Ab, HbA1C (diabetic subjects only) and 
plasma P-tau181 (Note – plasma collection for P-tau181 not required if subject has 
documented evidence of AD pathophysiology prior to screening). Urine to screen 
for drugs of abuse (amphetamines, cocaine, opiates and phencyclindine) will also 
be collected during the Screening Period. 
7.2.2. Collection of Whole Blood Samples for ApoE Genotyping   
Whole blood samples for genotyping ApoE will be collected on Study Day 1 (please 
review instructions as per lab manual). 
7.2.3. Preparation of Samples from PK and Plasma Biomarker Sub-study Participants  
At each blood collection for PK and biomarkers, blood samples will be drawn into a 
Vacutainer® tube (10 mL per tube) containing K2EDTA. The tubes will be placed on 
ice. Within 30 min of collection, the blood will be centrifuged at approximately 1000 
X G for 15 min, preferably at 4-5°C. Within 30 min of centrifuging, plasma will be 
transferred to polypropylene tubes, and stored at -70°C until shipped to the central lab 
(complete instructions as per lab manual).  
8. COGNITIVE AND FUNCTIONAL ASSESSMENTS 
8.1. 
MINI-MENTAL STATE EXAM (MMSE) 
The MMSE6 is a set of standardized questions covering several target areas: orientation, 
registration, attention and calculation, short-term verbal recall, naming, repetition, 3-
step command, reading, writing, and visuospatial cognitive assessment. Administration 
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of the MMSE is estimated to take approximately 10 minutes. 
8.2. 
CLINICAL DEMENTIA RATING (CDR) 
Washington University’s CDR7 characterizes six domains of cognitive and functional 
performance applicable to AD and related dementias: memory, orientation, judgment 
and problem solving, community affairs, home and hobbies, and personal care. The 
study partner is interviewed first by a qualified rater who assesses all six domains. The 
subject is then interviewed in the absence of the caregiver. A CDR global score can be 
calculated 
by 
accessing 
Washington 
University’s 
online 
algorithm 
(https://biostat.wustl.edu/~adrc/cdrpgm/index.html) where 0 = no dementia, and scores 
of 0.5, 1, 2, or 3 = questionable, mild, moderate, or severe dementia, respectively.  The 
sum of boxes (i.e., CDR-SB)8 can also be calculated by summing the six individual 
domain scores. This detailed quantitative general index may provide more information 
than the CDR-GS in patients with mild dementia.  
8.3. 
ALZHEIMER’S DISEASE ASSESSMENT SCALE – COGNITIVE SUBSCALE 12 (ADAS-
COG12) 
The ADAS-Cog9,10 is a psychometrician-administered battery comprised of several 
cognitive domains including memory, comprehension, praxis, orientation, and 
spontaneous speech. The ADAS-Cog12 (which includes Delayed Word Recall) will be 
administered to all subjects at various key visits throughout the study. 
8.4. 
NEUROPSYCHIATRIC INVENTORY (NPI)  
A study partner interview, the 12-item NPI11 records frequency and severity of common 
neuropsychiatric 
symptoms 
in 
dementia 
(Hallucinations, 
Delusions, 
Agitation/aggression, Dysphoria/depression, Anxiety, Irritability, Disinhibition, 
Euphoria, Apathy, Aberrant motor behavior, Sleep, and nighttime behavior change, 
Appetite and eating change). The study partner is then asked to rate their own distress 
for the subject’s behavioral symptoms occurring in the past 4 weeks.  
8.5. 
ALZHEIMER’S DISEASE COOPERATIVE STUDY – ACTIVITIES OF DAILY LIVING 
(ADCS-ADL-AD) 
The ADCS-ADL12 is a 23-item study partner questionnaire that covers both basic 
activities of daily living (ADL) (e.g., eating and toileting) and more complex ADL or 
instrumental ADL (e.g., using the telephone, managing finances, preparing a meal). 
8.6. 
COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS) 
The C-SSRS13 is an assessment tool used to assess the lifetime suicidality of a subject 
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(C-SSRS at baseline) as well as any new instances of suicidality (C-SSRS since last 
visit). 
8.7. 
ZARIT BURDEN INTERVIEW (ZBI) 
The ZBI14,15 is a 22-item scale designed to assess the stress or burden experienced by 
caregivers of people with dementia. The ZBI will be administered as an interview with 
the caregiver. The scale consists of 22 statements reflecting how people can feel when 
taking care of another person. The statements are phrased as questions for the caregiver 
to indicate how often they feel the way described in the statement. The 5 possible 
responses for each item are Never, Rarely, Sometimes, Quite Frequently, and Nearly 
Always.  
8.8. 
GERIATRIC DEPRESSION SCALE (GDS) 
The GDS16 is a 30-item yes/no question test designed to screen for depression in elderly 
persons. The GDS short form (15-items)17 version utilized in this study will be clinician 
administered with caregiver input. Subjects will be evaluated for symptoms of 
depression during the Screening Period.  
8.9. 
ELECTRONIC CAPTURE OF RATING SCALES 
The assessments MMSE, CDR, ADAS-Cog12, GDS, NPI, ADCS-ADL, C-SSRS, and 
ZBI will be captured electronically by an eCOA platform that is 21 CFR Part 11 
compliant. Data collected by eCOA will be transferred directly to the EDC vendor’s 
database.   
9. EARLY DISCONTINUATION 
Subjects may choose to discontinue study drug or study participation at any time, for 
any reason, and without prejudice. Moreover, a subject may be withdrawn at any time 
at the discretion of the Investigator or Sponsor for safety, behavioral or administrative 
reasons. Discontinued subjects should be followed according to medical practice 
standards, and the outcome documented. Follow-up is required if the subject is 
discontinued due to an adverse event (AE). Any comments (spontaneous or elicited) or 
complaints made by the subject and the reason for termination and the date of stopping 
the drug must be recorded in the Case Report Form (CRF) and source documents.  
The following must be completed and documented in the source documents and 
CRFs for all subjects who discontinue the study early: 
• The reason for early study discontinuation.  If the subject is withdrawn for more than 
one reason, each reason should be documented in the source documents and the 
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most clinically relevant reason should be entered on the CRF. 
• Vital signs (blood pressure, temperature and pulse), brief physical and neurologic 
examination, weight, clinical laboratory tests, ECG, use of concomitant 
medications and adverse events should be obtained at discharge prior to release. 
• Blood draw for plasma biomarkers 
• ADAS-Cog, MMSE, CDR, ADCS-ADL, NPI, ZBI and C-SSRS (as detailed in 
Section 7.1.6 – Early Termination Visit), if not performed within the last 30 days. 
10. ADVERSE EVENTS/SERIOUS ADVERSE EVENTS  
10.1. ADVERSE EVENTS - DEFINITION 
An Adverse Event (AE) is any undesirable event that occurs to a subject during a study, 
whether or not that event is considered study drug-related. Monitoring for AEs will start 
at dosing. Examples include: 
• Any treatment-emergent signs and symptoms (events that are marked by a change 
from the subject's baseline/entry status [e.g., an increase in severity or frequency of 
pre-existing abnormality or disorder]) 
• All reactions from study drug, an overdose, abuse of drug, withdrawal phenomena, 
sensitivity or toxicity to study drug 
• Apparently unrelated illnesses 
• Injury or accidents (Note: if a medical condition is known to have caused the injury 
or accident, the medical condition and the accident should be reported as two separate 
medical events [e.g., for a fall secondary to dizziness, both "dizziness" and "fall" 
should be recorded separately]) 
• Extensions or exacerbations of symptoms, subjective subject-reported events, new 
clinically significant abnormalities in clinical laboratory, physiological testing or 
physical examination 
 
All AEs, whether or not related to the study drug, must be fully and completely 
documented on the AE page of the CRF and in the subject's clinical chart. 
In the event that a subject is withdrawn from the study because of an AE, it must be 
recorded on the CRF as such. The subject should be followed and treated by the 
Investigator until the abnormal parameter or symptom has resolved or stabilized. 
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The Investigator must report all directly observed AEs and all spontaneously reported 
AEs. The Investigator will ask the subject a non-specific question (e.g., "Have you 
noticed anything different since your dose of the study medication?") to assess whether 
any AEs have been experienced since the last assessment. AEs will be identified and 
documented in the Electronic Data Capture (EDC) system in appropriate medical 
terminology. The severity and the relationship to the study drug will be determined and 
reported in EDC (see below). 
10.2. ADVERSE EVENTS - SEVERITY RATING 
The severity of each AE should be characterized and then classified into one of three 
clearly defined categories as follows: 
• Mild – the AE does not interfere in a significant manner with the subject's normal 
functioning level. It may be an annoyance. 
• Moderate – the AE produces some impairment of functioning but is not hazardous 
to health. It is uncomfortable or an embarrassment. 
• Severe – the AE produces significant impairment of functioning or incapacitation 
and is a definite hazard to the subject's health. 
These three categories are based on the Investigator's clinical judgment, which in turn 
depends on consideration of various factors such as the subject's report and the physician's 
observations. The severity of the AE should be recorded in the appropriate section of the 
EDC. 
10.3. ADVERSE EVENTS – RELATIONSHIP TO STUDY   DRUG 
The relationship of each AE to the study drug will be classified into one of three defined 
categories as follows: 
• Unlikely –  a causal relationship between the AE and the study drug is unlikely. 
• Possible –  a causal relationship between the AE and the study drug is possible. 
• Probable – a causal relationship between the AE and the study drug is probable. 
For example, the AE is a common adverse event known to occur with the 
pharmacological class of the study drug; or the AE abated on study drug 
discontinuation and reappeared upon rechallenge with the study drug. 
These three categories are based on the Investigator's clinical judgment, which in turn 
depends on consideration of various factors such as the subject's report, the timing of 
the AE in relationship to study drug administration/discontinuation, the physician's 
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observations and the physician's prior experience. The relationship of the AE to the study 
drug will be recorded in the appropriate section of the EDC. 
10.4. SERIOUS ADVERSE EVENTS AND UNEXPECTED ADVERSE EVENTS - DEFINITIONS 
A Serious Adverse Event (SAE) includes (but is not limited to) an experience occurring 
at any dose that results in any of the following outcomes: 
• Death 
• A life-threatening event (i.e., the subject is at immediate risk of death from the 
reaction as it occurs). "Life-threatening" does not include an event that, had it 
occurred in a more serious form, might have caused death. For example, drug­ 
induced hepatitis that resolved without evidence of hepatic failure would not be 
considered life-threatening even though drug-induced hepatitis can be fatal. 
• In-patient hospitalization (hospital admission, not an emergency room visit) or 
prolongation of existing hospitalization. 
• A persistent or significant disability/incapacity (i.e., a substantial disruption of 
the subject's ability to carry out normal life functions). 
• A congenital anomaly/birth defect. 
 
In addition, medical and scientific judgment should be exercised in deciding whether 
other situations should be considered an SAE (i.e., important medical events that may 
not be immediately life-threatening or result in death but may jeopardize the subject or 
may require medical or surgical intervention to prevent one of the other outcomes listed 
in the definition above). Examples of such medical events include (but are not limited 
to): allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in in-patient hospitalization, or 
the development of drug dependency or drug abuse. 
An unexpected AE is one for which the specificity or severity is not consistent with the 
current Investigator's Brochure. For example, hepatic necrosis would be unexpected (by 
virtue of greater severity) if the Investigator's Brochure listed only elevated hepatic 
enzymes or hepatitis. 
Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by 
virtue of greater specificity) if the Investigator's Brochure listed only cerebral vascular 
accidents. 
10.5. SERIOUS ADVERSE EVENTS REPORTING 
The reporting of SAEs by the Sponsor to regulatory authorities (e.g., FDA) is a 
regulatory requirement. Each regulatory agency has established a timetable for 
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reporting SAEs based upon established criteria.  Likewise, it is the responsibility of 
the Principal Investigator to report SAEs to the IRB. 
All SAEs must be reported immediately (within 24 h of learning of the event) by e-
mail to: 
Premier Research Global Pharmacovigilance 
 
 
Do not delay reporting a suspected SAE to obtain additional information.  Any 
additional information, if collected, can be reported to the Sponsor as a follow-up to 
the initial report. 
SAEs must be immediately reported to the responsible IRB. 
In the case of a death or other SAE that has occurred within 30 days after receiving 
study drug, the Principal Investigator must also report such an event within 24 hours 
of being notified. Your local IRB may also require these reports. 
In the event of any SAE (other than death), the subject will be instructed to contact the 
study physician (Principal Investigator or designee) using the phone number provided 
in the Informed Consent Form. All subjects experiencing an SAE will be seen by a 
Principal Investigator or designee as soon as feasible following the report of an SAE. 
11. STATISTICAL CONSIDERATIONS 
11.1. RANDOMIZATION 
Randomized treatments will be assigned by subject numbers in a randomly generated 
numeric sequence. 
The randomization code will not be revealed to study subjects, Investigators, clinical 
staff, study monitors or the Sponsor until all subjects have completed therapy and the 
database has been finalized and locked.  
Under normal circumstances, the blind should not be broken. The blind may be broken 
only if specific emergency treatment is indicated. The date, time and reason for the 
unblinding must be documented in the CRFs, and the medical monitor must be informed 
as soon as possible. 
11.2. ANALYSIS POPULATIONS 
The Intent-To-Treat (ITT) analysis set includes all randomized subjects. All efficacy 
analyses will be conducted in this analysis set and subjects will be included in the group 
to which they were randomized. 
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The Safety analysis set includes all subjects who receive study treatment. All safety 
analyses will be completed in the Safety analysis set and subjects will be included in the 
group based on the treatment actually received.  
11.3. STATISTICAL ANALYSIS 
 
11.3.1 Primary Efficacy Analysis 
Each of the two co-primary endpoints will be analyzed using a linear mixed model for 
repeated measurements. The dependent variable is the change from baseline and the 
model will include fixed effects for treatment group (two levels), week (5 levels, 
corresponding to Weeks 4, 16, 28, 40 and 52), the treatment group-by-week interaction, 
and the randomization stratification variable. The baseline value of the corresponding 
endpoint will be included as a covariate and the unstructured covariance model will be 
used. The Study Day 1 ADAS-Cog12 and ADCS-ADL assessments will represent the 
baseline value for these variables. 
 
For each of the two co-primary endpoints, the primary analysis will compare the 100 mg 
group and the placebo group at Week 52 using a two-sided test at the alpha = 0.05 level 
of significance. Study success requires that both co-primary comparisons are statistically 
significant. 
 
11.3.2 Secondary Analyses 
The iADRS18,19 is a linear combination of scores from two well-established, widely 
accepted, therapeutically sensitive measures of AD: the ADAS-Cog and ADCS-iADL 
(the instrumental component of the ADCS-ADL). The iADRS has been validated and 
statistical properties of the composite performance have been described20. All items of 
the ADAS-Cog12 and the ADCS-iADL will be included to generate this primary efficacy 
composite measurement without additional weighting. 
 
Secondary clinical endpoint data (iADRS, NPI, MMSE and ZBI) measured repeatedly will 
be analyzed using the same types of linear mixed models as described for the primary 
analysis.  
Plasma assays may include P-tau181, SavaDx and neurofilament light chain, and 
additional plasma biomarkers may be measured. All plasma biomarker data involving 
repeated measures will also be analyzed using the same types of linear mixed models as 
described for the primary analysis.  
CDR-SB data will be analyzed using ANCOVA models with treatment group as a factor 
and the baseline value as a covariate.  
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All secondary analyses will be conducted using two-sided tests at the alpha = 0.05 level 
of significance, with no adjustments for multiplicity. 
11.4. SAFETY ANALYSIS 
Adverse events reported on case report forms will be mapped to preferred terms and 
organ systems using the MedDRA mapping system. Vital signs and clinical laboratory 
results will be descriptively summarized in terms of change from screening values. 
11.5. SAMPLE SIZE 
Approximately seven hundred fifty (750) subjects will be enrolled in this study. The 
sample size was determined by a power analysis of ADAS-Cog in a similar population 
over 52 weeks. This analysis determined that group sizes of 300 are powered to show a 
45% difference from placebo at 52 weeks with 90% power and a two-sided significance 
level of 0.05.  The power calculation assumes a true mean change from baseline for 
placebo of 5.0 points and a standard deviation of 8.5 points.  Assuming a drop-out of 
20%, each treatment group should enroll 375 subjects. 
12. STUDY TERMINATION 
The study will be terminated following completion of the study or at any time at the 
discretion of the Sponsor. 
13. DATA COLLECTION, RETENTION AND MONITORING 
13.1. CASE REPORT FORMS 
The CRF will be provided as an Electronic Data Capture (EDC) system that will serve as 
the collection method for subject data. The subjects in the study will not be identified by 
name on any study documents to be collected by the Sponsor (or CRO designee) but will 
be identified by a unique subject number. 
All clinical information requested in this protocol will be recorded in the EDC 
system.  It is strongly recommended that data entry be completed within 48 h of a 
subject’s visit. In case of error noted on paper source documents, the correction will be 
noted, initialed and dated. 
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EDC data must be reviewed and verified for accuracy and signed-off by the staff 
personnel before database lock. Paper source documents, if used, will remain at the 
Investigator's site at the completion of the study. 
13.2. AVAILABILITY AND RETENTION OF INVESTIGATIONAL RECORDS 
The Investigator must make study data accessible to the monitor, other authorized 
representatives of the Sponsor (or designee) and Regulatory Agency (e.g., FDA) 
inspectors upon request. To assure accuracy of data collected in the EDC, it is 
mandatory that Sponsor representatives have access to original source documents (e.g., 
subject records, subject charts, and laboratory reports). During review of these 
documents, the subject's anonymity will be maintained with adherence to professional 
standards of confidentiality and applicable laws. A file for each subject must be 
maintained that includes the signed ICF and all source documentation related to that 
subject. The Investigator must ensure the reliability and availability of source 
documents for the EDC. 
Investigators are required to maintain all study documentation until notification by the 
Sponsor that any records may be discarded. 
The Investigator is responsible for maintaining adequate case histories in each 
subject's source records.  
13.3. SUBJECT CONFIDENTIALITY 
All reports and subject samples will be identified only by the assigned subject number 
and initials, as applicable by local law, to maintain subject confidentiality. Additional 
subject confidentiality measures (as required by region) will be covered within the 
Clinical Trial Agreement for each site as applicable. 
13.4. LIABILITY 
In the event of a side effect or injury, appropriate medical care as determined by the 
Investigator or his/her designated alternate will be provided. 
If a bodily injury is sustained resulting directly from the Study Drug, the Sponsor will 
reimburse for reasonable physician fees and medical expenses necessary for treatment of 
only the bodily injury that is not covered by the subject's medical or hospital insurance, 
provided that the injury is not due to a negligent or wrongful act or omission by the study 
doctor and his/her staff. No other compensation of any type will be provided by the 
Sponsor. Compensation for lost wages, disability or discomfort due to the study is not 
available. 
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13.5. ETHICAL AND LEGAL ISSUES 
The Investigator and site personnel are responsible for conducting this study in 
accordance with the ICH, GCP, and all other applicable laws and regulations. 
13.5.1. Institutional Review Board 
The protocol,  ICF, clinical sites and Investigators must be approved by an IRB before 
the study is initiated. The IRB must comply with U.S. CFR 21 Part 56 and local laws. 
Documentation of approval by the designated central IRB will be provided to the 
Investigators. The Sponsor will:  
• Obtain IRB approval of the protocol, ICF, advertisements to recruit subjects and 
IRB approval of any protocol amendments and ICF revisions before implementing 
the changes. 
• Provide the IRB with any required information before or during the study. 
• Submit progress reports to the IRB, as required, requesting additional review and 
approval, as needed; and provide copies of all relevant IRB communications to the 
Investigator. 
 
The Investigator is responsible for: 
• Notifying the IRB within 15 calendar days of all SAEs and unexpected AEs related 
to study medications. 
• Obtaining approval by their institution’s own IRB, if the Investigator’s institution 
has its own IRB. 
13.6. INFORMED CONSENT FORM 
The Sponsor will submit the ICF to the central IRB for approval. An IRB-approved 
copy of the ICF will be forwarded to the Investigator or site staff. 
The ICF documents study-specific information the Investigator provides to the subject 
and the subject's agreement to participate. The Investigator explains in plain terms the 
nature of the study along with the aims, methods, anticipated benefits, potential risks, 
and any discomfort that participation may entail. The ICF must be signed and dated 
before the subject enters the study. The original ICF and any amended ICF, signed and 
dated, must be retained in the subject's file at the study site and a copy must be given 
to the subject. 
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14.  INVESTIGATOR RESPONSIBILITIES 
The Investigator agrees to: 
• Conduct the study in accordance with the protocol, except to protect the safety, rights, 
or welfare of subjects. 
• Personally conduct or supervise the study. 
• Ensure that requirements for obtaining informed consent and IRB review 
and approval comply with ICH, CFR 21 Parts 50 and 56 and local laws. 
• Report to the Sponsor any AEs that occur during the study in accordance with 
ICH, CFR 21 Part 312.64 and local laws. 
• Read and understand the Investigator's Brochure including potential risks and 
side effects of the drug. 
• Ensure that all associates, colleagues, and employees assisting in the conduct of 
the study are informed about their obligations in meeting the above commitments. 
• Maintain adequate records in accordance with ICH, 21 CFR Part 312.62, and 
local laws and have records available for inspection by the Sponsor, FDA, or 
other authorized agency. 
• Promptly report to the IRB and the Sponsor all changes in research activity and 
unanticipated problems involving risks to subjects or others (including 
amendments and expedited safety reports). 
• Comply with all other requirements regarding obligations of Clinical 
Investigators and all other pertinent requirements listed in ICH, 21 CFR Part 
312 and local laws. 
15. REFERENCES 
1. Burns LH, Wang H-Y. Altered filamin A enables amyloid beta-induced tau 
hyperphosphorylation 
and 
neuroinflammation 
in 
Alzheimer’s 
disease. 
Neuroimmunology and Neuroinflammation 2017;4:263-71. 
2. Wang H-Y, Lee K-C, Pei Z, Khan A, Bakshi K, Burns L. PTI-125 binds and reverses 
an altered conformation of filamin A to reduce Alzheimer's disease pathogenesis. 
Neurobiology of Aging 2017;55:99-114. 
3. Wang H-Y, Bakshi K, Frankfurt M, et al. Reducing amyloid-related Alzheimer’s 
disease pathogenesis by a small molecule targeting filamin A. Journal of Neuroscience 
2012;32:9773-84. 
4. Wang H-Y, Pei Z, K.-C. Lee K-C, et al. PTI-125 reduces biomarkers of Alzheimer’s 
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disease in patients. The Journal of Prevention of Alzheimer's Disease 2020;7:256-64. 
5. Jack C, Bennett D, Blennow K, et al (2018) NIA-AA Research Framework: Toward a 
biological definition of Alzheimer's disease; Alzheimer’s and Dementia 14(4):535-562 
6. Folstein MF, Folstein SE, McHugh PR. “Mini-mental state.” A practical method for 
grading the cognitive state of patients for the clinician. Journal of  Psychiatric Research 
1975;12:189-98. 
7. Morris JC. The Clinical Dementia Rating (CDR): current version and scoring rules. 
Neurology 1993;43:2412- 4. 
8. O'Bryant SE, Lacritz LH, Hall J, et al. Validation of the new interpretive guidelines for 
the clinical dementia rating scale sum of boxes score in the national Alzheimer's 
coordinating center database. Archives of Neurology 2010;67:746–9. 
9. Mohs R, Knopman D, Petersen R, Ferris S, Ernesto C, Grundman M, Sano M, 
Bieliauskas L, Geldmacher D, Clark C, Thal L and the ADCS. Development of 
Cognitive Instruments for Use in Clinical Trials of Antidementia Drugs: Additions to 
the Alzheimer’s Disease Assessment Scale That Broadens its Scope. Alzheimer’s 
Disease and Associated Disorders, 1997;11(S2):S13-21. 
10. Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer’s disease. 
American Journal of Psychiatry 1984; 141(11): 1356-1364. 
11. Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. The 
Neuropsychiatric Inventory: comprehensive assessment of psychopathology in 
dementia, 1994;44(12):2308-14. 
12. Galasko D, Bennett D, Sano M, et al. An inventory to assess activities of daily living 
for clinical trials in Alzheimer’s disease. The Alzheimer's Disease Cooperative Study. 
Alzheimer Disease and Associated Disorders 1997;11(Suppl 2):S33-9. 
13. Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. The 
Columbia-Suicide Severity Rating Scale: initial validity and internal consistency 
findings from three multisite studies with adolescents and adults. American  Journal of  
Psychiatry 2011;168(12):1266-77. 
14. Zarit SH, Reever KE and Bach-Peterson J. (1980) Relatives of the impaired elderly: 
correlates of feelings of burden. Gerontologist Dec; 20: 649-655. 
15. Zarit SH, Zarit JM. The memory and behavior problems checklist and the burden 
interview. Gerontology Center, The Pennsylvania State University, 1990. 
16. Yesavage, J.A., Brink, T.L., Rose, T.L., Lum, O., Huang, V., Adey, M.B., & Leirer, 
V.O. (1983). Development and validation of a geriatric depression screening scale: A 
preliminary report. Journal of Psychiatric Research, 17, 37-49. 
17. Sheikh JI, Yesavage JA: Geriatric Depression Scale (GDS): Recent evidence and 
development of a shorter version. Clinical Gerontology: A Guide to Assessment and 
Intervention; 165-173, NY: The Haworth Press, 1986. 
18. Wessels AM, Siemers ER, Yu P, Andersen SW, Holdridge KC, Sims JR, Sundell K, 
Stern Y, Rentz DM, Dubois B, Jones RW, Cummings J, Aisen PS; A combined 
measure of cognition and function for clinical trials: the integrated Alzheimer’s Disease 
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Rating Scale (iADRS). Journal of Prevention of Alzheimer’s Disease, 2 (4) 2015, 227-
241. 
19. Wessels AM, Andersen SW, Dowsett SA, Siemers ER; The integrated Alzheimer’s 
Disease Rating Scale (iADRS) findings from the EXPEDITION3 trial. Journal of 
Prevention of Alzheimer’s Disease, 5 (2) 2018, 134-136. 
20. Liu-Seifert H, Andersen SW, Case M, Sparks JD, Holdridge KC, Wessels AM, Hendrix 
S, Aisen P, Siemers E; Statistical properties of continuous composite scales and 
implications for drug development. Journal of Biopharmaceutical Statistics 27 (6) 
2017, 1104-1114. 
 
 
 
 
 
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16.  APPENDIX A – SCHEDULE OF ACTIVITIES 
Procedures 
Screening 
Period (-60 
Days to 0) 
Baseline 
Day 1 
Week 
4 
Week 
16 
Week 
28 
Week 
40 
Week 52 
ET/ED3 
Week 53 
to 54 
Informed Consent 
X 
 
 
 
 
 
 
 
I/E Criteria 
X 
X 
 
 
 
 
 
 
Medical & Med 
History 
X 
 
 
 
 
 
 
 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
Concomitant Meds 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
 
Physical 
Examination  
X1 
X 
X 
X 
X 
X 
X 
 
Neurologic 
Examination 
X1 
X 
X 
X 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
 
Geriatric Depression 
Scale 
X 
 
 
 
 
 
 
 
Resting ECG 
X 
X 
X 
 
X 
 
X 
 
Biochemistry, 
Hematology, 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
 
Urine Drug Screen 
X 
 
 
 
 
 
 
 
TSH, free T4, B12, 
HBsAg, HCV-Ab 
X 
 
 
 
 
 
 
 
HbA1c (diabetic 
subjects only) 
X 
 
 
 
 
 
 
 
Plasma P-tau181 
X7 
 
 
 
 
 
 
 
Genotyping sample 
 
X 
 
 
 
 
 
 
MRI 
X 
 
 
 
 
 
 
 
PK and Plasma 
Biomarkers 
X2 
 
 
 
X2 
 
X2 
 
MMSE 
X 
 
 
 
X 
 
X 
 
ADAS-Cog12 
 
X 
X 
X 
X 
X 
X 
 
ADCS-ADL 
 
X 
X 
X 
X 
X 
X 
 
CDR 
X 
 
 
 
 
 
X 
 
NPI 
 
X 
 
 
X 
 
X 
 
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Procedures 
Screening 
Period (-60 
Days to 0) 
Baseline 
Day 1 
Week 
4 
Week 
16 
Week 
28 
Week 
40 
Week 52 
ET/ED3 
Week 53 
to 54 
ZBI 
 
X 
X 
X 
X 
X 
X 
 
C-SSRS 
X4 
X5 
X5 
X5 
X5 
X5 
X5 
 
Drug Dispensation 
 
X6 
X 
X 
X6 
X 
 
 
Drug Accountability 
 
 
X 
X 
X 
X 
X 
 
End of Study 
Follow-up Phone 
Call 
 
 
 
 
 
 
 
X 
 
 
1. Complete Physical and Neurologic Examinations during the Screening Period only, 
brief examinations thereafter 
2. PK and plasma biomarker sub-study subjects only (100 subjects total; 50 
subjects/group) 
3. Early Termination / Early Discontinuation subjects do not need to complete the 
electronic clinical outcome assessments if performed within 30 days of the ET/ED 
Visit 
4. During the Screening Period, the C-SSRS Baseline/Screening version will be 
administered 
5. At Study Day 1, as well as all remaining visits, the C-SSRS Since Last Visit version 
will be administered 
6. The first dose of Study Drug is administered at the clinic to all subjects on Day 1; for 
plasma PK and biomarker sub-study subjects only at the Week 28 visit, administer 
Study Drug after blood samples are collected 
7. Plasma P-tau181 not required if the subject has evidence for AD pathophysiology 
prior to screening 
 
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CONFIDENTIAL 
 
 
 
CLINICAL RESEARCH PROTOCOL 
PROTOCOL PTl-125-07 
 
A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
PARALLEL-GROUP, 52-WEEK STUDY EVALUATING THE SAFETY AND 
EFFICACY OF SIMUFILAM 100 MG TABLETS IN SUBJECTS WITH MILD-TO-
MODERATE ALZHEIMER’S DISEASE 
 
 
 
SPONSOR: 
 
CASSAVA SCIENCES, INC. 
7801 N. Capital of Texas Highway, Suite 260 
Austin, TX 78731 
Phone: 512-501-2444 
 
 
 
Confidentiality 
The information contained in this document and all information provided to you related to 
simufilam ("Drug") are the confidential and proprietary information of Cassava Sciences, Inc. 
and, except as may be required by federal, state, or local laws or regulations, may not be 
disclosed to others without prior written permission of Cassava. The Principal Investigator 
may, however, disclose such information to supervised individuals working on the Drug, 
provided such individuals agree to be bound to maintain the confidentiality of such Drug 
information. 
 
 
CASSAVA 
sciences 
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30 June 2021
Cassava Sciences, Inc. 
Simufilam (PTI-125) 
Clinical Protocol PTI-125-07 
FINAL Version 1.0, JUNE 30, 2021 
Cassava Sciences, Inc. 
CLINICAL RESEARCH PROTOCOL 
A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
PARALLEL-GROUP,52-WEEKSTUDY EVALUATING THE SAFETY AND 
EFFICACY OF SIMUFILAM 100 MG TABLETSINSUBJECTSWITHMILD-TO-
MODERATE ALZHEIMER'S DISEASE 
Approvals: 
SVP, Neuroscience 
Cassava Sciences, Inc. 
Chief Cl n cal Development Officer
Cassava Sciences, Inc. 
Page 2 of 43 
Date 
CONFIDENTIAL 
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Page 3 of 43 
 
 
 
 
CONFIDENTIAL 
 
 
Cassava Sciences, Inc. 
CLINICAL RESEARCH PROTOCOL 
 
 
 
A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
PARALLEL-GROUP, 52-WEEK STUDY EVALUATING THE SAFETY AND 
EFFICACY OF SIMUFILAM 100 MG TABLETS IN SUBJECTS WITH MILD-TO-
MODERATE ALZHEIMER’S DISEASE 
 
 
 
Signature of Agreement for Protocol PTI-125-07 
 
 
 
 
I have read this protocol and agree to conduct the study as outlined herein, in accordance 
with Good Clinical Practice (GCP) and complying with the obligations and requirements of 
clinical investigators and all other requirements listed in 21 CFR Part 312. 
 
 
 
 
 
 
 
 
Coordinating Principal Investigator Signature 
Date 
 
 
 
 
Print Coordinating Principal Investigator Name 
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TABLE OF CONTENTS 
1. 
LIST OF ABBREVIATIONS ....................................................................................7 
2. 
INTRODUCTION ......................................................................................................9 
2.1. Mechanism of Action ................................................................................................................. 9 
2.2. Safety pharmacology and toxicology ......................................................................................... 9 
2.3. Clinical Studies ........................................................................................................................ 10 
3. 
STUDY OBJECTIVES ............................................................................................13 
4. 
SUMMARY OF STUDY DESIGN .........................................................................13 
5. 
SUBJECT SELECTION ..........................................................................................14 
5.1. Study Population ...................................................................................................................... 14 
5.2. Inclusion Criteria ..................................................................................................................... 14 
5.3. Exclusion Criteria .................................................................................................................... 16 
6. 
STUDY DRUG .........................................................................................................20 
6.1. Simufilam Physical Description and Preparation ..................................................................... 20 
6.1.1. Packaging and Labelling ............................................................................................... 20 
6.1.2. Storage ........................................................................................................................... 20 
6.1.3. Drug Accountability ....................................................................................................... 20 
6.2. Administration and Dosing Regimen ....................................................................................... 21 
6.3. Concomitant Medications ........................................................................................................ 21 
7. 
STUDY PROCEDURES .........................................................................................21 
7.1. Evaluations by Visit ................................................................................................................. 21 
7.1.1. Screening Period (No greater than a 60-day duration prior to Study Day 1) ................ 21 
7.1.2. Rescreening of a Subject ................................................................................................ 22 
7.1.3. Study Day 1 (Dosing Initiation) ..................................................................................... 23 
7.1.4. Weeks 4, 16 and 40 Follow-up Visits ............................................................................. 24 
7.1.5. Weeks 28 Follow-up Visit ............................................................................................... 25 
7.1.6. Week 52 End-of-Treatment Visit / Early Termination (ET) Visit ................................... 25 
7.1.7. Week 53-54 End-of-study Follow-up .............................................................................. 26 
7.1.8. Treatment after Study Completion ................................................................................. 26 
7.1.9. Unscheduled Visits and Discontinuation due to AEs ..................................................... 26 
7.1.9    Stopping Criteria ............................................................................................................ 27 
7.2. Laboratory Assessments .......................................................................................................... 27 
7.2.1. Clinical Laboratory Tests ............................................................................................... 27 
7.2.2. Collection of Whole Blood Samples for ApoE Genotyping ............................................ 28 
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7.2.3. Preparation of Samples from PK and Plasma Biomarker Sub-study Participants ......... 28 
8. 
COGNITIVE AND FUNCTIONAL ASSESSMENTS ...........................................28 
8.1. Mini-Mental State Exam (MMSE) ........................................................................................... 28 
8.2. Clinical Dementia Rating (CDR) ............................................................................................. 28 
8.3. Alzheimer’s Disease Assessment Scale – Cognitive Subscale 12 (ADAS-Cog12) ................. 29 
8.4. Neuropsychiatric Inventory (NPI) ............................................................................................ 29 
8.5. Alzheimer’s Disease Cooperative Study – Activities of Daily Living (ADCS-ADL-AD) ...... 29 
8.6. Columbia-Suicide Severity Rating Scale (C-SSRS) ................................................................ 29 
8.7. Zarit Burden Interview (ZBI) ................................................................................................... 29 
8.8. Geriatric Depression Scale (GDS) ........................................................................................... 30 
8.9. Electronic Capture of Rating Scales......................................................................................... 30 
9. 
EARLY DISCONTINUATION ...............................................................................30 
10. 
ADVERSE EVENTS/SERIOUS ADVERSE EVENTS ..........................................31 
10.1. Adverse Events - Definition ...................................................................................................... 31 
10.2. Adverse Events - Severity Rating ............................................................................................ 32 
10.3. Adverse Events – Relationship to Study   Drug ....................................................................... 32 
10.4. Serious Adverse Events and Unexpected Adverse Events - Definitions .................................. 32 
10.5. Serious Adverse Events Reporting ........................................................................................... 33 
11. 
STATISTICAL CONSIDERATIONS .....................................................................34 
11.1. Randomization ......................................................................................................................... 34 
11.2. Analysis Populations ................................................................................................................ 34 
11.3. Statistical Analysis ................................................................................................................... 35 
11.3.1 Primary Efficacy Analysis .............................................................................................. 35 
11.3.2 Secondary Analyses ........................................................................................................ 35 
11.4. Safety Analysis ......................................................................................................................... 36 
11.5. Sample Size .............................................................................................................................. 36 
12. 
STUDY TERMINATION ........................................................................................36 
13. 
DATA COLLECTION, RETENTION AND MONITORING .................................36 
13.1. Case Report Forms ................................................................................................................... 36 
13.2. Availability and Retention of Investigational Records ............................................................ 37 
13.3. Subject Confidentiality ............................................................................................................ 37 
13.4. Liability .................................................................................................................................... 37 
13.5. Ethical and Legal Issues ........................................................................................................... 38 
13.5.1. Institutional Review Board .............................................................................................. 38 
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13.6. Informed Consent Form ........................................................................................................... 38 
14. 
INVESTIGATOR RESPONSIBILITIES ................................................................39 
15. 
REFERENCES .........................................................................................................39 
16. 
APPENDIX A – SCHEDULE OF ACTIVITIES ....................................................42 
 
LIST OF FIGURES 
 
Figure 1.  Phase 2a Mean Change from Baseline to Day 28 in CSF biomarkers (±SEM)      11 
Figure 2.  Phase 2b Mean Change from Baseline to Day 28 in CSF biomarkers (±SEM)      12 
Figure 3.  Phase 2b Mean Change from Baseline to Day 28 in Total Errors in Memory Test13 
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1. LIST OF ABBREVIATIONS 
3xTg  
 
 
triple transgenic 
α7nAChR  
 
 
α7 nicotinic acetylcholine receptor 
Aβ42 
 
 
 
amyloid beta1-42 
AChEI  
 
 
acetylcholinesterase inhibitor 
AD 
 
 
 
Alzheimer’s disease 
ADAS-Cog 
 
 
Alzheimer’s Disease Assessment Scale – Cognitive Subscale 
ADCS-ADL 
Alzheimer’s Disease Cooperative Study – Activities of Daily 
Living 
ADME 
 
 
absorption, distribution, metabolism, excretion 
AE 
 
 
 
Adverse Event 
ALT   
 
 
alanine transaminase 
ALP 
 
 
 
alkaline phosphatase 
ANOVA 
 
 
analysis of variance 
AST   
 
 
aspartate transaminase 
AUC  
 
 
area under the curve 
BMI 
 
 
 
Body Mass Index 
BUN  
 
 
blood urea nitrogen 
CDR-GS 
 
 
Clinical Dementia Rating – Global Score 
CDR-SB 
 
 
Clinical Dementia Rating – Sum of Boxes 
CFR 
 
 
 
Code of Federal Regulations 
Cmax  
 
 
maximum plasma concentration 
CRF 
 
 
 
Case Report Form 
CRO  
 
 
Contract Research Organization 
CR-MEMS 
 
 
Child-Resistant Medication Event Monitoring System 
CSF 
 
 
 
cerebrospinal fluid 
CSI 
 
 
 
Cassava Sciences, Inc. 
C-SSRS 
 
 
Columbia-Suicide Severity Rating Scale 
CT 
 
 
 
computerized tomography 
DSM-V 
 
 
Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition 
DSMB  
 
 
Data Safety Monitoring Board 
ECG  
 
 
electrocardiogram 
eCOA  
 
 
electronic Clinical Outcome Assessment 
eCRF  
 
 
electronic Case Report Form 
EDC  
 
 
Electronic Data Capture 
EDTA  
 
 
ethylenediaminetetraacetic acid 
ELISA  
 
 
enzyme-linked immunosorbent assay 
FDA  
 
 
Food and Drug Administration 
FLNA  
 
 
filamin A 
GCP 
 
 
 
good clinical practice 
GDS  
 
 
Geriatric Depression Scale 
GGT   
 
 
gamma glutamyl transpeptidase 
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GLP 
 
 
 
good laboratory practice 
hERG  
 
 
human ether-a-go-go-related gene 
iADRS 
 
 
integrated Alzheimer’s Disease Rating Scale 
IB 
 
 
 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human 
Use 
IR 
 
 
 
insulin receptor 
IRB 
 
 
 
independent review board 
iADRS 
 
 
Integrated Alzheimer’s Disease Rating Scale 
ISLT  
 
 
International Shopping List Test 
LDH   
 
 
lactose dehydrogenase 
LOQ  
 
 
limit of quantitation 
MCI 
 
 
 
mild cognitive impairment 
MMSE 
 
 
Mini-Mental State Examination 
MRI 
 
 
 
magnetic resonance imaging 
mTOR  
 
 
mammalian target of rapamycin 
NIA - AA 
 
 
National Institute on Aging - Alzheimer’s Association 
NMDAR 
 
 
N-methyl D-aspartate receptor 
NOAEL 
 
 
no observable adverse effect level 
NOEL  
 
 
no observable effect level 
NPI 
 
 
 
Neuropsychiatric Inventory 
PAL 
 
 
 
Paired Associate Learning 
PET 
 
 
 
positron emission tomography 
PK 
 
 
 
pharmacokinetics 
PTI-125 
 
 
former name of simufilam 
SavaDx 
 
 
blood-based diagnostic/biomarker candidate 
RBC  
 
 
red blood cell 
SAE 
 
 
 
serious adverse event 
SOP 
 
 
 
standard operating procedure 
Tmax  
 
 
time to Cmax 
ULN  
 
 
upper limit of normal 
WBC  
 
 
white blood cell 
YKL40 
chitinase-like protein 1, a secreted glycoprotein associated with 
inflammation and tissue remodeling 
ZBI 
Zarit Burden Interview  
 
 
 
 
 
 
 
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2. INTRODUCTION 
2.1. MECHANISM OF ACTION 
Cassava Sciences, Inc. is developing simufilam, a novel drug candidate designed to treat 
and slow the progression of Alzheimer’s disease (AD). Simufilam binds with femtomolar 
affinity to an altered conformation of filamin A (FLNA) that is induced by beta amyloid1-
42 (Aβ42), present in AD brain and critical to the toxicity of Aβ42.1-3 Simufilam binding 
reverses the altered FLNA conformation and restores FLNA’s native shape, preventing 
two toxic signaling cascades of Aβ42. Aβ42, in monomer or small oligomer form, hijacks 
the α7-nicotinic acetylcholine receptor (α7nAChR) and signals via this receptor to 
hyperphosphorylate tau. This signaling requires the recruitment of altered FLNA to this 
receptor. In addition, altered FLNA also links to toll-like receptor 4 (TLR4) to allow Aβ42 
to persistently activate this receptor, leading to inflammatory cytokine release and 
neuroinflammation. Normal FLNA does not associate with either α7nAChR or TLR4. In 
addition to disrupting the normal functions of α7nAChR and tau protein, Aβ42’s toxic 
signaling to hyperphosphorylate tau leads to the signature tangles in AD brain. In two AD 
mouse models and in postmortem human AD brain tissue, simufilam restored function of 
three receptors that are impaired in AD: the α7nAChR, the N-methyl-D-aspartate receptor 
(NMDAR), and the insulin receptor (IR).2,3 Simufilam also improved synaptic plasticity 
and reduced tau hyperphosphorylation, amyloid deposits, neurofibrillary tangles and 
inflammatory cytokine release.2,3 We therefore expect simufilam both to improve 
cognition and to slow AD progression. Both mouse models used a dose of 20 mg/kg/day 
(equivalent to 60 mg/m2/day).  
2.2. SAFETY PHARMACOLOGY AND TOXICOLOGY 
A robust nonclinical ADME, safety pharmacology, and general and genetic toxicology 
program has been conducted with simufilam. In vitro metabolic profiling showed minimal 
metabolism across several species including humans. Simufilam was rapidly absorbed and 
eliminated in in vivo studies in rat and dog with nearly 100% oral bioavailability, a 2.67-h 
half-life in dog, dose-proportional PK and no accumulation. Simufilam does not inhibit or 
induce major CYP450 enzymes, nor is a substrate or inhibitor of major human drug 
transporters at clinically relevant concentrations. Safety pharmacology studies showed no 
adverse effects on gross behavioral and physiological parameters in the Irwin test of CNS 
toxicity in rats, no adverse effects on respiratory rate, tidal volume or minute volume in the 
rat respiratory test, and no adverse effects on arterial blood pressure, heart rate and ECG 
parameters in the dog cardiovascular study. The in vitro hERG test for cardiotoxicity also 
indicated no adverse effect. A full battery of genotoxicity studies was conducted (in vitro 
bacterial Ames, in vitro chromosomal aberration, and in vivo rat micronucleus test) and all 
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were negative. An in vitro specificity screen showed no significant activation or inhibition 
of a panel of 68 receptors, channels and transporters. 
Simufilam was tested in single dose and repeat dose oral toxicity studies of up to 6 months 
in rats and 9 months in dogs. A 6-month repeat dose oral toxicity study in rats (PTI-125-
NC-049) used the same doses as a 28-day study (50, 500 and 1000 mg/kg/day), which 
found 500 mg/kg/day to be the no-adverse-effect-level (NOAEL). In the 6-month study, 
the toxicological response was characterized by decreased body weights and adverse 
structural and functional alterations in the liver of 500 and 1000 mg/kg/day animals, 
including increased hepatic weight, hepatocellular hypertrophy and vacuolation, 
single/multiple basophilic/ eosinophilic/clear cell focus, hepatocellular degeneration, 
pigmentation, and oval cell hyperplasia. The presence of bile pigment was consistent with 
cholestasis. These findings correlated with changes to the clinical chemistry profile, 
including increased ALP and total/direct bilirubin. Over the 1-month recovery period, there 
was complete recovery of the hepatocellular degeneration and partial recovery of 
hepatocellular hypertrophy; other microscopic findings in the liver remained. The NOAEL 
in this 6-month study was 50 mg/kg/day (equivalent to 300 mg/m2), corresponding to a 
safety margin of 6- and 1.6-fold based on Cmax and AUC over the 100 mg b.i.d. dose in 
human subjects. A second 6-month repeat dose oral toxicity study in rats determined the 
6-month NOAEL in the rat to be < 125 mg/kg/day, based on hepatocellular vacuolation in 
both sexes and hepatocellular hypertrophy in females at 125 and 250 mg/kg. Additional 
work is planned to evaluate whether these liver effects are rat specific. 
In a 9-month toxicity study in dogs (PTI-125-NC-050), the no-effect-level (NOEL) of 
simufilam was 25 mg/kg. The high dose of 200 mg/kg/day was decreased to 150 mg/kg/day 
after 1 month due to bodyweight loss considered unsustainable for 9 months. Clinical signs 
were slight hypoactivity and incidences of slight muscle fasciculations early in the study, 
and salivation. There were no pathology findings, but the high dose was considered adverse 
due to two unexplained deaths. The 75 mg/kg/day NOAEL (equivalent to 1500 mg/m2) 
provides 38- and 19-fold safety margins based on Cmax and AUC over the 100 mg b.i.d. 
dose in subjects. 
Simufilam showed no mutagenic or clastogenic responses in a standard battery of 
genotoxicity assays. 
2.3. 
CLINICAL STUDIES 
A first-in-human, double-blind, single ascending dose clinical study (PTI-125-01) was 
conducted in healthy normal volunteers, age 18-45 with oral dosing solution. Doses were 
placebo, 50, 100 and 200 mg (equivalent to 31, 62, and 123 mg/m2, respectively) 
administered to three different groups of volunteers. The study showed dose proportional 
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CONFIDENTIAL 
 
PK, a half-life ranging from 4.5 to 6 h, and there were no drug-related adverse events (AEs). 
In a 28-day phase 2a study (PTI-125-03), 13 subjects with mild-to-moderate AD received 
simufilam 100 mg b.i.d. as oral tablets. Subjects had Mini-Mental State Exam (MMSE) 
scores ≥ 16 and ≤ 24, and were age 50-85 with a CSF total tau/Aβ42 ratio ≥ 0.30. A second 
CSF sample was collected on Day 28, allowing assessment of change from baseline in 
biomarkers using commercial ELISA kits. All 8 biomarkers that are elevated in AD were 
significantly reduced from baseline (Fig. 1).4 Aβ42, which is low in AD, was increased 
slightly but non-significantly. Reduced inflammatory cytokines and YKL-40 indicated 
reduced neuroinflammation. A reduced neurodegenerative drive was suggested by 
reductions in neurogranin, neurofilament light chain, and total tau. The robust reduction in 
phospho-tau (P-Tau181) confirms the mechanism of action of simufilam. Simufilam was 
safe and well tolerated in all subjects. 
Figure 1   Phase 2a Mean Change from Baseline to Day 28 in CSF biomarkers (±SEM) 
 
 
 
A phase 2b randomized, placebo-controlled clinical study (PTI-125-02) of simufilam 50 or 
100 mg tablets or placebo (1:1:1) enrolled 64 mild-to-moderate AD subjects with MMSE 
16-26. Both 50 and 100 mg doses significantly improved eleven CSF biomarkers of AD 
pathology, neurodegeneration, neuroinflammation and blood-brain barrier integrity (Fig. 
2). CSF biomarker analyses were conducted blind to treatment and timepoint by an outside 
lab, and screening and Day 28 samples for each subject were measured in triplicate in the 
same ELISA plates. Albumin and immunoglobulin G (IgG) were measured by 
immunoblotting and quantified by densitometric quantitation. These data suggest disease 
modification and replicate Phase 2a results in a well-controlled study. 
 
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Cassava Sciences, Inc. 
Clinical Protocol PTI-125-07 
Simufilam (PTI-125) 
FINAL Version 1.0, JUNE 30, 2021 
 
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CONFIDENTIAL 
 
Figure 2   Phase 2b Mean Change from Baseline to Day 28 in CSF biomarkers (±SEM) 
 
 
The secondary endpoints in the Phase 2b study were two cognitive measures using the 
Cambridge Neuropsychological Test Automated Battery. Subjects were assessed on the 
Paired Associate Learning (PAL) test, measuring episodic memory, and a test of spatial 
working memory. The primary outcome measure for each was total errors, with errors 
imputed for more difficult levels not reached in the PAL test. Simufilam produced 
encouraging effect sizes (calculated by Hedge’s g for group sizes of 20), suggesting 
cognitive enhancement (Fig. 3). Effect sizes versus placebo for the test of episodic memory 
were 0.37 and 0.23 for the 50 and 100 mg groups, respectively, after removing the most 
and least impaired subjects by baseline score. For spatial working memory, effect sizes 
were 0.25 and 0.46 for these respective dose groups. Cognitive enhancement by simufilam 
is supported by preclinical data showing improved function of α7nAChR, NMDAR and 
insulin receptors and improved synaptic plasticity in 3xTg AD mice and in postmortem 
human AD brain tissue.  
In both Phase 2 clinical studies, simufilam was well tolerated and no subjects discontinued 
due to AEs.  
 
 
 
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Clinical Protocol PTI-125-07 
Simufilam (PTI-125) 
FINAL Version 1.0, JUNE 30, 2021 
 
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Figure 3   Phase 2b Mean Change from Baseline to Day 28 in Total Errors in Memory 
Test 
 
3. STUDY OBJECTIVES 
The primary objective of this study is to investigate the safety and efficacy of simufilam 
in slowing cognitive and functional decline following 52-week, repeat-dose oral 
administration in mild-to-moderate AD subjects, 50-87 years of age. Secondary objectives 
include the assessment of simufilam’s effect on neuropsychiatric symptoms and caregiver 
burden. A third objective is to investigate the effect of simufilam treatment on plasma 
biomarkers. 
4. SUMMARY OF STUDY DESIGN 
In this Phase 3 clinical study, approximately 750 subjects with mild-to-moderate AD will 
receive placebo or 100 mg tablets of simufilam, twice daily, for 52 weeks. Randomization 
(1:1) will be stratified by low or high MMSE (16-20 and 21-27). 
 
Subjects, 50-87 years of age, will be selected for screening based on a diagnosis of AD 
consistent with Stages 4 or 5 on the Alzheimer’s continuum (National Institute on Aging – 
Alzheimer’s Association 20185). Subjects must have MMSE ≥ 16 and ≤ 27, and a Clinical 
Dementia Rating Global Score (CDR-GS) of 0.5, 1 or 2. Finally, subjects must have 
confirmed PET or fluid biomarker evidence of AD pathophysiology prior to randomization 
(see Section 5.2 – Inclusion Criteria for details). 
 
Once subjects have been satisfactorily screened for study participation, visits to the 
research clinic will occur on Study Day 1 and at Weeks 4, 16, 28, 40 and 52.   
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CONFIDENTIAL 
 
 
The co-primary endpoints include the 12-item Alzheimer’s Disease Assessment Scale – 
Cognitive Subscale (ADAS-Cog12) and the Alzheimer’s Disease Cooperative Study – 
Activities of Daily Living (ADCS-ADL), both assessed as the change from baseline to the 
end of the double-blind treatment period (Week 52). 
 
Secondary endpoints include the integrated Alzheimer’s Disease Rating Scale (iADRS), 
Neuropsychiatric Inventory (NPI), MMSE, and Clinical Dementia Rating Sum of Boxes 
(CDR-SB). A brief questionnaire assessing caregiver burden, the Zarit Burden Interview 
(ZBI), will be collected as an additional secondary endpoint.  
 
Safety will be evaluated by adverse event monitoring, vital signs, clinical labs, and the 
Columbia Suicide Severity Rating Scale (C-SSRS) at every visit. All subjects will undergo 
MRI during screening to ensure entry criteria are met. ECGs will be conducted Day 1 and 
Weeks 4, 28 and 52. A complete physical and neurological examination will be performed 
at screening, and brief examinations will be performed at all other visits. Weight will be 
measured during the Screening Period, on Study Day 1 and at all other visits.  
 
A limited number of research sites will be invited to participate in the PK and plasma 
biomarker sub-study. Collection of PK samples will enable an exposure-response analysis. 
Approximately 100 subjects will participate (50 per group). Plasma samples will be 
collected during the Screening Visit and again at Weeks 28 and 52. Change from baseline 
for plasma biomarkers represent additional secondary endpoints. 
 
An independent Data Safety Monitoring Board (DSMB) will meet periodically to review 
subject safety assessments and determine if dosing may continue. A charter will be 
developed with specific guidance for the DSMB. 
 
5. SUBJECT SELECTION 
5.1. STUDY POPULATION 
Approximately 750 subjects will be enrolled in the study. 
5.2. INCLUSION CRITERIA 
Each subject must meet the following Inclusion Criteria:  
1. Capable of providing either written informed consent or, if incapable of written 
consent, permission to participate can be obtained from a legally authorized 
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representative. Verbal assent to the study procedures and schedule is required of all 
participants. Genotyping for apolipoprotein E (ApoE) will be included in the informed 
consent, and participants must consent to this to be included in the study. If, in the 
Investigator’s judgment, a subject loses capacity to consent during the duration of the 
study, a legally authorized representative must consent on behalf of the subject. All 
consent processes must be undertaken prior to any study procedures. 
2. Age ≥ 50 and ≤ 87 years at the time of the informed consent, male or female. 
3. Meets National Institute on Aging and Alzheimer's Association (NIA-AA) Research 
Framework criteria (2018) for individuals in clinical Stage 4 or Stage 5 of the 
Alzheimer’s continuum.5   
4. The subject and/or study partner report a gradual and progressive change in memory 
for ≥ 6 months. 
5. Evidence for AD pathophysiology, confirmed either prior to or during the screening 
period prior to randomization, as follows: 
a. Prior to screening, confirmed with appropriate documentation by either: 1) CSF 
total tau/Aβ42 ratio (must be ≥ 0.28), or 2) an abnormal amyloid or tau positron 
emission tomography (PET) scan consistent with AD; or 
b. During screening, subjects must demonstrate an elevated plasma P-tau181 level 
(a research biomarker that identifies AD pathophysiology with high accuracy; 
see lab manual for details). 
6. MMSE score ≥ 16 and ≤ 27 at screening. 
7. CDR-GS must be 0.5, 1 or 2.  
8. If female, either surgically sterile or postmenopausal for at least 1 year. 
9. Male subjects must be willing to use contraception during the study. With female 
partners of childbearing potential, male subjects, regardless of their fertility status, must 
agree to either remain abstinent or use condoms in combination with one additional 
highly effective method of contraception (e.g., oral or implanted contraceptives, or 
intrauterine devices) or an effective method of contraception (e.g., diaphragms with 
spermicide or cervical sponges) during the study and for 14 days after study drug dosing 
has been completed. 
10. Fluency in a language of the research site and the utilized assessment materials. 
11. Has adequate visual and auditory acuity (in the Investigator’s judgment) that is 
sufficient to complete all scheduled assessments (eyeglasses and hearing aids are 
permitted). 
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12. If receiving background AD medications, including cholinesterase inhibitors, 
memantine, neuroleptics, antidepressants, anxiolytics, or sleep medications, the dosing 
regimen must be stable for at least 12 weeks prior to Study Day 1 (randomization) and 
should be expected to remain stable during the study (Note – barbiturates, 
meprobamate, and high dose benzodiazepines are not allowed, while low dose 
benzodiazepines, zolpidem, zaleplon and suvorexant are permitted).  
13. The subject has not been a smoker or chewed tobacco for at least 3 years.  
14. Availability of a person (a study partner) who, in the Investigator's opinion, has 
frequent and sufficient contact with the study subject (defined as ≥ 10 hours per week), 
and can: 
a. provide accurate information regarding the study subject's cognitive and 
functional abilities,  
b. agree to comply with and participate at all scheduled visits and study 
procedures,  
c. sign the necessary consent form,  
d. maintain the same level of interaction with the study subject throughout the 
study duration. 
15. Individuals who have participated in a clinical study with an investigational drug 
targeting the underlying AD process are permitted to participate in this study on a case-
by-case basis after consultation between the Principal Investigator and the Sponsor 
(subjects known to have been randomized to placebo do not require such consultation 
and are permitted to participate). 
5.3. EXCLUSION CRITERIA 
Subjects meeting any of the following criteria will be excluded from the study: 
1. Residence in a skilled nursing facility requiring 24-hour care (Note – subjects may 
reside in an assisted living facility if they do not need 24-hour care). 
2. Any contraindications to study procedures (e.g., potential subjects having a pacemaker 
must be excluded due to the required MRI during screening). 
3. BMI < 18.5 or > 35.0. 
4. Evidence of a neurologic condition other than AD that, in the judgment of the 
Investigator, significantly contributes to the subject’s dementia, including, but not 
limited to, frontotemporal dementia, dementia with Lewy bodies, Parkinson's disease, 
corticobasal degeneration, Creutzfeldt-Jakob disease, progressive supranuclear palsy, 
Huntington's disease, or normal pressure hydrocephalus. 
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5. Subjects with any current primary psychiatric diagnosis other than AD if, in the 
judgment of the Investigator, the psychiatric disorder or symptom is likely to confound 
interpretation of drug effect, affect cognitive assessment, or affect the subject’s ability 
either to comply with study procedures or to complete the study.  Patients with a history 
of schizophrenia or chronic psychosis are excluded.  
6. Geriatric Depression Scale (15-item) score > 8. 
7. Affirms suicidal ideation in response to questions number 4 or 5 in the C-SSRS during 
the past 3 months (i.e., “active suicidal ideation with some intent to act, without specific 
plan,” or “active suicidal ideation with specific plan and intent”) or affirms any of the 
questions contained in the Suicidal Behavior section of the C-SSRS as applicable 
during the past 12 months.  
8. Meets DSM-V criteria for alcohol or substance use disorder within 2 years before the 
Screening Period. 
9. MRI presence of cerebral vascular pathology (including, but not limited to, 
hemorrhage, infarct > 1 cm3, or > 3 lacunar infarcts), cerebral contusion, symptomatic 
subdural hematoma, aneurysm, or space-occupying lesion deemed clinically significant 
in the opinion of the Investigator. 
10. History of transient ischemic attack (TIA) or stroke within 12 months of screening, or 
history of a stroke concurrent with the onset of dementia. 
11. History of seizure within 12 months of screening. 
12. History of severe head trauma; history of head trauma with loss of consciousness > 10 
min within 12 months of screening; history of head trauma concurrent with the onset 
of dementia; history of head trauma likely to be contributing to the subject’s cognitive 
impairment in the Investigator’s judgment. 
13. Onset of dementia secondary to cardiac arrest, surgery with general anesthesia, or 
resuscitation. 
14. Clinically significant, untreated or inadequately treated sleep apnea that is likely to be 
contributing to the subject’s cognitive impairment in the Investigator’s judgment. 
15. Insufficiently controlled diabetes mellitus, defined as: 
a. requiring insulin treatment (unless subject has been stable for at least 4 weeks 
prior to screening on a once-daily dose of long-acting insulin), or 
b. HbA1C > 8.0% during the Screening Period. 
16. Malignant tumor within 3 years before screening (except definitively treated squamous 
or basal cell carcinoma, cervical carcinoma in situ, localized non-progressive prostate 
cancer, localized stage 1 bladder cancer or colon polyp resolved by excision, per 
judgment of the Investigator). 
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17. Known positive HIV status. 
18. Positive HBsAg or HCV-Ab during screen. 
19. Positive urine drug screen for substances of abuse. 
20. Vitamin B12 level lower than the normal limit at the time of screening (and that remains 
below on repeat testing).  Subjects may be enrolled following initiation of B12 therapy 
for at least 4 weeks prior to randomization with confirmation of a normal level upon 
repeat testing. 
21. Thyroid-stimulating hormone (TSH) levels greater than the upper limit of normal and 
a free thyroxine (free T4) lower than the lower limit of normal; subjects on thyroid 
supplementation for hypothyroidism must be on a stable dose for ≥ 3 months before 
screening. 
22. Alanine transaminase (ALT) or aspartate transaminase (AST) ≥2x the upper limit of 
normal (ULN), total bilirubin ≥1.5x ULN, or alkaline phosphatase (ALP) ≥1.5 ULN at 
screening (Note – subjects with elevated total bilirubin are not excluded if they meet 
criteria for Gilbert’s syndrome, including: bilirubin is predominantly indirect [with 
normal direct bilirubin level]; and ALT, AST and ALP ≤1x ULN). 
23. History or diagnosis of clinically significant ischemic heart disease (e.g., myocardial 
infarction or unstable angina within 1 year of screening), moderate to severe congestive 
heart failure, cardiomyopathy, myocarditis or valvular heart disease of clinical 
significance in the Investigator’s judgment. 
24. History of or current clinically significant cardiac arrhythmia or heart block as 
evidenced by ECG in the judgment of the Investigator. 
25. Clinically significant abnormality on screening electrocardiogram (ECG), including, 
but not necessarily limited to, a confirmed QT interval by the Fridericia correction 
formula (QTcF) > 470 msec (females) or > 450 msec (males) based on WHO 2016 
guidelines. 
26. Insufficiently controlled hypertension (defined, at rest, as systolic BP > 160 mmHg or 
diastolic BP > 100 mmHg; if an initial BP reading is elevated, an additional 
measurement during the Screening Period could be used before excluding a potential 
subject for insufficiently controlled hypertension). 
27. Hypotension (systolic BP < 90 mmHg) or bradycardia with a heart rate less than 50 
beats per minute during screening (out of range values may be repeated once for 
confirmation). 
28. Use of medications that in the Investigator’s opinion will contribute to cognitive 
impairment, put the subject at higher risk for AEs, or impair the subject’s ability to 
perform cognitive testing or other study procedures. 
29. Donepezil > 10 mg/day, currently or within 12 weeks of Study Day 1 (randomization).  
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30. Discontinued AChEI < 12 weeks prior to randomization. 
31. Administration of aducanumab, either currently or previously prescribed (Note – 
administration of aducanumab at any point during this clinical study is prohibited). 
32. Antipsychotics (Note – low doses are allowed only if given for sleep disturbances, 
agitation, aggression or dementia-related psychosis, and only if the dose has been stable 
for at least 4 weeks prior to screening). 
33. Tricyclic antidepressants and monoamine oxidase inhibitors if prescribed within 4 
weeks prior to screening; all other antidepressants are allowed only if the dose has been 
stable for at least 4 weeks prior to screening. 
34. Immunosuppressants, including systemic corticosteroids, if taken in clinically 
immunosuppressive doses (steroid use for allergy or inflammation is permitted). 
35. Use of antiepileptic medications if taken for control of seizures (Note – use of 
antiepileptic medications are allowed if used for mood stabilization). 
36. Chronic intake of opioid-containing analgesics. 
37. Use of prescribed sedating H1 antihistamines. 
38. Use of nicotine therapy (all dosage forms including a patch), varenicline (Chantix), or 
similar therapeutic agent within 4 weeks prior to screening. 
39. Loss of a significant volume of blood (> 450 mL) within 4 weeks of randomization. 
40. COVID-19 infection within 3 months of screening (Note – the subject must be fully 
vaccinated for COVID-19 at least two weeks prior to Study Day 1 [randomization] if 
there is no history of a prior COVID-19 infection).  
41. Clinically significant abnormalities on screening laboratory tests in the judgment of the 
Investigator. 
42. Unstable medical condition that is clinically significant in the judgment of the 
Investigator, including significant neurologic, hepatic, renal, endocrinologic, 
cardiovascular, gastrointestinal, pulmonary, hematologic, immunologic or metabolic 
disease.  
43. Any other medical or neurological condition (other than Alzheimer’s disease), that, in 
the opinion of the Investigator, might represent a contributing cause to the subject’s 
cognitive impairment, or affect cognitive assessment, subject safety, ability to comply 
with study assessments, drug compliance and completion of the study. 
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6. STUDY DRUG 
6.1. SIMUFILAM PHYSICAL DESCRIPTION AND PREPARATION 
Investigational simufilam (100 milligram active strength) and matching placebo will 
be supplied by Cassava as coated tablets.   
All remaining unused simufilam study drug will be returned to the Sponsor or 
designee. 
6.1.1. Packaging and Labelling 
Simufilam or placebo tablets in plastic bottles will be supplied in 70-count bottles for 
a 4-week supply or 188-count bottles for a 12-week supply. Bottles include a desiccant 
canister and are closed with a foil seal and child-resistant (CR) cap. Each bottle contains 
7 or 10 days of extra medication to accommodate scheduling flexibility with clinic 
visits.   
 
A Medication Event Monitoring System (MEMS®) that is 21 CFR Part 11 compliant 
will be used to track adherence to the b.i.d. dosing schedule. CR-MEMS® caps will be 
supplied to replace the conventional CR cap on each bottle. One (1) CR-MEMS cap 
will be assigned to each subject for use throughout the study. Each CR-MEMS cap has 
an LCD display that provides immediate visual indication of the number of doses taken 
that day and the number of hours since the prior dose that day, resetting to zero each 
night. Instructions on management and use of CR-MEMS caps will be provided in the 
Pharmacy manual and during site training. 
 
Each bottle is labeled with a unique double-blind ID number that is randomly assigned 
to a treatment. A computer-based clinical study management system will specify the 
bottle ID number to be dispensed according to the subject’s treatment randomization. 
 
6.1.2. Storage 
The investigational drug supplies must be stored in a locked cabinet or room with 
limited access at controlled room temperature, 20-25º C (68-77º F) and protected from 
moisture.  
6.1.3. Drug Accountability 
The Investigator will be responsible for monitoring the receipt, storage, dispensing 
and accounting of all study medications according to site standard operating 
procedures (SOPs). All records documenting the chain of custody for the study 
medication must be retained in the site study file. Accurate, original site records 
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must be maintained of drug inventory and dispensing. All records must be made 
available to the Sponsor (or designee) and appropriate regulatory agencies upon 
request. 
6.2. ADMINISTRATION AND DOSING REGIMEN 
Subjects will be randomized to receive placebo or 100 mg simufilam twice daily 
(b.i.d.). Study drug should be taken at least 1 h before or after a meal. 
6.3. CONCOMITANT MEDICATIONS 
Use of prescription or non-prescription medications will be recorded during the study. 
Chronic medications must be stable for 4 weeks prior to screening [Note – see Inclusion 
Criterion #12 and Exclusion Criteria #29 and #30 for additional details regarding 
background medications frequently prescribed to patients with AD].   
7. STUDY PROCEDURES 
Appendix A presents the Schedule of Activities. 
Prior to any study-related activities, the Informed Consent Form (ICF) must be signed 
and dated by the subject (or a legally authorized representative) and the study partner.  
The format and content of the ICF must be agreed upon by the Principal 
Investigator(s), the appropriate IRB and the Sponsor. The signed and dated ICF must 
be retained by the Investigator in the subject's file. 
 
7.1. 
EVALUATIONS BY VISIT 
Follow-up visits can be scheduled +/- five (5) days from the targeted Study Visit date.  
 
7.1.1. Screening Period (No greater than a 60-day duration prior to Study Day 1) 
The Sponsor recognizes the Screening Period assessments and procedures may not 
necessarily be completed in a single visit. A subject is permitted to be screened over 
more than one calendar day if, in the Investigator’s judgment, such scheduling will 
optimize the accuracy of Screening Period assessments and procedures.  The following 
will be completed during the Screening Period: 
• Informed Consent.  
• Review of Inclusion and Exclusion Criteria 
• Collect demographic information (e.g., sex, date of birth, race/ethnicity, years 
of education) 
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• Medical and surgical history  
• Review concomitant medications, and any discontinued medications, in the 4 
weeks prior to screening. 
• To the extent such information is available, review and record any 
investigational drugs administered during past clinical study participation 
regardless of the date of such participation. 
• History of drug, alcohol and tobacco use  
• eCOA order of administration at screening: 
• MMSE 
• CDR  
• Geriatric Depression Scale 
• C-SSRS – Baseline/screening version  
• Complete physical and neurologic examination; including measurement of 
key vital signs (blood pressure [supine], temperature, pulse rate), height and 
weight (to calculate BMI) 
• A 12-lead ECG (5-min supine) 
• Laboratory assessments, including routine serum chemistry, TSH, free T4, 
Vitamin B12 levels, HBsAg, HCV-Ab, hematology, urinalysis and urine screen 
for drugs of abuse. Plasma for P-tau181 assessment will also be collected 
unless there is documented evidence of AD pathophysiology prior to screening. 
• Once the clinical and laboratory assessments above have been completed and 
verified to be consistent with study participation, schedule brain MRI to 
confirm subject meets MRI-specific entry criteria (Note – previous brain MRI 
results, with appropriate documentation, will be accepted for up to 6 months 
prior to the Study Day 1 Visit unless a recent clinical event warrants a repeat 
scan). 
• Subjects participating in the PK and plasma biomarker sub-study (100 total; 50 
subjects/group) will have, in addition to the blood collection during the 
Screening Period, subsequent blood collections at Weeks 28 and 52. 
7.1.2. Rescreening of a Subject 
Individuals who have given informed consent and fail to meet the Inclusion and/or 
Exclusion criteria (screen failure) may not be rescreened if the screen failure is due to 
non-eligible MMSE (<16), MRI or P-tau181 results.  If screen failure occurs for the 
following reasons, then the subject is allowed one rescreen:  
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• Low vitamin B12 requiring supplemental therapy (can rescreen after 4 weeks) 
• MMSE of 28 (can rescreen after 8 weeks) 
Other reasons for screen failure will require Sponsor approval to rescreen.   
7.1.3. Study Day 1 (Dosing Initiation) 
Subjects will come to the clinic in the morning. Prior to dosing, the following 
assessments will be conducted: 
• Confirmation of Inclusion/Exclusion criteria 
• Confirm subject has been fully vaccinated for COVID-19 for at least two weeks 
if there is no history of a prior COVID-19 infection 
• Review of concomitant medications 
• Adverse Event Monitoring 
• Vital signs (blood pressure [supine], temperature, pulse). 
• Weight 
• Brief physical and neurologic examination (Note: the brief physical and 
neurologic examination performed on Study Day 1 and at all subsequent visits 
will include an assessment of the following: general appearance; 
cardiovascular, pulmonary, and abdominal examination, as well as an 
examination of any other system in response to subject-reported symptoms; 
cranial nerves [II-XII], tone, power, deep tendon reflexes, coordination and 
gait) 
• Clinical laboratory tests (blood and urine) 
• eCOA order of administration: 
• 
ADAS-Cog12  
• 
ADCS-ADL 
• 
NPI 
• 
ZBI  
• 
C-SSRS – Since Last Visit version 
• ECG 
• Genotyping for ApoE  
 
Once all Study Day 1 procedures and assessments have been completed, the subject is 
randomized to a treatment and the bottle of Study Drug to be dispensed is assigned by 
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Cassava Sciences, Inc. 
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the computer-based study management system.  A child-resistant Medication Event 
Monitoring System (CR-MEMS®) cap is drawn from stock for permanent assignment 
to the subject and initialized via the computer interface. Before removing Study Drug 
from the bottle, remove the original closure and apply the CR-MEMS cap as a 
replacement. Just prior to administering the first dose of Study Drug, remove the CR-
MEMS cap and remove one (1) tablet. 
Subjects will be administered Study Drug at least 1 hour before leaving the clinic and 
at least 1 hour before or after a meal. The subject will be discharged with their supply 
of Study Drug. The study partner will be trained on the features and proper use of the 
CR-MEMS cap and instructed to administer Study Drug twice daily at least 1 h before 
or after a meal. The study partner should be advised that a dose can be up to 4 h late, 
but, if a dose is missed, the next dose should NOT be doubled. 
Information and instruction for the computer-based study management system, and the 
CR-MEMS cap will be covered during site training, and written reference information 
will be included in the pharmacy manual.   
For all follow-up visits, subjects will be instructed to come to the clinic in the morning 
and to bring their Study Drug bottle to the clinic. At each visit the CR-MEMS cap will 
be read into the computer-based study management system to inform the site about the 
subject’s Study Drug adherence. The CR-MEMS cap will be removed from the returned 
bottle and applied to the newly dispensed bottle of Study Drug.  
7.1.4. Weeks 4, 16 and 40 Follow-up Visits 
Subjects will return to clinic for these scheduled visits within a ± 5-day “window.” 
• 
Vital signs (blood pressure [supine], temperature and pulse) 
• 
Weight  
• 
Brief physical and neurologic examination  
• 
Adverse event monitoring 
• 
Use of concomitant medications 
• 
eCOA order of administration:  
• 
ADAS-Cog12 (whenever possible, within 1 h of the time of day 
administered at the Study Day 1 Visit, and by the same rater) 
• 
ADCS-ADL 
• 
ZBI 
• 
C-SSRS – Since Last Visit version 
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• Clinical laboratory tests (blood and urine) 
• Resting ECG (only at Week 4) 
7.1.5. Weeks 28 Follow-up Visit 
Subjects will return to clinic for these scheduled visits within a ± 5-day “window.” 
• 
Vital signs (blood pressure [supine], temperature and pulse) 
• 
Weight 
• 
Brief physical and neurologic examination 
• 
Adverse event monitoring 
• 
Use of concomitant medications 
• 
eCOA order of administration:  
• 
ADAS-Cog12 (whenever possible, within 1 h of the time of day 
administered at the Study Day 1 Visit, and by the same rater) 
• 
ADCS-ADL 
• 
MMSE 
• 
NPI 
• 
ZBI 
• 
C-SSRS – Since Last Visit version 
• 
Clinical laboratory tests (blood and urine) 
• 
For those 100 subjects participating in the PK and plasma biomarker sub-
study, collect their Week 28 blood samples 
• 
Resting ECG 
7.1.6. Week 52 End-of-Treatment Visit / Early Termination (ET) Visit 
Subjects will return to clinic for this scheduled visit within a ± 5-day “window.” 
• Vital signs (blood pressure [supine], temperature and pulse) 
• Weight 
• Brief physical and neurologic examination 
• Adverse Event monitoring 
• Use of concomitant medications 
• eCOA order of administration:  
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• 
ADAS-Cog12 (whenever possible, within 1 h of the time of day 
administered at the Study Day 1 Visit, and by the same rater) 
• 
ADCS-ADL 
• 
MMSE 
• 
CDR 
• 
NPI 
• 
ZBI 
• 
C-SSRS – Since Last Visit version 
• Clinical laboratory tests (blood and urine) 
• For those 100 subjects participating in the PK and plasma biomarker sub-study, 
collect their Week 52 blood samples 
• Resting ECG 
Note: Early Termination subjects do not need to complete the electronic Clinical 
Outcome Assessments if performed within 30 days of the ET Visit (see Section 9 – 
Early Discontinuation) 
7.1.7. Week 53-54 End-of-study Follow-up  
The subject will receive a follow-up phone call 7-14 days after the last dose for adverse 
event monitoring. If needed, a follow-up clinic visit will be scheduled. 
7.1.8. Treatment after Study Completion 
The Sponsor plans to initiate an open-label extension study for subjects who have 
completed participation in Study PTI-125-07. Should a subject elect to participate in 
the open-label extension study, the End-of-Study Follow-up (Section 7.1.7) will not be 
conducted. 
7.1.9. Unscheduled Visits and Discontinuation due to AEs 
For unscheduled visits due to AEs, any assessments conducted will be at the discretion 
of the Investigator and pertinent to the AE. If a decision is made to discontinue the 
subject from study drug, the Sponsor will be notified immediately. The subject should 
be followed and treated by the Investigator until the AE has resolved or stabilized (see 
Section 10.1 – Adverse Events).  Restarting the subject on study drug will be a mutual 
decision by the Investigator and the Sponsor. See also Section 9.0 – Early 
Discontinuation. 
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7.1.9    Stopping Criteria 
Liver chemistry threshold stopping criteria have been designed to ensure subject safety 
and to evaluate liver event etiology during administration of study drug. Potential 
discontinuation of study drug for abnormal liver function tests should be considered by 
the Investigator in consultation with the designated medical monitor if the study subject 
meets one or more of the following criteria: 
• ALT or AST ≥ 4x ULN; 
• ALT or AST ≥ 3x ULN and total bilirubin ≥ 2x ULN; 
• ALT or AST ≥ 3x ULN if associated with the appearance or worsening of 
fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash 
and/or eosinophilia; or 
• ALP elevations, if deemed of liver origin and drug-related as follows: 
o ALP > 3x ULN; 
o ALP > 2.5x ULN and total bilirubin > 2x ULN; or 
o ALP > 2.5x ULN if associated with the appearance or worsening of 
fatigue, nausea, vomiting, right upper quadrant pain or tenderness, 
fever, rash and/or eosinophilia. 
 
In the event of discontinuation due to abnormal liver function tests, the subject will be 
appropriately investigated to determine the potential cause and referred to a physician 
experienced in the treatment of hepatic disorders. 
 
Study drug should be discontinued if a subject: (1) positively affirms suicidal ideation in 
response to questions number 4 or 5 in the suicidal ideation section of the C-SSRS, or (2) 
reports any suicidal behavior or non-suicidal self-injurious behavior since their last visit in 
response to the C-SSRS Suicidal Behavior questions. 
 
Bodyweight loss of ≥ 2 kg resulting in a BMI < 18.5 is an additional stopping criterion. 
 
7.2. 
LABORATORY ASSESSMENTS 
7.2.1. Clinical Laboratory Tests 
The following clinical laboratory tests will be performed during the Screening Period, 
Study Day 1 pre-dose, and at all follow-up visits: 
 
• Hematology:  white blood cell (WBC) count with differential, red blood cell 
(RBC) count, hemoglobin, hematocrit, platelet count. 
• Serum Chemistry:  glucose, sodium, potassium, chloride, bicarbonate, calcium, 
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phosphate, blood urea nitrogen (BUN), total bilirubin, creatinine,  albumin, 
globulin, total protein, uric acid, alkaline phosphatase (ALP), 
alanine 
transaminase 
(ALT), 
aspartate transaminase 
(AST), 
gamma 
glutamyl 
transpeptidase (GGT), lactose dehydrogenase (LDH). 
• Urinalysis: color, specific gravity, pH, protein, glucose, ketones and occult blood. 
• Screening Period:  During the Screening Period only, bloods will be drawn for TSH, 
free T4, Vitamin B12, HepBsAg, HCV-Ab and plasma P-tau181 (Note – plasma 
collection for P-tau181 not required if subject has documented evidence of AD 
pathophysiology prior to screening).  Urine to screen for drugs of abuse 
(amphetamines, cocaine, opiates and phencyclindine) will also be collected during 
the Screening Period. 
7.2.2. Collection of Whole Blood Samples for ApoE Genotyping   
Whole blood samples for genotyping ApoE will be collected on Study Day 1 (please 
review instructions as per lab manual). 
7.2.3. Preparation of Samples from PK and Plasma Biomarker Sub-study Participants  
At each blood collection for PK and biomarkers, blood samples will be drawn into a 
Vacutainer® tube (10 mL per tube) containing K2EDTA. The tubes will be placed on 
ice. Within 30 min of collection, the blood will be centrifuged at approximately 1000 
X G for 15 min, preferably at 4-5°C. Within 30 min of centrifuging, plasma will be 
transferred to polypropylene tubes, and stored at -70°C until shipped to the central lab 
(complete instructions as per lab manual).  
8. COGNITIVE AND FUNCTIONAL ASSESSMENTS 
8.1. 
MINI-MENTAL STATE EXAM (MMSE) 
The MMSE6 is a set of standardized questions covering several target areas: orientation, 
registration, attention and calculation, short-term verbal recall, naming, repetition, 3-
step command, reading, writing, and visuospatial cognitive assessment. Administration 
of the MMSE is estimated to take approximately 10 minutes. 
8.2. 
CLINICAL DEMENTIA RATING (CDR) 
Washington University’s CDR7 characterizes six domains of cognitive and functional 
performance applicable to AD and related dementias: memory, orientation, judgment 
and problem solving, community affairs, home and hobbies, and personal care. The 
study partner is interviewed first by a qualified rater who assesses all six domains. The 
subject is then interviewed in the absence of the caregiver. A CDR global score can be 
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calculated 
by 
accessing 
Washington 
University’s 
online 
algorithm 
(https://biostat.wustl.edu/~adrc/cdrpgm/index.html) where 0 = no dementia, and scores 
of 0.5, 1, 2, or 3 = questionable, mild, moderate, or severe dementia, respectively.  The 
sum of boxes (i.e., CDR-SB)8 can also be calculated by summing the six individual 
domain scores. This detailed quantitative general index may provide more information 
than the CDR-GS in patients with mild dementia.  
8.3. 
ALZHEIMER’S DISEASE ASSESSMENT SCALE – COGNITIVE SUBSCALE 12 (ADAS-
COG12) 
The ADAS-Cog9,10 is a psychometrician-administered battery comprised of several 
cognitive domains including memory, comprehension, praxis, orientation, and 
spontaneous speech. The ADAS-Cog12 (which includes Delayed Word Recall) will be 
administered to all subjects at various key visits throughout the study. 
8.4. 
NEUROPSYCHIATRIC INVENTORY (NPI)  
A study partner interview, the 12-item NPI11 records frequency and severity of common 
neuropsychiatric 
symptoms 
in 
dementia 
(Hallucinations, 
Delusions, 
Agitation/aggression, Dysphoria/depression, Anxiety, Irritability, Disinhibition, 
Euphoria, Apathy, Aberrant motor behavior, Sleep, and nighttime behavior change, 
Appetite and eating change). The study partner is then asked to rate their own distress 
for the subject’s behavioral symptoms occurring in the past 4 weeks.  
8.5. 
ALZHEIMER’S DISEASE COOPERATIVE STUDY – ACTIVITIES OF DAILY LIVING 
(ADCS-ADL-AD) 
The ADCS-ADL12 is a 23-item study partner questionnaire that covers both basic 
activities of daily living (ADL) (e.g., eating and toileting) and more complex ADL or 
instrumental ADL (e.g., using the telephone, managing finances, preparing a meal). 
8.6. 
COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS) 
The C-SSRS13 is an assessment tool used to assess the lifetime suicidality of a subject 
(C-SSRS at baseline) as well as any new instances of suicidality (C-SSRS since last 
visit). 
8.7. 
ZARIT BURDEN INTERVIEW (ZBI) 
The ZBI14,15 is a 22-item scale designed to assess the stress or burden experienced by 
caregivers of people with dementia. The ZBI will be administered as an interview with 
the caregiver. The scale consists of 22 statements reflecting how people can feel when 
taking care of another person. The statements are phrased as questions for the caregiver 
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to indicate how often they feel the way described in the statement. The 5 possible 
responses for each item are Never, Rarely, Sometimes, Quite Frequently, and Nearly 
Always.  
8.8. 
GERIATRIC DEPRESSION SCALE (GDS) 
The GDS16 is a 30-item yes/no question test designed to screen for depression in elderly 
persons. The GDS short form (15-items)17 version utilized in this study will be clinician 
administered with caregiver input. Subjects will be evaluated for symptoms of 
depression during the Screening Period.  
8.9. 
ELECTRONIC CAPTURE OF RATING SCALES 
The assessments MMSE, CDR, ADAS-Cog12, GDS, NPI, ADCS-ADL, C-SSRS, and 
ZBI will be captured electronically by an eCOA platform that is 21 CFR Part 11 
compliant. Data collected by eCOA will be transferred directly to the EDC vendor’s 
database.   
9. EARLY DISCONTINUATION 
Subjects may choose to discontinue study drug or study participation at any time, for 
any reason, and without prejudice. Moreover, a subject may be withdrawn at any time 
at the discretion of the Investigator or Sponsor for safety, behavioral or administrative 
reasons. Discontinued subjects should be followed according to medical practice 
standards, and the outcome documented. Follow-up is required if the subject is 
discontinued due to an adverse event (AE). Any comments (spontaneous or elicited) or 
complaints made by the subject and the reason for termination and the date of stopping 
the drug must be recorded in the Case Report Form (CRF) and source documents.  
The following must be completed and documented in the source documents and 
CRFs for all subjects who discontinue the study early: 
• The reason for early study discontinuation.  If the subject is withdrawn for more than 
one reason, each reason should be documented in the source documents and the 
most clinically relevant reason should be entered on the CRF. 
• Vital signs (blood pressure, temperature and pulse), brief physical and neurologic 
examination, weight, clinical laboratory tests, ECG, use of concomitant 
medications and adverse events should be obtained at discharge prior to release. 
• Blood draw for plasma biomarkers 
• ADAS-Cog, MMSE, CDR, ADCS-ADL, NPI, ZBI and C-SSRS (as detailed in 
Section 7.1.6 – Early Termination Visit), if not performed within the last 30 days. 
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10. ADVERSE EVENTS/SERIOUS ADVERSE EVENTS  
10.1. 
ADVERSE EVENTS - DEFINITION 
An Adverse Event (AE) is any undesirable event that occurs to a subject during a study, 
whether or not that event is considered study drug-related. Monitoring for AEs will start 
at dosing. Examples include: 
• Any treatment-emergent signs and symptoms (events that are marked by a change 
from the subject's baseline/entry status [e.g., an increase in severity or frequency of 
pre-existing abnormality or disorder]) 
• All reactions from study drug, an overdose, abuse of drug, withdrawal phenomena, 
sensitivity or toxicity to study drug 
• Apparently unrelated illnesses 
• Injury or accidents (Note: if a medical condition is known to have caused the injury 
or accident, the medical condition and the accident should be reported as two separate 
medical events [e.g., for a fall secondary to dizziness, both "dizziness" and "fall" 
should be recorded separately]) 
• Extensions or exacerbations of symptoms, subjective subject-reported events, new 
clinically significant abnormalities in clinical laboratory, physiological testing or 
physical examination 
 
All AEs, whether or not related to the study drug, must be fully and completely 
documented on the AE page of the CRF and in the subject's clinical chart. 
In the event that a subject is withdrawn from the study because of an AE, it must be 
recorded on the CRF as such. The subject should be followed and treated by the 
Investigator until the abnormal parameter or symptom has resolved or stabilized. 
The Investigator must report all directly observed AEs and all spontaneously reported 
AEs. The Investigator will ask the subject a non-specific question (e.g., "Have you 
noticed anything different since your dose of the study medication?") to assess whether 
any AEs have been experienced since the last assessment. AEs will be identified and 
documented in the Electronic Data Capture (EDC) system in appropriate medical 
terminology. The severity and the relationship to the study drug will be determined and 
reported in EDC (see below). 
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10.2. ADVERSE EVENTS - SEVERITY RATING 
The severity of each AE should be characterized and then classified into one of three 
clearly defined categories as follows: 
• Mild – the AE does not interfere in a significant manner with the subject's normal 
functioning level. It may be an annoyance. 
• Moderate – the AE produces some impairment of functioning but is not hazardous 
to health. It is uncomfortable or an embarrassment. 
• Severe – the AE produces significant impairment of functioning or incapacitation 
and is a definite hazard to the subject's health. 
These three categories are based on the Investigator's clinical judgment, which in turn 
depends on consideration of various factors such as the subject's report and the physician's 
observations. The severity of the AE should be recorded in the appropriate section of the 
EDC. 
10.3. ADVERSE EVENTS – RELATIONSHIP TO STUDY   DRUG 
The relationship of each AE to the study drug will be classified into one of three defined 
categories as follows: 
• Unlikely –  a causal relationship between the AE and the study drug is unlikely. 
• Possible –  a causal relationship between the AE and the study drug is possible. 
• Probable – a causal relationship between the AE and the study drug is probable. 
For example, the AE is a common adverse event known to occur with the 
pharmacological class of the study drug; or the AE abated on study drug 
discontinuation and reappeared upon rechallenge with the study drug. 
These three categories are based on the Investigator's clinical judgment, which in turn 
depends on consideration of various factors such as the subject's report, the timing of 
the AE in relationship to study drug administration/discontinuation, the physician's 
observations and the physician's prior experience. The relationship of the AE to the study 
drug will be recorded in the appropriate section of the EDC. 
10.4. SERIOUS ADVERSE EVENTS AND UNEXPECTED ADVERSE EVENTS - DEFINITIONS 
A Serious Adverse Event (SAE) includes (but is not limited to) an experience occurring 
at any dose that results in any of the following outcomes: 
• Death 
• A life-threatening event (i.e., the subject is at immediate risk of death from the 
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reaction as it occurs). "Life-threatening" does not include an event that, had it 
occurred in a more serious form, might have caused death. For example, drug­ 
induced hepatitis that resolved without evidence of hepatic failure would not be 
considered life-threatening even though drug-induced hepatitis can be fatal. 
• In-patient hospitalization (hospital admission, not an emergency room visit) or 
prolongation of existing hospitalization. 
• A persistent or significant disability/incapacity (i.e., a substantial disruption of 
the subject's ability to carry out normal life functions). 
• A congenital anomaly/birth defect. 
 
In addition, medical and scientific judgment should be exercised in deciding whether 
other situations should be considered an SAE (i.e., important medical events that may 
not be immediately life-threatening or result in death but may jeopardize the subject or 
may require medical or surgical intervention to prevent one of the other outcomes listed 
in the definition above). Examples of such medical events include (but are not limited 
to): allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in in-patient hospitalization, or 
the development of drug dependency or drug abuse. 
An unexpected AE is one for which the specificity or severity is not consistent with the 
current Investigator's Brochure. For example, hepatic necrosis would be unexpected (by 
virtue of greater severity) if the Investigator's Brochure listed only elevated hepatic 
enzymes or hepatitis. 
Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by 
virtue of greater specificity) if the Investigator's Brochure listed only cerebral vascular 
accidents. 
10.5. SERIOUS ADVERSE EVENTS REPORTING 
The reporting of SAEs by the Sponsor to regulatory authorities (e.g., FDA) is a 
regulatory requirement. Each regulatory agency has established a timetable for 
reporting SAEs based upon established criteria.  Likewise, it is the responsibility of 
the Principal Investigator to report SAEs to the IRB. 
All SAEs must be reported immediately (within 24 h of learning of the event) by e-
mail to: 
Premier Research Global Pharmacovigilance 
 
 
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Do not delay reporting a suspected SAE to obtain additional information.  Any 
additional information, if collected, can be reported to the Sponsor as a follow-up to 
the initial report. 
SAEs must be immediately reported to the responsible IRB. 
In the case of a death or other SAE that has occurred within 30 days after receiving 
study drug, the Principal Investigator must also report such an event within 24 hours 
of being notified. Your local IRB may also require these reports. 
In the event of any SAE (other than death), the subject will be instructed to contact the 
study physician (Principal Investigator or designee) using the phone number provided 
in the Informed Consent Form. All subjects experiencing an SAE will be seen by a 
Principal Investigator or designee as soon as feasible following the report of an SAE. 
11. STATISTICAL CONSIDERATIONS 
11.1. RANDOMIZATION 
Randomized treatments will be assigned by subject numbers in a randomly generated 
numeric sequence. 
The randomization code will not be revealed to study subjects, Investigators, clinical 
staff, study monitors or the Sponsor until all subjects have completed therapy and the 
database has been finalized and locked.  
Under normal circumstances, the blind should not be broken. The blind may be broken 
only if specific emergency treatment is indicated. The date, time and reason for the 
unblinding must be documented in the CRFs, and the medical monitor must be informed 
as soon as possible. 
11.2. ANALYSIS POPULATIONS 
The Intent-To-Treat (ITT) analysis set includes all randomized subjects. All efficacy 
analyses will be conducted in this analysis set and subjects will be included in the group 
to which they were randomized. 
The Safety analysis set includes all subjects who receive study treatment. All safety 
analyses will be completed in the Safety analysis set and subjects will be included in the 
group based on the treatment actually received.  
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11.3. STATISTICAL ANALYSIS 
 
11.3.1 Primary Efficacy Analysis 
Each of the two co-primary endpoints will be analyzed using a linear mixed model for 
repeated measurements. The dependent variable is the change from baseline and the 
model will include fixed effects for treatment group (two levels), week (5 levels, 
corresponding to Weeks 4, 16, 28, 40 and 52), the treatment group-by-week interaction, 
and the randomization stratification variable. The baseline value of the corresponding 
endpoint will be included as a covariate and the unstructured covariance model will be 
used. The Study Day 1 ADAS-Cog12 and ADCS-ADL assessments will represent the 
baseline value for these variables. 
 
For each of the two co-primary endpoints, the primary analysis will compare the 100 mg 
group and the placebo group at Week 52 using a two-sided test at the alpha = 0.05 level 
of significance. Study success requires that both co-primary comparisons are statistically 
significant. 
 
11.3.2 Secondary Analyses 
The iADRS18,19 is a linear combination of scores from two well-established, widely 
accepted, therapeutically sensitive measures of AD: the ADAS-Cog and ADCS-iADL 
(the instrumental component of the ADCS-ADL). The iADRS has been validated and 
statistical properties of the composite performance have been described20. All items of 
the ADAS-Cog12 and the ADCS-iADL will be included to generate this primary efficacy 
composite measurement without additional weighting. 
 
Secondary clinical endpoint data (iADRS, NPI, MMSE and ZBI) measured repeatedly will 
be analyzed using the same types of linear mixed models as described for the primary 
analysis.  
Plasma assays may include P-tau181, SavaDx and neurofilament light chain, and 
additional plasma biomarkers may be measured. All plasma biomarker data involving 
repeated measures will also be analyzed using the same types of linear mixed models as 
described for the primary analysis.  
CDR-SB data will be analyzed using ANCOVA models with treatment group as a factor 
and the baseline value as a covariate.  
All secondary analyses will be conducted using two-sided tests at the alpha = 0.05 level 
of significance, with no adjustments for multiplicity. 
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11.4. SAFETY ANALYSIS 
Adverse events reported on case report forms will be mapped to preferred terms and 
organ systems using the MedDRA mapping system. Vital signs and clinical laboratory 
results will be descriptively summarized in terms of change from screening values. 
11.5. SAMPLE SIZE 
Approximately seven hundred fifty (750) subjects will be enrolled in this study. The 
sample size was determined by a power analysis of ADAS-Cog in a similar population 
over 52 weeks. This analysis determined that group sizes of 300 are powered to show a 
45% difference from placebo at 52 weeks with 90% power and a two-sided significance 
level of 0.05.  The power calculation assumes a true mean change from baseline for 
placebo of 5.0 points and a standard deviation of 8.5 points.  Assuming a drop-out of 
20%, each treatment group should enroll 375 subjects. 
12. STUDY TERMINATION 
The study will be terminated following completion of the study or at any time at the 
discretion of the Sponsor. 
13. DATA COLLECTION, RETENTION AND MONITORING 
13.1. CASE REPORT FORMS 
The CRF will be provided as an Electronic Data Capture (EDC) system that will serve as 
the collection method for subject data. The subjects in the study will not be identified by 
name on any study documents to be collected by the Sponsor (or CRO designee) but will 
be identified by a unique subject number. 
All clinical information requested in this protocol will be recorded in the EDC 
system.  It is strongly recommended that data entry be completed within 48 h of a 
subject’s visit. In case of error noted on paper source documents, the correction will be 
noted, initialed and dated. 
EDC data must be reviewed and verified for accuracy and signed-off by the staff 
personnel before database lock. Paper source documents, if used, will remain at the 
Investigator's site at the completion of the study. 
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13.2. AVAILABILITY AND RETENTION OF INVESTIGATIONAL RECORDS 
The Investigator must make study data accessible to the monitor, other authorized 
representatives of the Sponsor (or designee) and Regulatory Agency (e.g., FDA) 
inspectors upon request. To assure accuracy of data collected in the EDC, it is 
mandatory that Sponsor representatives have access to original source documents (e.g., 
subject records, subject charts, and laboratory reports). During review of these 
documents, the subject's anonymity will be maintained with adherence to professional 
standards of confidentiality and applicable laws. A file for each subject must be 
maintained that includes the signed ICF and all source documentation related to that 
subject. The Investigator must ensure the reliability and availability of source 
documents for the EDC. 
Investigators are required to maintain all study documentation until notification by the 
Sponsor that any records may be discarded. 
The Investigator is responsible for maintaining adequate case histories in each 
subject's source records.  
13.3. SUBJECT CONFIDENTIALITY 
All reports and subject samples will be identified only by the assigned subject number 
and initials, as applicable by local law, to maintain subject confidentiality. Additional 
subject confidentiality measures (as required by region) will be covered within the 
Clinical Trial Agreement for each site as applicable. 
13.4. LIABILITY 
In the event of a side effect or injury, appropriate medical care as determined by the 
Investigator or his/her designated alternate will be provided. 
If a bodily injury is sustained resulting directly from the Study Drug, the Sponsor will 
reimburse for reasonable physician fees and medical expenses necessary for treatment of 
only the bodily injury that is not covered by the subject's medical or hospital insurance, 
provided that the injury is not due to a negligent or wrongful act or omission by the study 
doctor and his/her staff. No other compensation of any type will be provided by the 
Sponsor. Compensation for lost wages, disability or discomfort due to the study is not 
available. 
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13.5. ETHICAL AND LEGAL ISSUES 
The Investigator and site personnel are responsible for conducting this study in 
accordance with the ICH, GCP, and all other applicable laws and regulations. 
13.5.1. 
Institutional Review Board 
The protocol, ICF, clinical sites and Investigators must be approved by an IRB before 
the study is initiated. The IRB must comply with U.S. CFR 21 Part 56 and local laws. 
Documentation of approval by the designated central IRB will be provided to the 
Investigators. The Sponsor will:  
• Obtain IRB approval of the protocol, ICF, advertisements to recruit subjects and 
IRB approval of any protocol amendments and ICF revisions before implementing 
the changes. 
• Provide the IRB with any required information before or during the study. 
• Submit progress reports to the IRB, as required, requesting additional review and 
approval, as needed; and provide copies of all relevant IRB communications to the 
Investigator. 
 
The Investigator is responsible for: 
• Notifying the IRB within 15 calendar days of all SAEs and unexpected AEs related 
to study medications. 
• Obtaining approval by their institution’s own IRB, if the Investigator’s institution 
has its own IRB. 
13.6. INFORMED CONSENT FORM 
The Sponsor will submit the ICF to the central IRB for approval. An IRB-approved 
copy of the ICF will be forwarded to the Investigator or site staff. 
The ICF documents study-specific information the Investigator provides to the subject 
and the subject's agreement to participate. The Investigator explains in plain terms the 
nature of the study along with the aims, methods, anticipated benefits, potential risks, 
and any discomfort that participation may entail. The ICF must be signed and dated 
before the subject enters the study. The original ICF and any amended ICF, signed and 
dated, must be retained in the subject's file at the study site and a copy must be given 
to the subject. 
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14.  INVESTIGATOR RESPONSIBILITIES 
The Investigator agrees to: 
• Conduct the study in accordance with the protocol, except to protect the safety, rights, 
or welfare of subjects. 
• Personally conduct or supervise the study. 
• Ensure that requirements for obtaining informed consent and IRB review 
and approval comply with ICH, CFR 21 Parts 50 and 56 and local laws. 
• Report to the Sponsor any AEs that occur during the study in accordance with 
ICH, CFR 21 Part 312.64 and local laws. 
• Read and understand the Investigator's Brochure including potential risks and 
side effects of the drug. 
• Ensure that all associates, colleagues, and employees assisting in the conduct of 
the study are informed about their obligations in meeting the above commitments. 
• Maintain adequate records in accordance with ICH, 21 CFR Part 312.62, and 
local laws and have records available for inspection by the Sponsor, FDA, or 
other authorized agency. 
• Promptly report to the IRB and the Sponsor all changes in research activity and 
unanticipated problems involving risks to subjects or others (including 
amendments and expedited safety reports). 
• Comply with all other requirements regarding obligations of Clinical 
Investigators and all other pertinent requirements listed in ICH, 21 CFR Part 
312 and local laws. 
15. REFERENCES 
1. Burns LH, Wang H-Y. Altered filamin A enables amyloid beta-induced tau 
hyperphosphorylation 
and 
neuroinflammation 
in 
Alzheimer’s 
disease. 
Neuroimmunology and Neuroinflammation 2017;4:263-71. 
2. Wang H-Y, Lee K-C, Pei Z, Khan A, Bakshi K, Burns L. PTI-125 binds and reverses 
an altered conformation of filamin A to reduce Alzheimer's disease pathogenesis. 
Neurobiology of Aging 2017;55:99-114. 
3. Wang H-Y, Bakshi K, Frankfurt M, et al. Reducing amyloid-related Alzheimer’s 
disease pathogenesis by a small molecule targeting filamin A. Journal of Neuroscience 
2012;32:9773-84. 
4. Wang H-Y, Pei Z, K.-C. Lee K-C, et al. PTI-125 reduces biomarkers of Alzheimer’s 
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disease in patients. The Journal of Prevention of Alzheimer's Disease 2020;7:256-64. 
5. Jack C, Bennett D, Blennow K, et al (2018) NIA-AA Research Framework: Toward a 
biological definition of Alzheimer's disease; Alzheimer’s and Dementia 14(4):535-562 
6. Folstein MF, Folstein SE, McHugh PR. “Mini-mental state.” A practical method for 
grading the cognitive state of patients for the clinician. Journal of  Psychiatric Research 
1975;12:189-98. 
7. Morris JC. The Clinical Dementia Rating (CDR): current version and scoring rules. 
Neurology 1993;43:2412- 4. 
8. O'Bryant SE, Lacritz LH, Hall J, et al. Validation of the new interpretive guidelines for 
the clinical dementia rating scale sum of boxes score in the national Alzheimer's 
coordinating center database. Archives of Neurology 2010;67:746–9. 
9. Mohs R, Knopman D, Petersen R, Ferris S, Ernesto C, Grundman M, Sano M, 
Bieliauskas L, Geldmacher D, Clark C, Thal L and the ADCS. Development of 
Cognitive Instruments for Use in Clinical Trials of Antidementia Drugs: Additions to 
the Alzheimer’s Disease Assessment Scale That Broadens its Scope. Alzheimer’s 
Disease and Associated Disorders, 1997;11(S2):S13-21. 
10. Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer’s disease. 
American Journal of Psychiatry 1984; 141(11): 1356-1364. 
11. Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. The 
Neuropsychiatric Inventory: comprehensive assessment of psychopathology in 
dementia, 1994;44(12):2308-14. 
12. Galasko D, Bennett D, Sano M, et al. An inventory to assess activities of daily living 
for clinical trials in Alzheimer’s disease. The Alzheimer's Disease Cooperative Study. 
Alzheimer Disease and Associated Disorders 1997;11(Suppl 2):S33-9. 
13. Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. The 
Columbia-Suicide Severity Rating Scale: initial validity and internal consistency 
findings from three multisite studies with adolescents and adults. American  Journal of  
Psychiatry 2011;168(12):1266-77. 
14. Zarit SH, Reever KE and Bach-Peterson J. (1980) Relatives of the impaired elderly: 
correlates of feelings of burden. Gerontologist Dec; 20: 649-655. 
15. Zarit SH, Zarit JM. The memory and behavior problems checklist and the burden 
interview. Gerontology Center, The Pennsylvania State University, 1990. 
16. Yesavage, J.A., Brink, T.L., Rose, T.L., Lum, O., Huang, V., Adey, M.B., & Leirer, 
V.O. (1983). Development and validation of a geriatric depression screening scale: A 
preliminary report. Journal of Psychiatric Research, 17, 37-49. 
17. Sheikh JI, Yesavage JA: Geriatric Depression Scale (GDS): Recent evidence and 
development of a shorter version. Clinical Gerontology: A Guide to Assessment and 
Intervention; 165-173, NY: The Haworth Press, 1986. 
18. Wessels AM, Siemers ER, Yu P, Andersen SW, Holdridge KC, Sims JR, Sundell K, 
Stern Y, Rentz DM, Dubois B, Jones RW, Cummings J, Aisen PS; A combined 
measure of cognition and function for clinical trials: the integrated Alzheimer’s Disease 
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Rating Scale (iADRS). Journal of Prevention of Alzheimer’s Disease, 2 (4) 2015, 227-
241. 
19. Wessels AM, Andersen SW, Dowsett SA, Siemers ER; The integrated Alzheimer’s 
Disease Rating Scale (iADRS) findings from the EXPEDITION3 trial. Journal of 
Prevention of Alzheimer’s Disease, 5 (2) 2018, 134-136. 
20. Liu-Seifert H, Andersen SW, Case M, Sparks JD, Holdridge KC, Wessels AM, Hendrix 
S, Aisen P, Siemers E; Statistical properties of continuous composite scales and 
implications for drug development. Journal of Biopharmaceutical Statistics 27 (6) 
2017, 1104-1114. 
 
 
 
 
 
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16.  APPENDIX A – SCHEDULE OF ACTIVITIES 
Procedures 
Screening 
Period (-60 
Days to 0) 
Baseline 
Day 1 
Week 
4 
Week 
16 
Week 
28 
Week 
40 
Week 52 
ET/ED3 
Week 53 
to 54 
Informed Consent 
X 
 
 
 
 
 
 
 
I/E Criteria 
X 
X 
 
 
 
 
 
 
Medical & Med 
History 
X 
 
 
 
 
 
 
 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
Concomitant Meds 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
 
Physical 
Examination  
X1 
X 
X 
X 
X 
X 
X 
 
Neurologic 
Examination 
X1 
X 
X 
X 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
 
Geriatric Depression 
Scale 
X 
 
 
 
 
 
 
 
Resting ECG 
X 
X 
X 
 
X 
 
X 
 
Biochemistry, 
Hematology, 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
 
Urine Drug Screen 
X 
 
 
 
 
 
 
 
TSH, free T4, B12, 
HBsAg, HCV-Ab 
X 
 
 
 
 
 
 
 
Plasma P-tau181 
X7 
 
 
 
 
 
 
 
Genotyping sample 
 
X 
 
 
 
 
 
 
MRI 
X 
 
 
 
 
 
 
 
PK and Plasma 
Biomarkers 
X2 
 
 
 
X2 
 
X2 
 
MMSE 
X 
 
 
 
X 
 
X 
 
ADAS-Cog12 
 
X 
X 
X 
X 
X 
X 
 
ADCS-ADL 
 
X 
X 
X 
X 
X 
X 
 
CDR 
X 
 
 
 
 
 
X 
 
NPI 
 
X 
 
 
X 
 
X 
 
ZBI 
 
X 
X 
X 
X 
X 
X 
 
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Procedures 
Screening 
Period (-60 
Days to 0) 
Baseline 
Day 1 
Week 
4 
Week 
16 
Week 
28 
Week 
40 
Week 52 
ET/ED3 
Week 53 
to 54 
C-SSRS 
X4 
X5 
X5 
X5 
X5 
X5 
X5 
 
Drug Dispensation 
 
X6 
X 
X 
X 
X 
 
 
Drug Accountability 
 
 
X 
X 
X 
X 
X 
 
End of Study 
Follow-up Phone 
Call 
 
 
 
 
 
 
 
X 
 
 
1. Complete Physical and Neurologic Examinations during the Screening Period only, 
brief examinations thereafter 
2. PK and plasma biomarker sub-study subjects only (100 subjects total; 50 
subjects/group) 
3. Early Termination / Early Discontinuation subjects do not need to complete the 
electronic clinical outcome assessments if performed within 30 days of the ET/ED 
Visit 
4. During the Screening Period, the C-SSRS Baseline/Screening version will be 
administered 
5. At Study Day 1, as well as all remaining visits, the C-SSRS Since Last Visit version 
will be administered 
6. The first dose of Study Drug is administered at the clinic 
7. Plasma P-tau181 not required if the subject has evidence for AD pathophysiology 
prior to screening 
 
Page 141 of 141

SAP_001.pdf: 
Study Title: A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel-group, 
52-week Study Evaluating the Safety and Efficacy of Simufilam 100 mg Tablets in Subjects 
with Mild-to-Moderate Alzheimer’s Disease 
ClinicalTrials.gov ID: NCT04994483 
 
Final Statistical Analysis Plan, Version 3.0, dated 15-Oct-2024 
Page 1 of 53


 
Version 3.0 | 15-Oct-2024  
Page 1 of 52 
 
   Statistical Analysis Plan 
Sponsor 
Cassava Sciences, Inc. 
Protocol Title: 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group, 52-Week Study Evaluating the Safety and 
Efficacy of Simufilam 100 mg Tablets in Subjects with Mild-to-
Moderate Alzheimer’s Disease. 
Protocol Number: 
PTI-125-07 
Premier Research PCN: 
CASA215477 
Document Version: 
Version 3.0 
Document Date:  
15 OCT 2024  
 
 
 
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Statistical Analysis Plan,  
 
Sponsor: Cassava Sciences, Inc.  
 
Protocol Number: PTI-125-07 
 
PCN Number: CASA215477 
 
Version 3.0 | 15-Oct-2024  
Page 2 of 52 
 
 
Approvals 
Role 
Signatures 
Premier Research 
Print Name: 
                   
                     Senior Biostatistician 
Sign Name: 
 
 
 
Premier Research 
Print Name: 
 
                     Principal Biostatistician 
Sign Name: 
 
 
Pentara Corporation 
 
Print Name: 
 
                     Distinguished Biostatistician 
Sign Name: 
 
 
 
Cassava Sciences, Inc.  
 
Print Name: 
 
                    Chief Medical Officer 
Sign Name: 
 
 
 
 
 
 
I 
l(
premier' 
research) 
L
Signing Reason: I am the author of this document 
Signing Time: 15-0ct-2024 113:27:46 EDT 
15814CE0CD6D43D395515FE1D435AF4A 
(
Signed by: 
I 
l(J L
4D0BFF367935488088290E3D71979512 
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Statistical Analysis Plan,  
 
Sponsor: Cassava Sciences, Inc.  
 
Protocol Number: PTI-125-07 
 
PCN Number: CASA215477 
 
Version 3.0 | 15-Oct-2024  
Page 3 of 52 
 
 
Document History 
 
SAP Version 
Approval Date 
Change 
Rationale 
1 
May 17, 2024 
n/a 
Original version 
2 
July 24, 2024 
Corrected for typos.  
Added clarifying 
comments.  
Added responder 
analyses. 
Updates based on 
further planned 
analysis. 
3 
October 15, 2024 
Address FDA 
feedback  
Align with regulators 
 
 
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Statistical Analysis Plan,  
 
Sponsor: Cassava Sciences, Inc.  
 
Protocol Number: PTI-125-07 
 
PCN Number: CASA215477 
 
Version 3.0 | 15-Oct-2024  
Page 4 of 52 
 
 
Table of Contents 
Approvals ........................................................................................................................................ 2 
Document History ........................................................................................................................... 3 
Table of Contents ............................................................................................................................ 4 
List of Tables .................................................................................................................................. 6 
List of Abbreviations ...................................................................................................................... 7 
1. 
Overview ........................................................................................................................... 11 
2. 
Overall Study Design and Plan ......................................................................................... 12 
2.1. 
Overall Design ............................................................................................................ 12 
2.2. 
Sample Size and Power ............................................................................................... 13 
2.3. 
Study Population ......................................................................................................... 13 
2.4. 
Treatments Administered ............................................................................................ 13 
2.5. 
Method of Assigning Participants to Treatment Groups ............................................ 13 
2.6. 
Blinding and Unblinding............................................................................................. 13 
2.7. 
Schedule of Events ...................................................................................................... 14 
2.8. 
Administration of Study Drug to Participants ............................................................ 15 
3. 
Study Objectives and Endpoints ....................................................................................... 16 
3.1. 
Study Objectives ......................................................................................................... 16 
3.1.1. Primary Objective ....................................................................................................... 16 
3.1.2. Secondary Objectives.................................................................................................. 16 
3.1.3. Tertiary Objectives...................................................................................................... 16 
3.2. 
Study Endpoints and Estimands.................................................................................. 16 
3.2.1. Efficacy Endpoints and Estimands ............................................................................. 16 
3.2.2. Safety Endpoints ......................................................................................................... 18 
3.2.3. Pharmacokinetic Variable(s) ....................................................................................... 18 
4. 
Statistical Analysis and Reporting .................................................................................... 18 
4.1. 
Chain of Custody for Clinical Efficacy Data .............................................................. 18 
4.2. 
Introduction ................................................................................................................. 19 
4.3. 
Interim Analysis and Data Monitoring ....................................................................... 19 
5. 
Analysis Populations ......................................................................................................... 20 
6. 
General Issues for Statistical Analysis .............................................................................. 20 
6.1. 
Statistical Definitions and Algorithms ........................................................................ 20 
6.1.1. Baseline ....................................................................................................................... 20 
6.1.2. Adjustments for Covariates......................................................................................... 20 
6.1.3. Multiple Comparisons ................................................................................................. 20 
6.1.4. Handling of Dropouts or Missing Data ....................................................................... 21 
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6.1.5. Analysis Visit Windows ............................................................................................. 21 
6.1.6. Pooling of Sites ........................................................................................................... 22 
6.1.7. Derived Variables and Conventions ........................................................................... 22 
6.1.8. Data Adjustments/Handling/Conventions .................................................................. 23 
7. 
Study Participants and Demographics .............................................................................. 25 
7.1. 
Disposition of Participants and Withdrawals .............................................................. 25 
7.2. 
Protocol Violations and Deviations ............................................................................ 26 
7.3. 
Demographics and Other Baseline Characteristics ..................................................... 26 
7.4. 
Exposure and Compliance .......................................................................................... 27 
8. 
Efficacy Analysis .............................................................................................................. 28 
8.1. 
Co-Primary Efficacy Analysis .................................................................................... 28 
8.1.1. Sensitivity Analyses of the Primary Efficacy Endpoint ............................................. 28 
8.2. 
Secondary Efficacy Analysis ...................................................................................... 29 
8.3. 
Tertiary/Exploratory Efficacy Analysis ...................................................................... 29 
8.4. 
Subgroup Analyses of Efficacy Variables .................................................................. 29 
8.5. 
Responder Analyses .................................................................................................... 30 
8.6. 
Disease Progression Analyses..................................................................................... 30 
8.7. 
Time-Based Analyses ................................................................................................. 31 
8.8. 
Pooling With Other Studies ........................................................................................ 31 
9. 
Safety and Tolerability Analysis ....................................................................................... 32 
9.1. 
Adverse Events ........................................................................................................... 32 
9.1.1. Severity of Adverse Events ......................................................................................... 32 
9.1.2. Relationship to Study Drug ......................................................................................... 32 
9.1.3. Serious Adverse Events (SAEs).................................................................................. 33 
9.2. 
Clinical Laboratory Evaluations ................................................................................. 34 
9.2.1. Stopping Criteria ......................................................................................................... 36 
9.3. 
Vital Signs ................................................................................................................... 36 
9.4. 
Standard 12-lead ECG ................................................................................................ 37 
9.5. 
Further Safety Evaluations .......................................................................................... 38 
9.5.1. Physical Examinations ................................................................................................ 38 
9.5.2. Neurologic Examinations............................................................................................ 38 
9.6. 
Concomitant Medications ........................................................................................... 38 
9.7. 
Columbia Suicide Severity Rating Scale (C-SSRS) ................................................... 38 
10. 
Changes from Planned Analysis ....................................................................................... 39 
11. 
Other Planned Analysis..................................................................................................... 40 
11.1. Renal Insufficiency Analysis ...................................................................................... 40 
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11.1.1 Calculation of eGFR: .................................................................................................. 40 
11.1.2 Statistical Methods and Analysis ................................................................................ 40 
11.1.2.1 
Statistical Summaries on Creatinine, eGFR and Renal Function ......................... 40 
11.1.2.2 
Statistical Summaries on Select TEAEs vs Renal Function at Baseline (Day 
1) 41
11.2. Pharmacokinetic Analysis ........................................................................................... 41 
12.
References ......................................................................................................................... 41 
13.
Tables, Listings, and Figures ............................................................................................ 41 
13.1. Demographic Data Summary Tables and Figures ...................................................... 41 
13.2. Efficacy Data .............................................................................................................. 42 
13.3. Safety Data .................................................................................................................. 45 
13.4. Planned Listing Descriptions ...................................................................................... 46 
13.5. Planned Figure Descriptions ....................................................................................... 48 
List of Tables 
Table 1: Schedule of Activities 
Table 2.1: Visit Windows for Safety (Except for ECG) Analysis 
Table 2.2: Visit Windows for Safety (ECG Only) Analysis 
Table 3: Protocol-Required Safety Laboratory Tests 
Table 4: Renal Function Categories by eGFR Ranges 
Table 5: Demographic Data Summary Tables and Figures 
Table 6: Efficacy Data 
Table 7: Safety Data 
Table 8: Planned Listings 
Table 9: Planned Figures 
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List of Abbreviations 
Abbreviation 
Definition 
AD 
Alzheimer’s disease 
ADAS-Cog12 
12-item Alzheimer’s disease assessment scale – cognitive subscale 
ADCS-ADL 
Alzheimer’s disease cooperative study – activities of daily living 
AE 
adverse event 
ANCOVA 
analysis of covariance 
ApoE 
apolipoprotein E 
ATC 
anatomical therapeutic chemical 
ASA 
American Statistical Association 
BID 
twice daily 
BMI 
body mass index 
CDISC 
Clinical Data Interchange Standards Consortium 
CDR-GS 
clinical dementia rating - global score 
CDR-SB 
clinical dementia rating – sum of boxes 
CI 
confidence interval 
CMH 
Cochran-Mantel-Haenszel 
CRF 
case report form 
CS 
clinically significant 
CSR 
clinical study report 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DSMB 
data safety monitoring board 
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Abbreviation 
Definition 
ECG 
electrocardiogram 
eCOA 
electronic clinical outcome assessment 
ED 
early discontinuation 
EDC 
electronic data capture 
ET 
early termination 
EMA 
European Medicines Agency 
FDA 
U.S. Food and Drug Administration 
GCP 
code of good clinical practice 
GDS 
Geriatric Depression Scale 
iADRS 
integrated Alzheimer’s disease rating scale 
ICH 
International Conference on Harmonization 
ID 
identification 
IRT 
interactive response technology 
LS 
least squares 
MAR 
missing at random 
MedDRA 
medical dictionary for regulatory activities 
ITT 
intent-to-treat 
MMRM 
mixed model for repeated measurements 
MMSE 
mini-mental state exam 
MNAR 
missing not at random 
MRI 
magnetic resonance imaging 
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Abbreviation 
Definition 
NCS 
not clinically significant 
NE 
neurological examination 
NPI or NPI-10  
neuropsychiatric inventory, 10-item  
PE 
physical exam 
PET 
positron emission tomography 
PK 
pharmacokinetic 
PT 
preferred term 
RSS 
Royal Statistical Society 
SAE 
serious adverse event 
SAF 
safety analysis set  
SAP 
statistical analysis plan 
SPA 
FDA special protocol assessment 
SD 
standard deviation 
SDV 
source data verified 
SE 
standard error 
SI 
international system of units 
SOC 
system organ class 
SOP 
standard operating procedures 
REML 
restricted maximum likelihood 
TEAE 
treatment-emergent adverse event 
TLF 
tables, listings and figures 
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Abbreviation 
Definition 
WHO-DD 
World Health Organization drug dictionary 
ZBI 
Zarit Burden Interview 
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1. 
Overview 
This statistical analysis plan (SAP) describes the planned analysis and reporting for Cassava 
Sciences’ protocol PTI-125-07, one of two Phase 3 protocols designed to provide safety and efficacy data 
for simufilam, a novel small molecule drug, in support of a New Drug Application filing for the treatment of 
mild-to-moderate Alzheimer’s Disease (AD) dementia.  
Protocol PTI-125-07 is a registrational Phase 3 study being conducted under a Food and Drug 
Administration (FDA) Special Protocol Assessment (SPA) dated August 2021. An SPA 
documents FDA’s agreement that the design and planned analysis of a study can adequately 
address objectives in support of a regulatory submission. 
PTI-125-07 is titled:  A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, 
52-Week Study Evaluating the Safety and Efficacy of Simufilam 100 mg Tablets in Subjects with 
Mild-to-Moderate Alzheimer’s Disease, dated 15-FEB-2023 (version 3.0).  
Reference materials for this SAP include the protocol and the accompanying sample data 
collection documents. Operational aspects related to collection and timing of planned clinical 
assessments are not repeated in this SAP unless relevant to the planned analysis. 
The structure and content of this SAP provides sufficient detail to meet the requirements 
identified by the FDA, European Medicines Agency (EMA), and International Conference on 
Harmonization (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human 
Use: ICH Topic E9 Statistical Principles for Clinical Trials (ICH, 1998) and the addendum R1 
(ICH, 2020). All work planned and reported for this SAP will follow internationally accepted 
guidelines, published by the American Statistical Association (ASA, 2022) and the Royal 
Statistical Society (RSS, 2014), for statistical practice. 
The planned analyses identified in this SAP may be included in clinical study reports (CSRs), 
regulatory submissions, or future manuscripts. Post-hoc exploratory analyses not necessarily 
identified in this SAP may be performed to further examine study data. Any post-hoc or 
unplanned, exploratory analysis performed will be clearly identified as such in the final CSR. 
The statistical plan described hereafter is an a priori plan. It will be approved before any 
unblinded inferential or descriptive analysis of data pertaining to Cassava Sciences’ study PTI-
125-07. 
This document does not include the details of the planned analyses for the external Data Safety 
Monitoring Board (DSMB). The schedule of planned analyses is described in the DSMB charter 
and separate shells for tables, listings, and figures (TLF) are prepared for the DSMB meetings. 
Descriptive summary tables for efficacy endpoints will generally include: number of participants 
with data, mean, standard deviation, median, 25% percentile, 50% percentile, 75% percentile, 
minimum and maximum. Inferential efficacy summary tables will include within group mean 
changes from baseline along with the difference between groups in mean change and the 
associated standard errors and p values.   
Baseline is defined as the most recent non-missing measurement collected prior to the first dose.  
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2. 
Overall Study Design and Plan 
2.1. 
Overall Design 
This is a randomized, double-blind, placebo-controlled, parallel-group study. In this Phase 3 
clinical study, approximately 750 participants with mild-to-moderate AD dementia will receive 
placebo or 100 mg tablets of simufilam, twice daily, for 52 weeks. Randomization (1:1) will be 
stratified by low or high mini-mental state exam (MMSE) (16-20 and 21-27). Study participants 
50-87 years of age will be selected for screening based on a diagnosis of AD consistent with 
Stages 4 or 5 on the Alzheimer’s continuum (National Institute on Aging – Alzheimer’s 
Association 2018). Participants must have MMSE ≥ 16 and ≤ 27, and a Clinical Dementia Rating 
Global Score (CDR-GS) of 0.5, 1 or 2. Finally, participants must have confirmed fluid biomarker 
or amyloid positron emission tomography (PET) evidence of AD pathophysiology prior to 
randomization. 
Once participants have been satisfactorily screened for study participation, visits to the research 
clinic will occur on Study Day 1 and at Weeks 4, 16, 28, 40 and 52.  
The co-primary endpoints include: 
1. The 12-item Alzheimer’s Disease Assessment Scale – Cognitive Subscale (ADAS-
Cog12) and 
2. The Alzheimer’s Disease Cooperative Study – Activities of Daily Living (ADCS-
ADL).  
Secondary endpoints include: the integrated Alzheimer’s Disease Rating Scale (iADRS), the 10-
item Neuropsychiatric Inventory (NPI-10), MMSE, and the Clinical Dementia Rating Sum of 
Boxes (CDR-SB). A brief questionnaire assessing caregiver burden, the Zarit Burden Interview 
(ZBI), will be collected as an additional secondary endpoint.  
Safety will be evaluated by adverse event monitoring, vital signs, clinical labs, and the Columbia 
Suicide Severity Rating Scale (C-SSRS) at every visit. Participants will undergo magnetic 
resonance imaging (MRI) during screening to ensure entry criteria are met (unless a recent MRI 
confirms entry criteria). Resting electrocardiograms (ECGs) will be conducted at baseline (Study 
Day 1) and Weeks 4, 28 and 52. A complete physical and neurological examination will be 
performed at screening, and brief examinations will be performed at all other visits. Weight will 
be measured during the Screening Period, at baseline (Study Day 1) and at all other visits.  
A limited number of research sites will be invited to participate in the pharmacokinetic (PK) and 
plasma biomarker sub-study. Collection of PK samples will enable an exposure-response 
analysis. Approximately 100 participants will participate (50 per group). Plasma samples will be 
collected during the Screening Visit and again at Weeks 28 and 52. Change from baseline for 
plasma biomarkers represent additional secondary endpoints.  
An independent DSMB will meet periodically to review participant safety assessments and 
determine if dosing may continue. A charter was developed with specific guidance for the 
DSMB.  
There are no unblinded interim analyses of efficacy outcomes at any time prior to formal 
completion of the study and unblinding of the data. 
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2.2. 
Sample Size and Power 
Planned enrollment was approximately seven hundred fifty (750) participants with mild-to-
moderate AD dementia. The sample size was determined by a power analysis of ADAS-Cog 
using data from a similar population over 52 weeks. This analysis determined that group sizes of 
300 are powered to show a 45% mean difference from placebo at 52 weeks with 90% power and 
a two-sided significance level of 0.05. The power calculation assumes a true mean change from 
baseline for placebo of 5.0 points and a standard deviation of 8.5 points. Assuming a drop-out of 
20%, each treatment group should enroll approximately 375 participants. The final sample size 
was 804 randomized participants. 
2.3. 
Study Population 
The study population is comprised of approximately 800 male or female participants between the 
ages of 50 and 87 with mild-to-moderate AD dementia. Participants are enrolled (randomized) 
from approximately 77 clinical sites in the U.S., Canada and Australia.  
2.4. 
Treatments Administered 
Participants were randomized in a 1:1 ratio to: 
•
simufilam 100 mg tablets BID, or
•
matching placebo tablets BID.
The randomization was stratified by baseline low or high MMSE score (16-20 vs. 21-27). 
2.5. 
Method of Assigning Participants to Treatment Groups 
The randomization schedule was computer generated by an independent statistician and 
randomly allocated each treatment to randomization numbers. The randomization numbers were 
assigned sequentially through a central interactive response technology (IRT) system as 
participants entered the study. The randomization was stratified as described in section 2.4. 
The randomization schedule will not be revealed to participants, clinical investigators, clinical 
staff, study monitors, statistical personnel or Cassava Sciences until all participants have 
completed treatment and the database has been finalized and locked.  
Participants who discontinue from the study or are terminated will not be replaced. 
The IRT system will be used throughout the study for screening, randomization, study drug 
dispensation and management, and emergency unblinding.  Individual participant treatment is 
automatically assigned by the IRT at baseline (Study Day 1) to participants who meet all entry 
criteria.  The participant’s randomization number is a unique number corresponding to the 
treatment allocated to the participant. 
At each dosing visit, the site will access the IRT system, and enter the necessary participant-
specific information. For randomized participants, this information is used by the IRT system to 
dispense the correct dose and amount of study drug in a uniquely numbered bottle. 
2.6. 
Blinding and Unblinding 
All participants, investigators, and study personnel, including but not limited to sites, the 
Sponsor and Premier Research will be blinded to treatment assignment and receipt of study drug 
during the conduct of the study, through database lock. The treatment assignment will not be 
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unblinded during the conduct of the study except in emergency situations where the 
identification of the study drug is required for the safety of an individual study participant. The 
investigator should make every effort to contact the medical monitor prior to individual 
participant unblinding or as soon as possible after unblinding without making the medical 
monitor aware of the treatment assignment. 
If a treatment assignment is unblinded, the date and name of the person who was unblinded, and 
the reason for unblinding, are recorded in the appropriate source documents. The participant will 
be discontinued immediately from the study but will be followed up as required by standard 
medical practice. Unblinding will be managed via the IRT system. 
Prior to unblinding, data that may functionally unblind personnel, including PK and biomarker 
results, will be handled with diligence. Any data that may unblind study personnel or the study 
team will be presented in blinded fashion only or withheld until after study unblinding. 
2.7. 
Schedule of Events 
Table 1:  Schedule of Activities 
Procedures 
Screening 
Period (-60 
Days to 0) 
Baseline 
Visit 
(Study 
Day 1) 
Week 
4 
Week 
16 
Week 
28 
Week 
40 
Week 52 
ET/ED3 
Safety 
Follow-
up8 
Informed Consent 
X 
I/E Criteria 
X 
X 
Medical & Surgical 
History 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Meds 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
X1 
X 
X 
X 
X 
X 
X 
Neurologic 
Examination 
X1 
X 
X 
X 
X 
X 
X 
Height 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
Resting ECG 
X 
X9 
X 
X 
X 
Biochemistry, 
Hematology, 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
Urine Drug Screen 
X 
TSH, free T4, B12, 
HBsAg, HCV-Ab 
X 
HbA1c (diabetic 
participants only) 
X 
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Procedures 
Screening 
Period (-60 
Days to 0) 
Baseline 
Visit 
(Study 
Day 1) 
Week 
4 
Week 
16 
Week 
28 
Week 
40 
Week 52 
ET/ED3 
Safety 
Follow-
up8 
Plasma P-tau181 or P-
tau217 
X7 
Genotyping sample 
X 
MRI 
X 
PK and Plasma 
Biomarkers 
X2 
X2 
X2 
MMSE 
X 
X 
X 
CDR 
X 
X 
Geriatric Depression 
Scale 
X 
ADAS-Cog12 
X 
X 
X 
X 
X 
X 
ADCS-ADL 
X 
X 
X 
X 
X 
X 
NPI 
X 
X 
X 
ZBI 
X 
X 
X 
X 
X 
X 
C-SSRS
X4 
X5 
X5 
X5 
X5 
X5 
X5 
Drug Dispensation 
X6 
X 
X 
X6 
X 
Drug Accountability 
X 
X 
X 
X 
X 
End of Study Follow-
up Phone Call 
X 
1.
Complete Physical and Neurologic Examinations during the Screening Period only, brief examinations
thereafter.
2.
PK and plasma biomarker sub-study participants only (100 participants total; 50 participants/group).
3.
Early Termination (ET) / Early Discontinuation (ED) participants do not need to complete the electronic
clinical outcome assessments if performed within 30 days of the ET/ED Visit.
4.
During the Screening Period, the C-SSRS baseline/Screening version will be administered.
5.
At Study Day 1, as well as all remaining visits, the C-SSRS Since Last Visit version will be administered.
6.
The first dose of Study Drug is administered at the clinic to all participants on Study Day 1; for plasma PK
and biomarker sub-study participants only at the Week 28 visit, administer Study Drug after blood samples
are collected.
7.
Plasma P-tau181 or plasma P-tau217 not required if the participant has evidence for AD pathophysiology
prior to screening.
8.
This phone call will occur Week 53 to 54 for those participants who complete all study visits, or 1 to 2
weeks after ET. If the participant reports an adverse event, the participant should be followed and treated by
the Investigator until the AE has resolved or stabilized.
9.
ECG on Study Day 1 collected in triplicate.
2.8. 
Administration of Study Drug to Participants
Simufilam or placebo tablets will be supplied in 70-count bottles for a 4-week supply or 188-
count bottles for a 12-week supply. Each bottle will contain 7 or 10 days of extra medication to 
accommodate scheduling flexibility with clinic visits. Each bottle is labeled with a unique 
double-blind identification (ID) number that is randomly assigned to a treatment. A computer-
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based clinical study management (i.e., IRT) system will specify the bottle ID number to be 
dispensed according to the participant’s treatment randomization. 
3.
Study Objectives and Endpoints
3.1. 
Study Objectives
The general objectives of this study are to assess simufilam’s safety and to test the hypothesis 
that oral simufilam will slow the cognitive and functional decline in study participants with mild-
to-moderate AD dementia. Secondary objectives include the assessment of simufilam’s effect on 
neuropsychiatric symptoms and caregiver burden. A third objective is to investigate the effect of 
simufilam treatment on plasma biomarkers. 
3.1.1. Primary Objective 
The primary objective is to assess simufilam’s effect on the co-primary endpoints of ADAS-
Cog12 and the ADCS-ADL, baseline to the end of double-blind treatment (Week 52). 
3.1.2. Secondary Objectives 
The secondary objectives are to assess simufilam’s effect on the iADRS, NPI-10, MMSE, CDR-
SB, and the ZBI, baseline to Week 52. 
Additional secondary objectives are to compare the co-primary and secondary endpoints in the 
subgroup of mild AD patients (stage 4 AD) with baseline MMSE scores of 21-27. 
3.1.3. Tertiary Objectives 
To investigate the effect of simufilam treatment on exploratory plasma biomarkers. 
3.2. 
Study Endpoints and Estimands 
3.2.1. Efficacy Endpoints and Estimands 
3.2.1.1. 
Co-Primary Efficacy Endpoints and Estimands 
The primary estimand for the primary efficacy endpoint is defined as follows: 
Population 
Participants with mild-to-moderate AD dementia who meet the study’s 
inclusion and exclusion criteria. 
Treatments 
Simufilam 100 mg twice daily or placebo. 
Endpoints 
ADAS-Cog12 (range 0 – 80, higher score indicates greater impairment) and 
ADCS-ADL (range 0 – 78, lower score indicates greater impairment).  
Summary 
Measure 
Difference between treatments in least squares (LS) mean change from 
baseline to Week 52. 
Intercurrent 
Events 
All deviations from the intended dosing regimens and use of concomitant 
medication will be handled consistently using a treatment policy strategy. 
Early study discontinuation will be consistently accounted for using a 
hypothetical strategy to estimate what would have been observed if the 
participant had not discontinued. 
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3.2.1.2. Secondary Efficacy Endpoint(s) and Estimand(s) 
The secondary efficacy endpoints of this study include the following:  
• Mean change in the ADAS-Cog12 from baseline to Weeks 4, 16, 28 and 40  
• Mean change in ADCS-ADL from baseline to Weeks 4, 16, 28 and 40  
• Mean change in the iADRS (range 0 – 139, lower score indicates greater impairment) 
from baseline to Weeks 4, 16, 28, 40 and 52  
• Mean change in the NPI-10 (range 0 – 120, higher score indicates greater impairment) 
from baseline to Weeks 28 and 52 
• Mean change in the MMSE (range 0 – 30, lower score indicates greater impairment) from 
the screening visit to Weeks 28 and 52 
• Mean change in the CDR-SB (range 0 – 18, higher score indicates greater impairment) 
from the screening visit to Week 52 
• Mean change in the ZBI (range 0 – 88, higher score indicates greater caregiver burden) 
from baseline to Weeks 4, 16, 28, 40 and 52.  
The estimands for the secondary efficacy endpoint(s) are similar to the co-primary estimands. 
Each secondary estimand has the following components: 
Population 
Participants with mild-to-moderate AD dementia who meet the study’s inclusion 
and exclusion criteria. 
Treatments 
Simufilam 100 mg twice daily or placebo 
Endpoints 
ADAS-Cog12, ADCS-ADL, iADRS, NPI-10, MMSE, CDR-SB, ZBI 
Summary 
Measure 
Difference between treatments in LS mean change from baseline to the time 
points designated above 
Intercurrent 
Events 
All deviations from the intended dosing regimens and use of concomitant events 
medications will be handled consistently using a treatment policy strategy. Early 
study discontinuation will be consistently accounted for using a hypothetical 
strategy to estimate what would have been observed if the participant had not 
discontinued.   
In addition, secondary estimands include the primary and secondary endpoints assessed in the 
population of participants with stage 4 AD. Stage 4 (mild) is defined as participants with baseline 
MMSE 21-27. Stage 4 and 5 represent all randomized participants. 
3.2.1.3. Tertiary Efficacy Endpoint(s) and Estimand(s) 
The exploratory (tertiary) efficacy endpoints of this study include the following:  
• Mean change in plasma biomarkers from baseline to weeks 28, and 52 may include: P-
tau181 and/or P-tau217, GFAP, neurofilament light chain (NfL), and additional plasma 
biomarkers. Results will be presented in a separate report that will be appended to the 
CSR. 
Estimands for exploratory endpoints will have the same treatments, population, summary 
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measure and handling of intercurrent events as for the primary and secondary endpoints. 
3.2.2. Safety Endpoints 
The safety endpoints of this study include the following: 
• Incidence of adverse events (AEs) including treatment-emergent, serious, related to study 
drug, and leading to withdrawal along with AEs by severity and relationship to study 
drug 
• Mean change in clinical laboratory values from baseline to Weeks 4, 16, 28, 40, and 52 
Shifts in the normality of clinical laboratory values from baseline to Weeks 4, 16, 28, 40, 
and 52 
• Mean change in vital signs (blood pressure [supine], temperature, pulse rate) from 
baseline to Weeks 4, 16, 28, 40, and 52 
 
• Mean change in body weight from baseline to Weeks 4, 16, 28, 40, and 52 
• Shifts in physical exam (PE) findings from baseline to Weeks 4, 16, 28, 40, and 52 
• Shifts in neurological exam (NE) findings from baseline to Weeks 4, 16, 28, 40, and 52 
• Mean change in ECG parameters from baseline to Weeks 4, 28, and 52 
• Concomitant medications/treatments usage 
• Shifts in the C-SSRS from baseline to Weeks 4, 16, 28, 40, and 52. 
3.2.3. Pharmacokinetic Variable(s) 
Plasma pharmacokinetic (PK) exposure response is part of a sub-study. A visit wise listing of 
Pharmacokinetic results will be provided. Summary will be presented in a separate report that 
will be appended to the CSR. 
4. 
Statistical Analysis and Reporting 
This SAP addresses the safety and efficacy objectives of the study and describes the statistical 
methods that Premier Research International LLC and Pentara Corporation will use to analyze 
the clinical data after the database has been finalized and locked.  
4.1. 
Chain of Custody for Clinical Efficacy Data 
Study sites collect clinical efficacy data from study participants using an electronic clinical 
outcome assessment (eCOA) device managed by Signant Health, an independent, outside data 
management and rater training vendor. Upon receipt of the data, Signant Health’s clinical team 
conducts quality reviews of eCOA endpoints and provides feedback to study raters as 
appropriate. Signant Health also maintains the clinical efficacy database and transmits it 
periodically throughout the study to Premier Research to reconcile and package with additional 
data collected via electronic data capture (EDC). Premier Research also conducts quality reviews 
and may issue queries to study sites to reconcile any discrepancies. Upon completion of the study 
and once all visits have been deemed source data verified (SDV), Premier Research will analyze 
all study data related to safety and directly transmit study data to Pentara Corporation for 
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analysis of all efficacy data. The pre-specified efficacy outcomes for this SAP will be executed 
by Pentara Corporation (an outside, independent biostatistical consulting firm headed by 
Suzanne Hendrix, PhD). 
4.2. 
Introduction 
Data processing, tabulation of descriptive statistics, calculation of inferential statistics, and 
graphical representations will use SAS (release 9.4 or higher). If the use of other software is 
required, the final clinical study report will specify the software that was used. 
In general, summaries will be provided by study treatment group, unless otherwise noted. The 
column headings for the summaries will include the randomized treatment groups (Placebo BID, 
Simufilam 100 mg BID), unless otherwise noted. 
Continuous (quantitative) variable summaries will include the number of participants with non-
missing values (n), mean, 2-sided 95% confidence interval (CI), standard deviation (SD) and/or 
standard error (SE) if applicable, median, and minimum and maximum values.  
Categorical (qualitative) variable summaries will include the frequency and percentage of 
participants who are in the category for each possible value. In general, the denominator for the 
percentage calculation will be based upon the total number of participants in the study population 
for the treatment groups (or cohorts) unless otherwise specified.  
The minimum and maximum will be reported with the same degree of precision (i.e., the same 
number of decimal places) as the observed data. Measures of location (mean and median) and 
bounds of CIs will be reported to 1 degree of precision more than the observed data and 
measures of spread (SD and SE) will be reported to 2 degrees of precision more than the 
observed data. Percentages will be presented to 1 decimal place. 
Statistical testing and inference methods for safety and efficacy analyses are described below. 
Efficacy results will be considered statistically significant after consideration of the strategy for 
controlling the Type 1 error as described in Section 6.1.2 of this SAP. Nominal p-values may be 
computed for other efficacy analyses as a measure of the association between the endpoint and 
the treatment effect rather than formal tests of hypotheses. Unless otherwise stated, all statistical 
tests will be conducted at the alpha = 0.05 (two-sided) level, and a difference resulting in a p- 
value of ≤ 0.05 will be considered statistically significant. Corresponding 95% two-sided CIs 
will be presented for statistical tests. 
All formal statistical comparisons will be based on LS means from the relevant contrasts in the 
mixed model for repeated measurements (MMRM) or analysis of covariance (ANCOVA). 
This study is considered a registration study. Statistical tests will be regarded as formal tests of 
specific hypotheses. 
The data from nominal/scheduled protocol clinic visits will be included in visit-based summary 
tables. Unscheduled assessments, if they occur, and the ET visit data will be mapped to 
scheduled assessments according to the visit windows defined in section 6.1.5 for all safety and 
efficacy analyses. See Section 6.1.4 and 6.1.5 of this SAP for more details. 
4.3. 
Interim Analysis and Data Monitoring 
No interim efficacy analyses or sample size re-estimations were conducted. 
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An external DSMB will be involved in the management of this study. The DSMB meeting will 
be held periodically for the duration of the study.  The purpose of the DSMB is to review the 
progress of the study with special regard to safety and make recommendations to the Sponsor on 
how to handle any safety concerns that arise.  Further details regarding the DSMB can be found 
in the DSMB charter which was finalized before the first meeting was scheduled. 
5.
Analysis Populations
The following analysis sets are planned for this study: 
•
Intent-To-Treat (ITT) Analysis Set: The ITT analysis set includes all randomized
participants. The primary efficacy analysis will be based on this analysis set.
•
Intent-To-Treat (ITT-mild) Analysis Set: The ITT-mild analysis set includes all
randomized participants who have a baseline MMSE of 21-27.
•
Safety Analysis Set (SAF): The SAF analysis set includes all participants who received
at least one dose of study treatment. All safety analyses will be completed in the SAF
analysis set and participants will be included in the group based on the treatment
received.
•
PK sub-study Analysis Set: The PK sub-study analysis set includes all participants who
sign the PK consent and/or re-consent form and have at least one non-missing post
baseline PK assessment available.
Assignment of participants to analysis sets will be confirmed at a blinded data review meeting to 
be held before the study database is locked.   
6.
General Issues for Statistical Analysis
6.1. 
Statistical Definitions and Algorithms 
6.1.1. Baseline 
The last observation recorded on or before the first dose of treatment will be used as the baseline 
observation for all calculations of change from baseline. In most cases, this will be the baseline 
visit (Day 1) pre-dose observation. In some cases, however, the baseline values may be obtained 
from the 60-day screening phase. For example, because MMSE is taken at screening but not at 
the baseline visit, the MMSE value obtained at screening will be used as the baseline value. 
6.1.2. Adjustments for Covariates 
Efficacy analyses will include as covariates the baseline value of the endpoint being analyzed 
and the MMSE baseline score, along with the interaction of these covariates with Visit. 
Investigative site (pooled, see section 6.1.6) will also be included as a categorical fixed effect. 
6.1.3. Multiple Comparisons 
The co-primary endpoints of ADAS-Cog12, and ADCS-ADL will each be tested at p=0.05 using 
the ITT analysis set. Multiplicity among secondary endpoints in the ITT analysis set will be 
controlled using a hierarchical, gatekeeping strategy. Secondary endpoints will be tested in the 
following order: iADRS, CDR-SB, ZBI, MMSE, and NPI-10. Testing will proceed in this order 
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until the first non-significant p value (p > 0.05). The first endpoint with p > 0.05 and all 
subsequent endpoints in the order will be declared non-significant, and all endpoints preceding 
the first non-significant test will be declared significant.  
For the set of significant endpoints in the ITT analysis set, the corresponding endpoints in the 
mild subgroup (ITT-mild analysis set) will be tested. Testing for the mild cohort will proceed in 
the same order as for the secondary endpoints referenced above until the first non-significant p 
value. The first endpoint with p > 0.05 and all subsequent endpoints in the order will be declared 
non-significant, and all endpoints preceding the first non-significant test will be declared 
significant. 
6.1.4. Handling of Dropouts or Missing Data 
Although every attempt will be made to ensure participants remain in the study to completion 
and all data is collected as scheduled, the occurrence of missing data cannot be completely 
prevented. 
An incomplete start or stop date of an AE or a medication will be imputed as described in section 
6.1.8.   
Any participant who withdraws from the study will be considered to have missing data at all 
subsequent visits. The primary analytic approach for efficacy assumes missing at random (MAR) 
to estimate what would have been observed if the participant had not discontinued. A reference-
based multiple imputation sensitivity analysis (copy reference) will be employed in which 
missing not at random is assumed such that after discontinuation, drug-treated participants will 
have placebo-like values imputed for their missing data. 
If up to two individual items of the total 12 items for the ADAS-Cog12 (maximum score = 80) 
are missing for non-cognitive reasons, the total score will be imputed by multiplying the 
observed score (i.e. the score for the non-missing items) by a factor that includes the maximum 
scores for the missing item(s) as follows:   
Imputed score = Observed score * (80/[80-maximum score for missing items]). 
As an example, if the first item “Word Recall” (maximum score = 10) and the second item 
“Commands” (maximum score = 5) are missing, the observed score will be multiplied by the 
factor 80/(80-[10+5]) or 80/65 or 1.23. The imputed score will be rounded to the nearest integer. 
ADAS-Cog12 tests with more than two missing items will be considered missing scores. 
Missing items on other assessments will not be imputed; such scores will be considered missing. 
6.1.5. Analysis Visit Windows 
All scheduled visits and associated variables for the treatment phase will be analyzed based on the 
study week to which they are assigned.  
For the safety summaries and analyses, scheduled analysis visits will be windowed to the nearest 
scheduled visit and the unscheduled visits/assessments and early termination visits will be 
mapped to a scheduled visit using the following visit windows (Table 2.1 and Table 2.2). Visit 
windows will be assigned by splitting the periods between visits at the mid-point between the 
visits.  
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If both scheduled and unscheduled visits fall within the same visit window, scheduled visit will 
be used over unscheduled visits. If both scheduled and early termination visits fall within the 
same visit window, the data from the early termination visit will supersede. 
If more than one unscheduled visit falls within the same visit window, the one closest to the 
target date will be used in the analysis. If equidistant, the earliest visit will be used. 
If the analysis visit (for Unscheduled or ET assessments) falls on a visit window in which that 
specific assessment is not scheduled, then that assessment will not be used for analysis. 
Table 2.1:  Visit Windows for Safety (Except for ECG) Analysis 
Scheduled Visit 
Scheduled Visit Day 
(Target Day) 
Window for Assignment of 
Analysis Visit (Study Days1) 
Week 4 
Day 29 
Day 2 – Day 71 
Week 16 
Day 113 
Day 72 – Day 155 
Week 28 
Day 197 
Day 156 – Day 239 
Week 40 
Day 281 
Day 240 – Day 323 
Week 52 
Day 365 
Day 324 – Day 407 
 1Study Day relative to the date of first dose of study drug. 
 
Table 2.2:  Visit Windows for Safety (ECG only) Analysis 
Scheduled Visit 
Scheduled Visit Day 
(Target Day) 
Window for Assignment of 
Analysis Visit (Study Days1) 
Week 4 
Day 29 
Day 2 – Day 113 
Week 28 
Day 197 
Day 114 – Day 281 
Week 52 
Day 365 
Day 282 – Day 449 
1Study Day relative to the date of first dose of study drug. 
For the efficacy summaries and analyses, scheduled analysis visits are visits upon scheduled time 
points as specified in the Schedule of Time and Events. Scheduled analysis visits will be 
windowed to the nearest scheduled visit. Assessments that fall within the same window will be 
averaged. There will be one valid value of assessment kept for each scheduled analysis visit in 
summary / analysis statistics.  
Unscheduled visits are visits with data not collected at scheduled time points. Unscheduled visits 
will be windowed to the nearest scheduled visit as described above. All unscheduled visits will 
be included as collected in eCRF in listings. 
6.1.6. Pooling of Sites 
Sites with < 2 participants in any treatment arm at Week 52 will be pooled into a common site. 
All sites with ≥2 participants in both treatment arms at Week 52 will not be pooled. 
6.1.7. Derived Variables and Conventions 
Age: the age at baseline will be used. 
Alzheimer’s disease status 
- 
MMSE = 21-27 (mild dementia) 
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- 
MMSE = 16-20 (moderate dementia)   
Change from baseline = post-baseline value at timepoint – value at baseline 
Time since diagnosis of AD (months) = (date of first dose – date of diagnosis) / 30.4375 
Treatment duration (days) = (date of last dose of study drug – date of first dose of study 
drug) +1  
Study Drug Exposure = treatment duration (days), that is the number of days a participant is on 
study drug will be calculated as the number of days from date of first dose to date of last dose 
plus 1.  
Study Drug Compliance (%) = 100 x Total number of tablets taken / Total number of expected 
tablets.  That is, study medication compliance will be calculated based on the numbers of tablets 
dispensed minus the number of tablets returned divided by the expected number of tablets based 
on the duration of the participant’s participation in the study. 
Study drug compliance will not be calculated for participants whose date of last study drug is 
unknown. 
Total Dose (mg) = ∑ [ Number of doses takeni x Dose received (mg)i ] 
where,  
i = 1 to k, (k = number of time periods participant is receiving a constant dose) 
Average Daily Dose (mg/day) = Total Dose (mg) / Treatment Duration (days) 
Dose variables (dose, total dose, and average daily dose) not calculated for placebo 
participants.  
The iADRS for this trial is a composite endpoint that combines scores from the 12-item 
AD Assessment Scale-Cognitive subscale (ADAS-Cog12) and the AD Cooperative Study 
- instrumental Activities of Daily Living (ADCS-iADL). The ADCS-iADL is defined as 
items 6a and 7-23 of the ADCS-ADL. 
iADRS score = [-1(ADAS-Cog12) + 80] + ADCS-iADL 
6.1.8. Data Adjustments/Handling/Conventions 
All collected data will be presented in listings or Clinical Data Interchange Standards 
Consortium (CDISC) datasets. Analysis results will be presented and summarized in either tables 
and/or figures. Data not participant to analysis according to this plan will not appear in any tables 
or graphs but will be included in the data listings. 
All p-values will be displayed in four decimals and rounded using standard scientific notation 
(e.g., 0.XXXX). If a p-value less than 0.0001 occurs, it will be shown in tables as < 0.0001. 
The version 24.0 of the Medical Dictionary for Regulatory Activities (MedDRA) will be used to 
classify all AEs by system organ class (SOC) and preferred term (PT). 
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Prior and concomitant medications will be classified using Anatomical Therapeutic Chemical 
class (ATC level 2) and preferred term (ATC level 4) from World Health Organization Drug 
Dictionary (WHO-DD), WHODrug Global B3 version March2021. 
Medications that start before the first dose of study drug are considered prior medications 
whether or not they were stopped prior to the first dose of study drug. Any medication 
continuing or starting on or after the first dose of study drug will be considered as concomitant. 
If a medication starts prior to the first dose of study drug and continues after the first dose of 
study drug, the medication will be considered as both prior and concomitant. 
Adverse events or medications with entirely missing start dates will be classified as treatment-
emergent or concomitant, as appropriate. 
For partial AE or medication start dates: (a) if only the day is missing, and the month and year 
match the first dose date and the end date is on or after the first dose date, or AE/medication is 
ongoing, then the date is assigned the first dose date thus the event/medication will be considered 
as treatment-emergent/concomitant; if the month and/or year do not match the first dose date or 
the end date is prior to the first dose date, then the day is assigned the first day of the month (01); 
(b) if month or the day and month are missing, and the year matches the first dose date and the 
end date is on or after the first dose date, or AE/medication is ongoing, then the date is assigned 
the first dose date; if the year does not match the first dose date or the end date is prior to the first 
dose date, then the day/month are assigned the first day of the year (01JAN). 
For partial end dates: (a) if only the day is missing, then the day is assigned the last day of the 
month; (b) if both day and month are missing, they are assigned the last day of the year 
(31DEC). 
For analysis purposes, repeat laboratory results will not be used unless the original value is 
indicated as missing or invalid.  In such cases, the first non-missing repeat value will be used for 
data analysis. The international system of units (SI) will be used in reporting all laboratory 
values. 
Participants will be analyzed by the treatment received for all safety and tolerability assessments. 
Participants are stratified through the IRT system based upon MMSE score entered. Once an 
MMSE score is entered, that participant is randomized to either high MMSE (21-27) or low 
MMSE (16-20) strata. At study start, it was decided to stratify participants in this manner so 
there would be a balance in the number of participants on placebo vs active drug (and within 
treatment arms) within each stratum. The stratification of the participants does not impact their 
probability of being assigned to different treatment arms. Once randomized through IRT, the 
MMSE score and the stratification assigned cannot be changed. 
For instances where the MMSE score was incorrectly entered into IRT, the MMSE score given 
by the vendor will be used to calculate the strata for safety and efficacy analyses if there are any 
subgroup analyses. 
All collected data will be presented in listings. Data not subject to analysis according to this plan 
will not appear in any tables or graphs but will be included only in the data listings. 
A treatment related AE is any AE with a relationship to the study drug of “Possibly Related” or 
“Probably Related” or “Reasonable Possibility”. 
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If partial dates occur, the convention for replacing missing dates for the purpose of statistical 
analysis is as follows: if just day is missing then the day assigned is the first day of the month or 
the date of first dose (if in the same month), whichever is later; if just month is missing then the 
month assigned is the month of the first dose, unless that results in a date before the first dose in 
which case the month after the first dose is used; and if both month and day are missing then the 
month assigned is the month of the first dose and the day assigned is either the first day of the 
month or the first dose date, whichever is later. 
If partial times occur, the convention is as follows: if the missing time occurs on the day of the 
first dose and both the hour and minute are missing then the time assigned is the time of the first 
dose, otherwise if both the hour and minute are missing and the date is not the date of first dose 
the time assigned is 12:00; if the date is the same as the date of the first dose and only hour is 
missing the hour assigned is 12 or the hour of first dose, whichever is later, and if the date is the 
same as the date of first dose and only the minute is missing the minute assigned is 30 or the 
minute of first dose, whichever is later. Otherwise, the hour assigned is 12 if the hour is missing 
and the date is not the same as the date of first dose and the minute assigned is 30 is the date is 
not the same as the date of first dose. 
These conventions will be applied only to adverse event onset dates and times with the following 
precaution:  if the missing date and time reflect the date and time of onset of an adverse event, 
the modified date and time will be constructed to match the first documented date/time post drug 
administration while preserving the order in which the AE was reported in the CRF. 
7. 
Study Participants and Demographics 
Participant disposition, demographics and other baseline characteristics, prior medications, and 
study drug exposure and compliance will be summarized by randomized treatment group and 
overall, using the ITT analysis set, unless otherwise specified below in each section. 
7.1. 
Disposition of Participants and Withdrawals 
Since this is a long-term study in a patient population that is elderly with multiple possible 
comorbidities, some participant withdrawal will occur. Efforts will be taken to obtain 
information on participants who are initially categorized as lost to follow-up. From the 
randomized population, the disposition of participants withdrawing from each treatment arm will 
be summarized and compared. 
Participant disposition will include tabulations of the number of overall participants who screen 
failed for blinded treatment period. The following will be summarized by randomized treatment 
group and overall: 
• Number of participants who enrolled/randomized, 
• Number and percentage of participants in each analysis set, 
• Number and percentage of participants who completed the study, and 
• Number and percentage of participants who discontinued from the study, including the 
reason for study discontinuation. 
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The percentage of participants will be based on the ITT analysis set. All disposition results will 
be presented in a data listing. 
7.2. 
Protocol Violations and Deviations 
The severity (important/non-important) will be classified using the following definitions as per 
Premier Research standard operating procedures (SOPs). A protocol deviation is any 
noncompliance with the clinical trial protocol or International Council for Harmonization of 
Technical Requirements for Pharmaceuticals for Human Use (ICH) E6 (R2) Good Clinical 
Practice (GCP) requirements.  
Protocol deviations will be tracked, recorded, and reviewed prior to database lock, following the 
Protocol Deviation Guidance Plan for this study. 
Potentially important deviations will be reviewed by the Sponsor and Premier to determine the 
final classification. Protocol deviations which are deemed to be “Important” and “Non-
Evaluable” (i.e., a deviation that has a potential impact on the efficacy analysis), will be 
classified into a separate category.  
The protocol deviation categories will be:  
• Inclusion Criteria 
• Exclusion Criteria 
• Study Drug 
• Assessment – Safety 
• Assessment – Efficacy 
• Lab/Endpoint Data 
• Visit Window 
• Informed Consent 
• Prohibited Concomitant Medication 
• Overdose/Misuse 
• Other 
The number and proportion of participants with important protocol violations/deviations will be 
tabulated by category/type and treatment group in the safety analysis set. These protocol 
violations/deviations will also be presented in a participant listing by randomized treatment.  
7.3. 
Demographics and Other Baseline Characteristics 
All participant demographics and other baseline characteristics will be summarized by 
randomized treatment group using the ITT analysis set.  Demographic and other baseline 
characteristics will also be summarized for the safety analysis set if it is different from the ITT 
analysis set.  
 
Demographic and baseline characteristics [age, sex (including child-bearing potential for 
women), methods of contraception, race, ethnicity, weight, height, body mass index (BMI), and 
education level] will be summarized using the descriptive statistics. Height and weight will be 
calculated at screening and then the BMI will be calculated at screening.  
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Additionally, baseline characteristics including AD family history, Covid-19 infection and 
vaccination history results, and Apolipoprotein E (ApoE) genotyping will be summarized.      
The number and percent of participants reporting medical history, grouped by MedDRA system 
organ class and preferred term, will be tabulated by randomized treatment group. All medical 
history data will be presented in a data listing.  
Prior medications will be summarized descriptively by treatment group using the number and 
percentage of participants by Anatomical Therapeutic Chemical class (ATC level 2) and 
preferred term (ATC level 4). All “Cognitive enhancers” defined by verbatim terms: donepezil 
(Aricept, Adlarity), galantamine (Razadyne, Reminyl), rivastigmine (Exelon) and memantine 
(Namenda, Ebixa, Nemdatine) will be summarized separately. All prior medication data will be 
listed. The cognitive enhancers will be flagged in the prior medication listing. 
For the continuous variables, the number of non-missing values and the mean, standard 
deviation, minimum, median, and maximum will be tabulated.  
For the categorical variables, the count and percentage of each value will be tabulated. 
7.4. 
Exposure and Compliance 
Study drug exposure and compliance data will be collected in the case report form (CRF). 
Study drug exposure data will be summarized as treatment duration (days), study drug exposure 
(days), and average daily dose (mg/day) by treatment received and overall. 
Study drug compliance data will be summarized as total number of planned doses (tablets), total 
number of doses (tablets) taken, and compliance (%) by treatment received and visit. 
Compliance will be summarized as a continuous outcome using mean, SD, median, min, and 
max, and as a categorical variable. For the categorical analysis, a participant will be considered 
compliant if the amount of medication taken is within the range of 75% - 125% of the amount of 
medication planned to be taken. 
All study drug administration, accountability and exposure data will be listed. 
 
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8.
Efficacy Analysis
8.1. 
Co-Primary Efficacy Analysis 
Visit wise mean changes from baseline will be analyzed in the ITT analysis set using a restricted 
maximum likelihood (REML)-based repeated measures approach (MMRM). The MMRM 
analysis assumes a missing at random (MAR) missing-data mechanism, meaning that drop out is 
related to observed outcomes of the dependent variable and covariates, but not to the unobserved 
outcomes. The analysis will include the categorical, fixed effects of treatment group, visit, and 
pooled site, along with the continuous, fixed covariates of baseline value of the endpoint being 
analyzed (baseline), baseline MMSE score, and the interactions of treatment group, baseline, and 
baseline MMSE with visit. An unstructured (co)variance structure will be used to model the 
within-participant errors. If this analysis fails to converge, the following structures will be tested 
in this order, with the first structure yielding convergence to be used as the appropriate structure 
for that variable: heterogeneous Toeplitz, heterogeneous compound symmetric, and compound 
symmetric. If one of the structures other than unstructured is used, variance of the Maximum 
Likelihood Estimator (MLE) will be based on the Sandwich Estimator (empirical option in 
PROC MIXED statement). If none of the structures yield convergence, site will be removed from 
the model and the sequence of covariance structures will be refit as described above. The 
Kenward-Roger approximation will be used to estimate denominator degrees of freedom.  
Significance tests for the between-treatment group differences will use a two-sided 0.05 level, 
with the primary analysis based on the ITT analysis set. 
8.1.1. Sensitivity Analyses of the Primary Efficacy Endpoint 
A missing not at random (MNAR)-based copy reference approach will be used as a sensitivity 
analysis to assess robustness of inferences on the co-primary analyses to departures from MAR. 
Mean changes from baseline in the co-primary endpoints will be analyzed based on data 
observed while the participants remain on study as well as data imputed using multiple 
imputation for time points at which no value is observed. 
Imputation of values in the reference (placebo) arm will assume MAR. Imputation of values in 
the active arm will be based on the imputation model for the placebo group, thereby imputing 
placebo-like values for drug group dropouts. This approach assumes any benefit from the active 
treatment diminishes over time in accordance with the correlations between repeated 
measurements.  
Intermittent (non-monotone) missing data will be imputed first based on MCMC. An example 
code fragment is included below. YOBS1-5 are the five postbaseline values of the endpoint 
being imputed. 
PROC MI DATA = XXX OUT = YYY_MIOUT NIMPUTE=200 SEED=123; 
   BY TRT; 
   MCMC IMPUTE = MONOTONE; 
   VAR BASELINE MMSE_BASELINE YOBS1 YOBS2 YOBS3 YOBS4 YOBS5; 
RUN; 
The remaining monotone missing data for all participants who discontinue study prematurely 
will be imputed using a sequential regression multiple imputation model based on data from the 
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reference arm (placebo) only. Missing values in the placebo and active arms will be imputed 
from the imputation model developed from the placebo arm. No rounding or range restrictions 
will be applied to imputed continuous values.  
Example code to implement this analysis is listed below.  
PROC MI DATA=YYY_MIOUT SEED=1214 OUT=YYY_MIOUT2 round=1 NIMPUTE=200; 
 
CLASS TRT; 
 
MONOTONE METHOD=REG; 
 
VAR  BASELINE MMSE BASELINE YOBS1 YOBS2 YOBS3 YOBS4 YOBS5; 
 
MNAR MODEL (Y1 / modelobs=(trt’1’)); 
  
MNAR MODEL (Y2 / modelobs=(trt’1’)); 
 
MNAR MODEL (Y3 / modelobs=(trt’1’)); 
 
MNAR MODEL (Y4 / modelobs=(trt’1’)); 
 
MNAR MODEL (Y5 / modelobs=(trt’1’)); 
Run; 
 
Results from analyses of the multiply imputed data sets Will be combined using Rubin’s rules as 
implemented in PROC MI Analyze. 
To assess sensitivity of inferences to handling of the intercurrent event of death, the following 
approach will be used. Missing data resulting from patient death will be imputed using the worst 
observed result at each respective visit. The primary analysis as described above will be applied 
to this data set. At the time of SAP finalization, only four patients had died. Therefore, how this 
ICE is handled is unlikely to appreciably influence results. 
  
8.2. 
Secondary Efficacy Analysis 
The iADRS, MMSE, NPI-10, and ZBI, in the ITT analysis set, and the ADAS-Cog12, ADCS-
ADL, iADRS, MMSE, NPI-10, and ZBI, in the ITT-mild analysis set will be analyzed using the 
MMRM model as described for the primary analysis, with the exception for MMSE where the 
baseline value for the endpoint being analyzed is the MMSE baseline; therefore, the model for 
MMSE will include the categorical fixed effects of treatment group, Visit, and pooled site, along 
with the continuous, fixed covariate of baseline MMSE score and the interactions of treatment 
group and baseline MMSE with Visit. 
The CDR-SB is only collected at Screening and Week 52. Therefore, the CDR-SB will be 
analyzed using ANCOVA with a model that includes treatment group, pooled site, and baseline 
MMSE. Plasma biomarkers will be analyzed with the MMRM analysis as described above. 
8.3. 
Tertiary/Exploratory Efficacy Analysis 
Plasma biomarkers will be analyzed with the MMRM analysis as described above. 
8.4. 
Subgroup Analyses of Efficacy Variables 
The co-primary endpoints and iADRS will be analyzed by baseline severity, with subgroups 
defined as screening MMSE ≥ 21 and ≤ 27 versus MMSE < 21. An additional subgroup analysis 
for the co-primary endpoints and the iADRS will use screening MMSE ≥ 20 and ≤ 27 versus 
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MMSE < 20. For these analyses, an MMRM model as previously described will be used, except 
that the model will have additional fixed effects for subgroup and its two-way interactions with 
treatment and Visit, and the 3-way subgroup-by-treatment-by-Visit interaction; and, baseline 
scores for the endpoint being analyzed and baseline MMSE and their interactions with Visit will 
be removed from the model due to their possible confounding with subgroup. Specifically, the 
analysis will include the categorical, fixed effects of treatment group, subgroup, pooled site, and 
Visit, along with the two-way interactions of treatment group with Visit and subgroup with Visit, 
and the three-way treatment group, subgroup, Visit interaction.  
Similar models will be used to analyze subgroups by age (defined as < 65, 65-74 or ≥ 75), sex 
(defined as male or female), ethnicity (categories defined per FDA Guidance), ApoE4 genotype 
(defined as APOE4 non-carrier, carrier or homozygous) and medication use (cognitive 
enhancers, defined as yes or no). 
There will be two additional subgroup analyses for the NPI-10. The first will include participants 
with a baseline NPI-10 score ≥ 2.  The second will analyze the agitation/aggression domain 
scores in participants with a non-zero baseline score in that domain.  
Note that there will be two sets of results for the mild subgroup. In section 8.2 the mild subgroup 
analyses are conducted by applying the primary analysis model to the ITT-mild analysis set. 
Those analyses are the primary means of drawing inference for the mild subgroup. The subgroup 
analyses described here for the mild / moderate subgroups are the primary means of drawing 
inference for differential efficacy between the subgroups. The analyses specified in section 8.2 
are the primary means of understanding efficacy within the mild subgroup because that approach 
allows for including the same model as other secondary and primary endpoints. 
8.5. 
Responder Analyses 
A responder analysis will report the number and percentage of participants in each treatment 
group who remain stable or show improved scores on the co-primary endpoints (analyzed 
separately), baseline to week 52. These analyses will be conducted for all participants, and for 
the mild and moderate subgroups.  
A second responder analysis for the NPI-10 will report the number and percentage of participants 
in each treatment group with a score of 0 at baseline and these numbers and percentages with a 
score of 0 again at week 52. This analysis will also be conducted for mild and moderate 
subgroups.  
The significance of the difference between treatments in response rates will be assessed using the 
Cochran-Mantel-Haenszel (CMH) test in all participants, stratified by mild / moderate disease 
status; and the difference in response rates within disease subgroups will be assessed using the 
CMH test stratified by ApoE4 carrier status.  
8.6. 
Disease Progression Analyses 
A progression analysis will report the number and percentage of participants in each treatment 
group who entered the study with mild disease at baseline (MMSE 21-27) and who then progress 
to moderate or to more severe disease (MMSE 16-20 and MMSE <16, respectively) by week 52. 
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A second progression analysis will report the number and percentage of participants in each 
treatment group who entered the study with moderate disease at baseline (MMSE 16-20) and 
who then progressed to more severe disease (MMSE <16) by week 52. 
The significance of the difference between treatments in the rate of disease progression will be 
assessed using the CMH test in all participants, stratified by mild / moderate disease status; and 
the difference in progression rate within disease subgroups will be assessed using the CMH test 
stratified by ApoE4 carrier status.  
 
8.7. 
Time-Based Analyses 
Mean changes from baseline in the co-primary endpoints will be described in terms of time 
savings. The mean change from baseline at Week 52 in the active arm will be mapped back to 
the time point at which the mean change in the placebo arm was equal to the active arm change 
at Week 52. A cubic spline interpolation will be used for precise time mapping between visits. 
Similar mappings will be done for the mean changes ± the SE of the mean changes. If a time 
mapping is outside the range spanned by the reference trajectory (e.g., mapping standard errors 
near the beginning or end of follow-up), time will be mapped off the range spanned by the 
reference trajectory via the line connecting the first visit for change from baseline (0, 0) for 
change from baseline measures and last visit measures. This time component test will be done 
based on all participants and for the mild and moderate subgroups.     
8.8. 
Pooling With Other Studies  
Pending the outcomes of individual studies, data from Protocol PTI-125-07 may be pooled with 
data from Protocol PTI-125-06. These pooled analyses will include data from weeks 0 – 52 from 
Protocol PTI-125-06 to match the duration of Protocol PTI-125-07. Objectives and estimands for 
the pooled data will mirror those in Protocol PTI-125-07. Analyses will also be similar but will 
include an additional categorical fixed effect of study. 
 
 
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9. 
Safety and Tolerability Analysis 
All safety analyses will be performed on the safety analysis set.  
Safety measures including AEs, clinical laboratory values, physical examination findings, 
neurologic examination findings, vital signs, ECGs, and concomitant medication usage will be 
summarized descriptively. No inferential statistical tests will be performed, unless otherwise 
specified. For quantitative variables, descriptive statistics including number of observations, 
mean, median, standard deviation, minimum, and maximum will be presented for observed and 
change from baseline values at each study visit. Qualitative variables will be summarized using 
counts and percentages. 
For all safety and tolerability analyses, participants will be analyzed by the actual treatment and 
dose received and, if applicable, overall. 
All safety and tolerability data will be presented in participant listings. 
9.1. 
Adverse Events 
An AE is any undesirable event that occurs to a participant during a study, whether that event is 
considered related to Study Drug.  
All summaries of AEs will be based on treatment-emergent adverse events (TEAEs) unless 
specified otherwise. 
An adverse event is considered a TEAE if: 
• 
The adverse event first occurred on or after the date of the first dose of study drug; or  
• 
The adverse event was present before the date of the first dose of study drug, but it 
increased in severity or became serious on or after the date of the first dose of study drug. 
9.1.1. Severity of Adverse Events 
The severity of each AE should be characterized and then classified into one of three clearly 
defined categories as follows: 
• Mild 
• Moderate 
• Severe 
These three categories are based on the Investigator's clinical judgment, which in turn depends 
on consideration of various factors such as the participant's report and the physician's 
observations. 
The missing severity of an AE will be imputed to “severe”. 
9.1.2. Relationship to Study Drug 
The relationship of each AE to the Study Drug will be based on the Investigator’s assessment as 
to whether there is a reasonable possibility the AE was caused by the Study Drug. 
The causal relationship between an AE and the study drug will be categorized as two cases in the 
CRFs as follows: 
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Case 1: If AE started while participant was consented under protocol v 2.0, then the categories 
will be 
• Unlikely Related, 
• Possibly Related, and 
• Probably Related. 
The missing relationship to study drug of an AE will be imputed to “Probably Related”. 
Treatment-related TEAEs are defined as the TEAEs with relationship to study drug is “Possibly 
Related” or “Probably Related”.  
Case 2: If AE started while participant was consented under protocol v 3.0 and/or above, then 
the categories will be 
• Not Related, and 
• Reasonable Possibility. 
The missing relationship to study drug of an AE will be imputed to “Reasonable Possibility”. 
Treatment-related TEAEs are defined as the TEAEs with relationship to study drug is 
“Reasonable Possibility.” 
For the analysis purposes (regardless of protocol amendment version), treatment-related TEAEs 
are defined as the TEAEs with relationship to study drug is “Possibly Related” or “Probably 
Related” or “Reasonable Possibility.”   
9.1.3. Serious Adverse Events (SAEs) 
A Serious Adverse Event (SAE) includes (but is not limited to) an experience occurring at any 
dose that results in any of the following outcomes: 
• Death, 
• Life-threatening, 
• In-patient hospitalization, 
• A persistent or significant disability/incapacity,  
• A congenital anomaly/birth defect, and 
• Other medically important event 
The number and proportion of participants who experience the event according to MedDRA 
system organ class (SOC) and preferred term (PT) will be presented by treatment group. TEAEs 
will be further summarized, individually, by maximum severity and relationship to study drug. 
Adverse events related to study drug, AEs leading to withdrawal, SAEs, and deaths will be 
similarly summarized. 
An overall summary of TEAEs will be provided by treatment. This summary will present 
number and percentage of participants with TEAEs per the following classifications:  
• Participants with any TEAEs  
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• Participants with Treatment-Emergent Drug-Related AEs   
• Participants with Treatment-Emergent AEs by Maximum Severity as Mild, Moderate, 
and Severe. 
• Participants with TEAE leading to discontinuation from study  
• Participants with Treatment-Emergent SAEs 
• Participants with Treatment-Emergent SAEs leading to discontinuation from study  
• Participants with Treatment-Emergent SAEs resulting in death 
The following summary tables for TEAEs will be presented: 
• Number and percent of participants reporting treatment-emergent AEs, grouped by 
MedDRA system organ class and preferred term 
• Number and percent of participants reporting treatment-emergent drug-related AEs, 
grouped by MedDRA system organ class, and preferred term 
• Number and percent of participants reporting treatment-emergent AEs, grouped by 
MedDRA system organ class, preferred term, and maximum severity 
• Number and percent of participants reporting treatment-emergent SAEs will be tabulated 
by system organ class and preferred term and presented by treatment. 
• Number and percent of participants reporting treatment-emergent AEs leading to study 
discontinuation, grouped by MedDRA system organ class and preferred term 
For the summary tables above, the SOC terms and PTs will be presented in decreasing order of 
the total number of participants (frequency) who experienced each AE.  System organ class 
terms and PTs with the same frequency will be presented alphabetically. In the case of multiple 
occurrences of the same TEAE within the same participant, each participant will only be counted 
once for each preferred term. 
The following data listings for AEs will be provided for each participant by displaying the events 
captured on the CRF: 
• All AEs, 
• All serious AEs, 
• All AEs leading to study discontinuation, and 
• All AEs leading to Death. 
In the AE data listings, all AEs will be displayed. AEs that are not treatment-emergent will be 
flagged in the AE listings. 
9.2. 
Clinical Laboratory Evaluations 
The following clinical laboratory tests will be performed during the Screening Period, Baseline 
(Study Day 1) pre-dose, and at all follow-up visits (Week 4, Week 16, Week 28, Week 40, and 
Week 52/ET/ED). 
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Table 3: 
Protocol-Required Safety Laboratory Tests 
Hematology 
Erythrocytes (RBC) 
Hemoglobin (HGB) 
Hematocrit (HCT) 
Platelets (PLAT) 
Basophils (BASO) 
Eosinophils (EOS) 
Lymphocytes (LYM) 
Monocytes (MONO)  
Neutrophils (NEUT) 
Basophils/Leukocytes (BASOLE) 
Leukocytes (WBC) 
Eosinophils/Leukocytes (EOSLE) 
Lymphocytes/Leukocytes (LYMLE 
Monocytes/Leukocytes (MONOLE) 
Neutrophils/Leukocytes (NEUTLE) 
Serum Chemistry 
Alanine aminotransferase (ALT) 
Albumin (ALB) 
Alkaline phosphatase (ALP) 
Aspartate aminotransferase (AST) 
Bicarbonate (BICARB) 
Bilirubin (BILI) 
Calcium (CA) 
Chloride (CL)  
Gamma-glutamyl transferase (GGT) 
Globulin (GLOBUL)  
Glucose (GLUC) 
Creatinine (CREAT)  
Lactate dehydrogenase (LDH) 
Phosphate (PHOS) 
Potassium (K) 
Protein (PROT) 
Sodium (SODIUM) 
Urea Nitrogen (UREAN) 
Urate (URATE) 
Urinalysis* 
Color (COLOR) 
Glucose (GLUC) 
Ketones (KETONES) 
Leukocyte esterase (LEUKASE) 
Nitrite (NITRITE) 
pH (PH) 
Protein (PROT) 
Specific gravity (SPGRAV) 
Occult Blood (OCCBLD) 
* A “reflex” microscopic examination will be performed if protein, occult blood, nitrites, or leukocyte esterase is 
present on the basic analysis. 
Screening Period: During the Screening Period only, bloods will be drawn for TSH, free T4, 
Vitamin B12, HepBsAg, HCV-Ab, HbA1C (diabetic participants only) and plasma P-tau181 or 
P-tau217 (Note – plasma collection for P-tau181 or P-tau217 not required if participant has 
documented evidence of AD pathophysiology prior to screening). Urine to screen for drugs of 
abuse (amphetamines, cocaine, opiates and phencyclindine) will also be collected during the 
Screening Period. 
All hematology, chemistry, and urinalysis laboratory results will be presented in SI units, if 
available. Only laboratory parameters in the Table 3, will be tabulated. 
The observed values and changes from baseline of all quantitative safety laboratory results for 
clinical chemistry, hematology, and urinalysis (only for pH and Specific Gravity results) will be 
summarized using descriptive statistics showing the number of observations (n), mean (SD), 
median, minimum, and maximum value. A separate summary table with the number and 
percentage of participants for each categorical urinalysis parameter (glucose, protein, occult 
blood, ketone, nitrite, and leukocyte esterase) will be provided. 
Baseline values for all clinical chemistry, hematology, and urinalysis parameters will be 
categorized as being below the normal range (Low), within the normal range (Normal), and 
above the normal range (High). Shift from baseline tables will present the number and 
percentage of participants who have observations that are Normal, Low, or High when such 
range characterizations are available. Shift tables will be presented for values shifting from 
Baseline (Study Day 1) to the Week 52/ET/ED. 
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Listings of all observed chemistry, hematology, and urinalysis laboratory data will be provided.  
Laboratory results outside the normal range will be flagged. The abnormal values will be flagged 
with ‘L’ (low) for values below the lower limit of the laboratory’s normal range or ‘H’ (high) for 
values above the upper limit of the laboratory’s normal range. Abnormal values will be graded as 
not clinically significant (NCS) or clinically significant (CS). 
Abnormal results from the microscopic examination will be listed. All other laboratory 
assessments will only be listed. 
9.2.1. Stopping Criteria 
Potential discontinuation of study drug for abnormal liver function tests should be considered if 
the study participant meets one or more of the following liver chemistry threshold stopping 
criteria:  
• ALT or AST ≥ 4x ULN;  
• ALT or AST ≥ 3x ULN and total bilirubin ≥ 2x ULN;  
• ALT or AST ≥ 3x ULN if associated with the appearance or worsening of fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, fever, rash and/or eosinophilia;  
or  
• ALP elevations, if deemed of liver origin and drug-related as follows:  
o ALP > 3x ULN;  
o ALP > 2.5x ULN and total bilirubin > 2x ULN; or  
o ALP > 2.5x ULN if associated with the appearance or worsening of fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, fever, rash and/or 
eosinophilia, 
where ULN = Upper Limit of Normal. 
Study drug should be discontinued if a participant: (1) positively affirms suicidal ideation in 
response to questions number 4 or 5 in the suicidal ideation section of the C-SSRS, or (2) reports 
any suicidal behavior or non-suicidal self-injurious behavior since their last visit in response to 
the C-SSRS Suicidal Behavior questions.  
Bodyweight loss (compared to weight at Baseline Visit [Study Day 1]) of ≥ 2 kg resulting in a 
BMI < 18.5 is an additional stopping criterion. 
Individual results of stopping criteria will be listed and summarized by presenting the number 
and percentage of participants who meet at least one post-dose stopping criteria. 
9.3. 
Vital Signs 
Descriptive summaries of observed values and changes from baseline will be presented for 
systolic blood pressure, diastolic blood pressure, heart rate, and temperature which will be 
measured at the following visits. 
Screening Period, Baseline (Study Day 1), Week 4, Week 16, Week 28, Week 40, and Week 
52/ET/ED. 
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Body weight will be summarized descriptively in the tabulations for the visits at which it will be 
measured. 
Body Mass Index (BMI): Baseline BMI results will be used from vital sign page in EDC and 
post baseline BMI results will be derived using post baseline body weights at each visit and 
screening height. A visit wise descriptive summary and change from baseline analysis of BMI 
will be provided. 
Formula for BMI = weight in kg/ (height in metre)2. 
All vital signs results will be listed. 
9.4. 
Standard 12-lead ECG  
12-lead ECGs will be performed at the following visits: 
Screening Period, Baseline (Study Day 1), Week 4, Week 28, and Week 52/ET/ED. 
12-lead ECG readings will be obtained using an ECG machine that automatically calculates the 
heart rate and measures PR interval, QRS interval, RR interval, QT interval, QTcB interval 
(corrected QT according to Bazett), and QTcF interval (corrected QT according to Fridericia). 
All scheduled ECGs should be performed after the participant has rested quietly for at least 5 
minutes in a supine position.  
12-lead ECGs will be performed in triplicate at Baseline (Study Day 1) and thus the triplicates 
will be averaged for the summaries. 
The ECG results will be interpreted as ‘Normal’, and ‘Abnormal, Not Clinically Significant 
(NCS)’, and ‘Abnormal, Clinically Significant (CS)’. 
The overall assessment by treatment group will be summarized at each timepoint using number 
and percent of participants. 
For Heart Rate (beats/min), PR interval (msec), RR Interval (msec), QRS Interval (msec), QT 
Interval (msec), QTcF (msec), QTcB (msec), the observed and change from baseline data will be 
descriptively summarized by treatment group showing the number of observations (n), mean, 
SD, median, minimum, and maximum value.  
The number and percentage of participants having observed QT, QTcB and QTcF values that 
satisfy the following conditions will be summarized: 
• ≤ 450 msec 
• > 450 to ≤ 500 msec 
• > 500 msec 
The number and percentage of participants having change from baseline QT, QTcB and QTcF 
values that satisfy the following conditions will be presented: 
• ≤ 0 msec 
• > 0 to ≤ 30 msec 
• > 30 to ≤ 60 msec 
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• > 60 msec 
All ECG findings will be listed. 
9.5. 
Further Safety Evaluations 
9.5.1. Physical Examinations 
A complete physical examination will include the body systems: Skin, Head, Ears, Eyes, Nose, 
Throat, Neck/Thyroid, Lymph Nodes, Cardiovascular, Respiratory, Abdomen, Musculoskeletal, 
Extremities, and Other; and it will be performed at the Screening visit only. All participants with 
‘Normal’, ‘Abnormal, Not Clinically Significant (NCS)’, and ‘Abnormal, Clinically Significant 
(CS)’ physical exam (complete) findings will only be listed.  
A brief physical examination will include the body systems: general appearance, Cardiovascular, 
Respiratory, Abdomen, and Other; and it will be performed at the following visits: 
Baseline (Study Day 1), Week 4, Week 16, Week 28, Week 40, and Week 52/ET/ED. 
The number and percentage of participants with ‘Normal’, ‘Abnormal, Not Clinically Significant 
(NCS)’, and ‘Abnormal, Clinically Significant (CS)’ physical exam (brief) findings will be 
summarized by study visits.  
All brief physical examination findings will be listed. 
9.5.2. Neurologic Examinations 
A complete neurologic examination will be performed at the Screening visit only. All complete 
neurologic examination findings will only be listed. 
A brief neurologic examination will include the exam categories; cranial nerves [II-XII], tone, 
power, deep tendon reflexes, coordination, and gait; and it will be performed at the following 
visits: Baseline (Study Day 1), Week 4, Week 16, Week 28, Week 40, and Week 52/ET/ED. 
The number and percentage of participants with ‘normal’, ‘Abnormal’, and ‘Not Done’ 
neurologic exam (brief) findings will be summarized by study visits.  
All brief neurologic examination findings will be listed. 
9.6. 
Concomitant Medications 
Concomitant medications will be summarized descriptively by treatment group using the number 
and percentage of participants by Anatomical Therapeutic Chemical class (ATC level 2) and 
preferred term (ATC level 4).  
All “Cognitive enhancers” defined by verbatim terms: donepezil (Aricept, Adlarity), galantamine 
(Razadyne, Reminyl), rivastigmine (Exelon) and memantine (Namenda, Ebixa, Nemdatine) will 
be summarized separately. All concomitant medication data will be listed. The cognitive 
enhancers will be flagged in the concomitant medication listing. 
9.7. 
Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is routinely used to quantify the presence and severity of suicidal ideation and 
behavior. Both the ideation and behavior subscales are sensitive to change over time. 
Two versions of the C-SSRS will be used in this study: the Baseline/Screening version and the 
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Since Last Visit version. The Baseline/Screening version of the C-SSRS assesses lifetime 
suicidal ideation and behavior. The Since Last Visit version of the C-SSRS assesses suicidal 
thoughts or behaviors the participant may have had since the last time the C-SSRS was 
administered.  
At the screening visit, the C-SSRS Baseline/Screening version will be administered. At all 
subsequent visits (Baseline, Week 4, Week 16, Week 28, Week 40, and Week 52/ET/ED ), the 
C-SSRS Since Last Visit version will be administered. 
The C-SSRS includes “yes” or “no” responses for assessment of suicidal ideation and behavior 
as well as numeric ratings for severity of ideation, if present (from 1 to 5, with 5 being the most 
severe).  A score of 0 is assigned if no ideation is present. 
Self-injurious behavior without suicidal intent is also a C-SSRS outcome (although not suicide-
related) and has a binary response (yes/no). 
Composite endpoints are defined below: 
• Suicidal ideation: A “yes” answer at any time during treatment to any one of the five 
suicidal ideation questions (Categories 1-5) on the C-SSRS. 
• Suicidal behavior: A “yes” answer at any time during treatment to any one of the five 
suicidal behavior questions (Categories 6-10) on the C-SSRS. 
• Suicidal ideation or behavior: A “yes” answer at any time during treatment to any one of 
the ten suicidal ideation and behavior questions (Categories 1-10) on the C-SSRS. 
Baseline is defined as the most severe ideation and behavior reported prior to the first dose of 
study drug (C-SSRS assessment date <= first dose date of study drug). Suicidality data collected 
on the C-SSRS will be listed for all participants. Tables will include results from the Suicidal 
Ideation and Suicidal Behavior sections of the C-SSRS.  The number and percentage of 
participants with a response of “Yes” at any point as well as by study visit on the Suicidal 
Ideation and Suicidal Behavior items will be summarized by treatment received.   
Additionally, shifts of whether participants experienced suicidal ideation, behavior, or both from 
pre-treatment to post-treatment will be summarized in a shift table. An additional shift table of 
maximum ideation from pre-treatment to post-treatment will also be provided. 
All C-SSRS data will be listed. 
All other safety evaluations including brain MRI data, urine drug screen results, screening 
laboratory assessments, Genotyping results collected at Baseline (Study Day 1), and Follow-up 
Phone Call data will be listed. 
10. 
Changes from Planned Analysis 
Not Applicable. 
 
 
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11. 
Other Planned Analysis 
11.1. Renal Insufficiency Analysis 
The purpose of this analysis is to characterize the effect of renal impairment on the safety, and 
tolerability of simufilam. 
Participants will be categorized into normal renal function or renal impairment groups based on 
their estimated glomerular filtration rate (eGFR) as shown in the table below. 
Table 4: Renal Function Categories by eGFR Ranges 
Renal Impairmenta 
Estimated eGFR (mL/min) 
None (Normal) 
≥ 90 
Mild Renal Impairment 
60 - 89 
Moderate renal impairment 
≥30 to <60 
Severe Renal Impairment 
≥15 to <30 
a. 
Stages of renal impairment are based on Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation 
(2021) – for Adult Participants (≥ 18 years)  
11.1.1 Calculation of eGFR:  
The eGFR (in mL/min) will be calculated using the Chronic Kidney Disease Epidemiology 
Collaboration (CKD-EPI) equation (2021) – for Adult Participants (≥ 18 years): 
𝑒𝐺𝐹𝑅= 142 × [min(𝑆𝐶𝑟𝑘
⁄ , 1)]𝛼× [max(𝑆𝐶𝑟𝑘
⁄ , 1)]−1.200 × 0.9938𝐴𝑔𝑒× 1.012 (𝑖𝑓 𝑓𝑒𝑚𝑎𝑙𝑒) 
where 
SCr = standardized serum creatinine in mg/dL  
k = 0.7 for females or 0.9 for males  
α = -0.241 for females or -0.302 for males  
min (SCr/k, 1) is the minimum value of SCr/k or 1.0 
max (SCr/k, 1) is the maximum value of SCr/k or 1.0 
age in years 
As the Creatinine is collected at the visits; Day 1 (Baseline), Week 4, Week 16, Week 40, and 
Week 52, eGFR will be calculated at the same visits. 
11.1.2 Statistical Methods and Analysis 
11.1.2.1 
Statistical Summaries on Creatinine, eGFR and Renal Function 
The descriptive statistics of the observed and the change from baseline in Creatinine will be 
summarized by treatment group and renal function through Week 52. The same information will 
be graphically displayed using a clustered bar chart. 
The descriptive summary statistics of eGFR will be presented by treatment group and renal 
function through Week 52. 
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The number of participants and percentages of renal function will be presented for the 
subgroups; MMSE (16-20, 21-27), age (>=75, 65-74, and < 65), sex, and ethnicity, by treatment 
group at Baseline (Day 1). 
11.1.2.2 
Statistical Summaries on Select TEAEs vs Renal Function at Baseline (Day 1) 
The effect of renal impairment on TEAEs will be characterized by displaying the summary 
statistics as well as the plots. 
A summary of TEAEs by relatedness and renal function derived at Baseline (Day 1) will be 
provided by treatment groups. 
A summary of select TEAEs Incidence by Renal Function derived at Baseline (Day 1) will be 
provided along with a clustered bar plot, where the select TEAEs of interest (Preferred Terms of 
the 10 most frequent TEAEs at the end of the study) when assessing the impact of study drug 
according to renal function. 
11.2. Pharmacokinetic Analysis 
The PK analysis is being completed by another organization and is not included in this SAP. 
12.
References
1. Protocol number PTI-125-07, A Phase 3, Randomized, Double-Blind, Placebo-
Controlled, Parallel-Group, 52-Week Study Evaluating the Safety and Efficacy of 
Simufilam 100 mg Tablets in Subjects with Mild-to-Moderate Alzheimer’s Disease, 
dated 15-FEB-2023 (version 3.0).
2. ASA. (2018) Ethical Guidelines for Statistical Practice. Prepared by the Committee on 
Professional Ethics, April 2018. http://www.amstat.org/about/ethicalguidelines.cfm
3. ICH (1998). ICH Harmonised Tripartite Guideline. Statistical Principles for Clinical 
Trials E9; 1998. https://database.ich.org/sites/default/files/E9_Guideline.pdf
4. RSS. (2014) The Royal Statistical Society: Code of Conduct, 2014.
https://rss.org.uk/about/policy-and-guidelines/code-of-conduct/.
13.
Tables, Listings, and Figures
13.1. Demographic Data Summary Tables and Figures 
Table 5: Demographic Data Summary Tables and Figures 
Table Number 
Population 
Table Title/Summary 
14.1.1 
All Subjects 
Subject Disposition (Includes All Early Terminations) 
14.1.2.1.1 
ITT 
Demographics and Baseline Characteristics 
14.1.2.1.2 
ITT-mild 
Demographics and Baseline Characteristics 
14.1.2.2 
Safety 
Demographics and Baseline Characteristics 
14.1.2.3.1 
ITT 
Medical History 
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14.1.2.3.2 
ITT-mild 
Medical History 
14.1.2.4.1.1 
ITT 
Prior Medications 
14.1.2.4.1.2 
ITT-mild 
Prior Medications 
14.1.3.1 
Safety 
Study Drug Exposure 
14.1.3.2 
Safety 
Study Drug Compliance by Visit 
14.1.4.1 
ITT 
Important Protocol Deviations 
14.1.4.2 
ITT-mild 
Important Protocol Deviations 
13.2. Efficacy Data 
Table 6: Efficacy Data 
Table Number 
Population 
Table Title/Summary 
14.2.1 
ITT 
Summary of Primary, Secondary, and Exploratory Endpoints-Primary 
Efficacy model 
14.2.2.1.1 
ITT 
Summary of Change from Baseline to Week 52 in ADAS-Cog12 Total 
Score by Visit and Treatment 
14.2.2.1.2 
ITT 
Summary of Change from Baseline to Week 52 in ADAS-Cog12 Total 
Score By Visit and Treatment: Responder Analysis 
14.2.2.1.3 
ITT 
Summary of Change from Baseline to Week 52 in ADAS-Cog12 Total 
Score By Visit and Treatment: Time Component Test 
14.2.2.2 
ITT-mild 
Summary of Change from Baseline to Week 52 in ADAS-Cog12 Total 
Score By Visit and Treatment 
14.2.2.3 
ITT 
Summary of Change from Baseline to Week 52 in ADAS-Cog12 Total 
Score By Visit and Treatment: Imputation Missing Not at Random 
14.2.2.4.1 
ITT 
Summary of Change from Baseline to Week 52 in ADAS-Cog12 Total 
Score By Visit and Treatment Stratified by Mild (21-27)/Moderate (<21) 
AD Status 
14.2.2.4.2 
ITT 
Summary of Change from Baseline to Week 52 in ADAS-Cog12 Total 
Score By Visit and Treatment Stratified by Mild (21-27)/Moderate (<21) 
AD Status: Responder Analysis 
14.2.2.4.3 
ITT 
Summary of Change from Baseline to Week 52 in ADAS-Cog12 Total 
Score By Visit and Treatment Stratified by Mild (21-27)/Moderate (<21) 
AD Status: Time Component Test 
14.2.2.5.1 
ITT 
Summary of Change from Baseline to Week 52 in ADAS-Cog12 Total 
Score By Visit and Treatment Stratified by Mild (20-27)/Moderate (<20) 
AD Status 
14.2.2.5.2 
ITT 
Summary of Change from Baseline to Week 52 in ADAS-Cog12 Total 
Score By Visit and Treatment Stratified by Mild (20-27)/Moderate (<20) 
AD Status : Responder Analysis 
14.2.2.6 
ITT 
Summary of Change from Baseline to Week 52 in ADAS-Cog12 Total 
Score By Visit and Treatment Stratified by Age 
14.2.2.7 
ITT 
Summary of Change from Baseline to Week 52 in ADAS-Cog12 Total 
Score By Visit and Treatment Stratified by Gender 
14.2.2.8 
ITT 
Summary of Change from Baseline to Week 52 in ADAS-Cog12 Total 
Score By Visit and Treatment Stratified by Ethnicity 
14.2.2.9 
ITT 
Summary of Change from Baseline to Week 52 in ADAS-Cog12 Total 
Score By Visit and Treatment Stratified by Race 
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Table Number 
Population 
Table Title/Summary 
14.2.2.10 
ITT 
Summary of Change from Baseline to Week 52 in ADAS-Cog12 Total 
Score By Visit and Treatment Stratified by ApoE Genotype 
14.2.2.11 
ITT 
Summary of Change from Baseline to Week 52 in ADAS-Cog12 Total 
Score By Visit and Treatment Stratified by Baseline Cognitive Enhancer 
Status 
14.2.3.1.1 
ITT 
Summary of Change from Baseline to Week 52 in ADCS-ADL Total 
Score By Visit and Treatment 
14.2.3.1.2 
ITT 
Summary of Change from Baseline to Week 52 in ADCS-ADL Total 
Score By Visit and Treatment: Responder Analysis 
14.2.3.1.3 
ITT 
Summary of Change from Baseline to Week 52 in ADCS-ADL Total 
Score By Visit and Treatment: Time Component Test 
14.2.3.2 
ITT-mild 
Summary of Change from Baseline to Week 52 in ADCS-ADL Total 
Score By Visit and Treatment 
14.2.3.3 
ITT 
Summary of Change from Baseline to Week 52 in ADCS-ADL Total 
Score By Visit and Treatment: Imputation Missing Not at Random 
14.2.3.4.1 
ITT 
Summary of Change from Baseline to Week 52 in ADCS-ADL Total 
Score By Visit and Treatment Stratified by Mild (21-27)/Moderate (<21) 
AD Status 
14.2.3.4.2 
ITT 
Summary of Change from Baseline to Week 52 in ADCS-ADL Total 
Score By Visit and Treatment Stratified by Mild (21-27)/Moderate (<21) 
AD Status : Responder Analysis 
14.2.3.4.3 
ITT 
Summary of Change from Baseline to Week 52 in ADCS-ADL Total 
Score By Visit and Treatment Stratified by Mild (21-27)/Moderate (<21) 
AD Status : Time Component Test 
14.2.3.5.1 
ITT 
Summary of Change from Baseline to Week 52 in ADCS-ADL Total 
Score By Visit and Treatment Stratified by Mild (20-27)/Moderate (<20) 
AD Status 
14.2.3.5.2 
ITT 
Summary of Change from Baseline to Week 52 in ADCS-ADL Total 
Score By Visit and Treatment Stratified by Mild (20-27)/Moderate (<20) 
AD Status : Responder Analysis 
14.2.3.6 
ITT 
Summary of Change from Baseline to Week 52 in ADCS-ADL Total 
Score By Visit and Treatment Stratified by Age 
14.2.3.7 
ITT 
Summary of Change from Baseline to Week 52 in ADCS-ADL Total 
Score By Visit and Treatment Stratified by Gender 
14.2.3.8 
ITT 
Summary of Change from Baseline to Week 52 in ADCS-ADL Total 
Score By Visit and Treatment Stratified by Ethnicity 
14.2.3.9 
ITT 
Summary of Change from Baseline to Week 52 in ADCS-ADL Total 
Score By Visit and Treatment Stratified by Race 
14.2.3.10 
ITT 
Summary of Change from Baseline to Week 52 in ADCS-ADL Total 
Score By Visit and Treatment Stratified by ApoE Genotype 
14.2.3.11 
ITT 
Summary of Change from Baseline to Week 52 in ADCS-ADL Total 
Score By Visit and Treatment Stratified by Baseline Cognitive Enhancer 
Status 
14.2.4.1 
ITT 
Summary of Change from Baseline to Week 52 in iADRS Total Score 
By Visit and Treatment 
14.2.4.2 
ITT-mild 
Summary of Change from Baseline to Week 52 in iADRS Total Score 
By Visit and Treatment 
14.2.4.3 
ITT 
Summary of Change from Baseline to Week 52 in iADRS Total Score 
By Visit and Treatment Stratified by Mild (21-27)/Moderate (<21) AD 
Status 
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Table Number 
Population 
Table Title/Summary 
14.2.4.4 
ITT 
Summary of Change from Baseline to Week 52 in iADRS Total Score 
By Visit and Treatment Stratified by Mild (20-27)/Moderate (<20) AD 
Status 
14.2.4.5 
ITT 
Summary of Change from Baseline to Week 52 in iADRS Total Score 
By Visit and Treatment Stratified by Age 
14.2.4.6 
ITT 
Summary of Change from Baseline to Week 52 in iADRS Total Score 
By Visit and Treatment Stratified by Gender 
14.2.4.7 
ITT 
Summary of Change from Baseline to Week 52 in iADRS Total Score 
By Visit and Treatment Stratified by Ethnicity 
14.2.4.8 
ITT 
Summary of Change from Baseline to Week 52 in iADRS Total Score 
By Visit and Treatment Stratified by Race 
14.2.4.9 
ITT 
Summary of Change from Baseline to Week 52 in iADRS Total Score 
By Visit and Treatment Stratified by ApoE Genotype 
14.2.4.10 
ITT 
Summary of Change from Baseline to Week 52 in iADRS Total Score 
By Visit and Treatment Stratified by Baseline Cognitive Enhancer Status 
14.2.5.1 
ITT 
Summary of Change from Baseline to Week 52 in MMSE Total Score 
By Visit and Treatment 
14.2.5.2 
ITT-mild 
Summary of Change from Baseline to Week 52 in MMSE Total Score 
By Visit and Treatment 
14.2.6.1 
ITT 
Summary of Change from Baseline to Week 52 in CDR-SB Total Score 
By Visit and Treatment 
14.2.6.2 
ITT-mild 
Summary of Change from Baseline to Week 52 in CDR-SB Total Score 
By Visit and Treatment 
14.2.7.1.1 
ITT 
Summary of Change from Baseline to Week 52 in NPI Total Score By 
Visit and Treatment 
14.2.7.1.2 
ITT 
Summary of Change from Baseline to Week 52 in NPI Total Score By 
Visit and Treatment in Subgroup of Individuals with an NPI-10 Score ≥2 
14.2.7.1.3 
ITT 
Summary of Change from Baseline to Week 52 in NPI Agitation and 
Aggression Domain Scores By Visit and Treatment in Subgroup of 
Individuals with a non-zero Domain Score at Baseline 
14.2.7.1.4 
ITT 
Summary of Change from Baseline to Week 52 in NPI Total Score By 
Visit and Treatment: Responder Analysis 
14.2.7.2.1 
ITT-mild 
Summary of Change from Baseline to Week 52 in NPI Total Score By 
Visit and Treatment 
14.2.7.2.2 
ITT 
Summary of Change from Baseline to Week 52 in NPI Total Score By 
Visit and Treatment Stratified by Mild (21-27)/Moderate (<21) AD 
Status : Responder Analysis 
14.2.7.2.3 
ITT 
Summary of Change from Baseline to Week 52 in NPI Total Score By 
Visit and Treatment Stratified by Mild (20-27)/Moderate (<20) AD 
Status : Responder Analysis 
14.2.8.1 
ITT 
Summary of Change from Baseline to Week 52 in Zarit Burden Index By 
Visit and Treatment 
14.2.8.2 
ITT-mild 
Summary of Change from Baseline to Week 52 in Zarit Burden Index By 
Visit and Treatment 
14.2.9.1 
ITT 
Summary of Change from Baseline to Week 52 in P-tau 217 By Visit and 
Treatment 
14.2.10.1 
ITT 
Summary of Change from Baseline to Week 52 in GFAP By Visit and 
Treatment 
14.2.11.1 
ITT 
Summary of Change from Baseline to Week 52 in NfL by Visit and 
Treatment 
14.2.12.1 
ITT 
Summary of Change from Baseline to Week 52 in Total Tau by Visit and 
Treatment 
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Table Number 
Population 
Table Title/Summary 
14.2.13.1 
ITT 
Summary of Individuals Entering the Study with Mild (MMSE:21-27) 
Alzheimer's Disease (AD) and Progressed to Moderate (MMSE:16-20) or 
Severe (MMSE:<16) AD by Week 52 
14.2.13.2 
ITT 
Summary of Individuals Entering the Study with Moderate (MMSE:16-
20) Alzheimer's Disease and Progressed to Severe (Moderate:<16) AD 
by Week 52 
13.3. Safety Data 
Table 7: Safety Data 
Table Number 
Population 
Table Title/Summary 
14.3.1 Displays of Adverse Events 
14.3.1.1 
Safety 
Overall Summary of Treatment Emergent Adverse Events 
14.3.1.2 
Safety 
Summary of Treatment Emergent Adverse Events by System Organ 
Class and Preferred Term 
14.3.1.3 
Safety 
Summary of Treatment Emergent Drug-Related Adverse Events by 
System Organ Class and Preferred Term 
14.3.1.4 
Safety 
Summary of Treatment Emergent Adverse Events by System Organ 
Class, Preferred Term, and Maximum Severity 
14.3.1.5 
Safety 
Summary of Serious Treatment Emergent Adverse Events by System 
Organ Class and Preferred Term 
14.3.1.6 
Safety 
Summary of Treatment Emergent Adverse Events Leading to Study 
Discontinuation by System Organ Class and Preferred Term 
14.3.2 Summary of Deaths, Other Serious and Significant Adverse Events 
14.3.2.1 
Safety 
Listing of Serious Adverse Events 
14.3.2.2 
Safety 
Listing of Adverse Events Leading to Study Discontinuation 
14.3.2.3 
Safety 
Listing of Adverse Events Leading to Death 
14.3.5 Laboratory Data Summary Tables 
14.3.5.1.1 
Safety 
Summary of Laboratory Results - Serum Chemistry 
14.3.5.1.2 
Safety 
Summary of Shift from Baseline in Serum Chemistry Results 
14.3.5.2.1 
Safety 
Summary of Laboratory Results-Hematology 
14.3.5.2.2 
Safety 
Summary of Shift from Baseline in Hematology Results 
14.3.5.3.1 
Safety 
Summary of Laboratory Results -Urinalysis 
14.3.5.3.2 
Safety 
Summary of Categorical Urinalysis Results 
14.3.5.4 
Safety 
Summary of Stopping Criteria by Treatment 
14.3.6 Other Safety Data Summary Tables 
14.3.6.1 
Safety 
Summary of Vital Signs Results 
14.3.6.2 
Safety 
Summary of Weights and BMI 
14.3.7.1 
Safety 
Summary of Concomitant Medications 
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Table Number 
Population 
Table Title/Summary 
14.3.7.2 
Safety 
Summary of Concomitant Medications-Cognitive Enhancers Taken Prior 
to First Dose of Study Drug 
14.3.7.3 
Safety 
Summary of Concomitant Medications-Cognitive Enhancers Taken Post 
First Dose of Study Drug 
14.3.8.1 
Safety 
Summary of Electrocardiogram Quantitative Results 
14.3.8.2 
Safety 
Summary of Electrocardiogram Interpretation Results 
14.3.8.3 
Safety 
Summary of Observed Categorical ECGs 
14.3.8.4 
Safety 
Summary of Change from Baseline Categorical ECGs 
14.3.9.1 
Safety 
Summary of Physical Examination (Brief) Results 
14.3.9.2 
Safety 
Summary of Neurological Examination (Brief) Results 
14.3.10.1 
Safety 
Summary of Columbia-Suicide Severity Rating Scale (C-SSRS) Suicidal 
Ideation and Suicidal Behavior Experienced at Any Time Post-Treatment 
14.3.10.2 
Safety 
Summary of Columbia-Suicide Severity Rating Scale (C-SSRS) Suicidal 
Ideation and Suicidal Behavior by Study Visit 
14.3.10.3 
Safety 
Shift of Columbia-Suicide Severity Rating Scale (C-SSRS) Suicidal 
Ideation and Suicidal Behavior from Pre-Treatment to Post-Treatment 
14.3.10.4 
Safety 
Shift of Columbia-Suicide Severity Rating Scale (C-SSRS) Suicidal 
Ideation Scores from Baseline to Treatment Period 
14.3.5 Other Data Summary Tables 
14.5.1.1 
Safety 
Summary of Creatinine (umol/L) by Renal Function by Visit 
14.5.1.2 
Safety 
Summary of eGFR (mL/min) by Renal Function by Visit 
14.5.1.3 
Safety 
Summary of Renal Function by Subgroups at Baseline 
14.5.2.1 
Safety 
Summary of TEAEs by Relatedness by Renal Function 
14.5.2.2 
Safety 
Summary of Select TEAEs by Renal Function 
13.4. Planned Listing Descriptions 
The following are planned data and participant data listings for protocol number PTI-125-07.  
In general, one listing will be produced per CRF domain. All listings will be sorted by treatment, 
and participant number. All calculated variables will be included in the listings. 
In all listings a blank line will be placed between each participant. Within a data listing, if an 
item appears line after line (e.g., repetition of participant number), then only the first occurrence 
will be displayed. 
In data listings, the information for one participant will be kept on one page if at all possible, 
rather than splitting a participant’s information across pages. 
Table 8: Planned Listings 
Data Listing Number 
Table Title/Summary 
16.2 Subject Data Listings 
16.2.1 Subject Discontinuations/Completions 
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Data Listing Number 
Table Title/Summary 
16.2.1.1 
Subject Disposition 
16.2.1.2 
Inclusion and Exclusion Criteria 
16.2.1.3 
Subject Randomization 
16.2.2 Protocol Deviations 
16.2.2 
Protocol Deviations 
16.2.3 Subjects Excluded from the Efficacy Analyses 
16.2.3 
Analysis Populations 
16.2.4 Demographic Data and Other Baseline Characteristics 
16.2.4.1 
Demographic and Baseline Characteristics 
16.2.4.2 
Medical or Surgical History 
16.2.4.3 
Alzheimer's Disease History 
16.2.4.4 
COVID-19 History 
16.2.4.5 
Brain MRI 
16.2.5 Compliance and/or Drug Concentration Data 
16.2.5.1 
Study Drug Administration   
16.2.5.2 
Drug Accountability 
16.2.5.3 
Compliance 
16.2.6 Individual Efficacy Response Data 
16.2.6.1 
Listing of Mini Mental State Exam (MMSE) Score by Visit and Treatment and 
Population 
16.2.6.2 
Listing of Geriatric Depression Scale (GDS) by Visit and Treatment and Population 
16.2.6.3 
Listing of ADAS-Cog12 Score by Visit and Treatment and Population 
16.2.6.4 
Listing of ADCS-Activities of Daily Living (ADCS-ADL) by Visit and Treatment and 
Population 
16.2.6.5 
Listing of Clinical Dementia Rating Scale (CDR) by Visit and Treatment and 
Population 
16.2.6.6 
Listing of Neuropsychiatric Inventory (NPI) by Visit and Treatment and Population 
16.2.6.7 
Listing of Zarit Caregiver Burden Interview (ZBI-22) by Visit and Treatment and 
Population 
16.2.6.8 
Listing of P-Tau 217 by Visit and Treatment 
16.2.6.9 
Listing of GFAP by Visit and Treatment 
16.2.6.10 
Listing of NFL by Visit and Treatment 
16.2.6.11 
Listing of Total Tau by Visit and Treatment  
16.2.7 Adverse Event Listings 
16.2.7.1 
Treatment Emergent Adverse Events 
16.2.7.2. 
Select Treatment Emergent Adverse Events Used for Renal Function  
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Data Listing Number 
Table Title/Summary 
16.2.8 Laboratory Values (by Subject) 
16.2.8.1.1 
Laboratory Results: Serum Chemistry 
16.2.8.1.2 
Laboratory Results: Hematology 
16.2.8.1.3 
Laboratory Results: Urinalysis 
16.2.8.1.4 
Screening Laboratory Assessments 
16.2.8.2 
Urine Drug Screen 
16.2.8.3 
Genotyping Sample Collection 
16.2.8.4 
Pharmacokinetic Results 
16.2.8.5 
Subjects Who Met Stopping Criteria   
16.2.8.6 
Creatinine, eGFR, and Renal Function 
16.2.9 Other Clinical Observations and Measurements (by Subject) 
16.2.9.1.1.1 
Physical Examination (Complete) 
16.2.9.1.1.2 
Physical Examination (Brief) 
16.2.9.1.2.1 
Neurologic Examination (Complete) 
16.2.9.1.2.2 
Neurologic Examination (Brief) 
16.2.9.2.1 
Vital Signs 
16.2.9.3.1 
Prior and Concomitant Medications 
16.2.9.3.2 
Concomitant Medications – Cognitive Enhancers 
16.2.9.4.1 
12-Lead Electrocardiogram (ECG) Quantitative Results 
16.2.9.4.2 
12-Lead Electrocardiogram (ECG) Categorical Results 
16.2.9.5 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
16.2.9.6.1 
COVID-19 Impact 
16.2.9.6.2 
COVID-19 Study Drug Impact 
16.2.9.7 
Follow-up Phone Calls 
13.5. Planned Figure Descriptions 
The following are planned summary figures for protocol number PTI-125-07. The figure 
numbers and page numbers are place holders only and will be determined when the figures are 
produced. 
Table 9: Planned Figures 
Figure Number 
Population 
Figure Title/Summary 
14.6.1.1 
Safety 
Plot of Creatine (umol/L) Changes from Baseline by Renal 
Function and Treatment at Each Post-Baseline Visit 
14.6.1.2 
Safety 
Plot of eGFR (mL/min) Changes from Baseline by Renal Function 
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and Treatment at Each Post-Baseline Visit 
14.6.2.1 
Safety 
Plot of Drug-Related TEAEs by Renal Function and Treatment  
14.6.2.2 
Safety 
Plot of Select TEAEs by Renal Function and Treatment 
Efficacy 
 
 
14.2.1 
ITT 
Summary of Primary, Secondary, and Exploratory Endpoints-
Primary Efficacy model 
14.2.2.1.1 
ITT 
Summary of Change from Baseline to Week 52 in ADAS-Cog12 
Total Score By Visit and Treatment 
14.2.2.1.2 
ITT 
Summary of Change from Baseline to Week 52 in ADAS-Cog12 
Total Score By Visit and Treatment: Responder Analysis 
14.2.2.1.3 
ITT 
Summary of Change from Baseline to Week 52 in ADAS-Cog12 
Total Score By Visit and Treatment:Time Component Test 
14.2.2.2 
ITT-mild 
Summary of Change from Baseline to Week 52 in ADAS-Cog12 
Total Score By Visit and Treatment 
14.2.2.3 
ITT 
Summary of Change from Baseline to Week 52 in ADAS-Cog12 
Total Score By Visit and Treatment: Imputation Missing Not at 
Random 
14.2.2.4.1 
ITT 
Summary of Change from Baseline to Week 52 in ADAS-Cog12 
Total Score By Visit and Treatment Stratified by Mild (21-
27)/Moderate (<21) AD Status 
14.2.2.4.2 
ITT 
Summary of Change from Baseline to Week 52 in ADAS-Cog12 
Total Score By Visit and Treatment Stratified by Mild (21-
27)/Moderate (<21) AD Status: Responder Analysis 
14.2.2.4.3 
ITT 
Summary of Change from Baseline to Week 52 in ADAS-Cog12 
Total Score By Visit and Treatment Stratified by Mild (21-
27)/Moderate (<21) AD Status: Time Component Test 
14.2.2.5.1 
ITT 
Summary of Change from Baseline to Week 52 in ADAS-Cog12 
Total Score By Visit and Treatment Stratified by Mild (20-
27)/Moderate (<20) AD Status 
14.2.2.5.2 
ITT 
Summary of Change from Baseline to Week 52 in ADAS-Cog12 
Total Score By Visit and Treatment Stratified by Mild (20-
27)/Moderate (<20) AD Status : Responder Analysis 
14.2.2.6 
ITT 
Summary of Change from Baseline to Week 52 in ADAS-Cog12 
Total Score By Visit and Treatment Stratified by Age 
14.2.2.7 
ITT 
Summary of Change from Baseline to Week 52 in ADAS-Cog12 
Total Score By Visit and Treatment Stratified by Gender 
14.2.2.8 
ITT 
Summary of Change from Baseline to Week 52 in ADAS-Cog12 
Total Score By Visit and Treatment Stratified by Ethnicity 
14.2.2.9 
ITT 
Summary of Change from Baseline to Week 52 in ADAS-Cog12 
Total Score By Visit and Treatment Stratified by Race 
14.2.2.10 
ITT 
Summary of Change from Baseline to Week 52 in ADAS-Cog12 
Total Score By Visit and Treatment Stratified by ApoE Genotype 
14.2.2.11 
ITT 
Summary of Change from Baseline to Week 52 in ADAS-Cog12 
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Total Score By Visit and Treatment Stratified by Baseline 
Cognitive Enhancer Status 
14.2.3.1.1 
ITT 
Summary of Change from Baseline to Week 52 in ADCS-ADL 
Total Score By Visit and Treatment 
14.2.3.1.2 
ITT 
Summary of Change from Baseline to Week 52 in ADCS-ADL 
Total Score By Visit and Treatment: Responder Analysis 
14.2.3.1.3 
ITT 
Summary of Change from Baseline to Week 52 in ADCS-ADL 
Total Score By Visit and Treatment: Time Component Test 
14.2.3.2 
ITT-mild 
Summary of Change from Baseline to Week 52 in ADCS-ADL 
Total Score By Visit and Treatment 
14.2.3.3 
ITT 
Summary of Change from Baseline to Week 52 in ADCS-ADL 
Total Score By Visit and Treatment: Imputation Missing Not at 
Random 
14.2.3.4.1 
ITT 
Summary of Change from Baseline to Week 52 in ADCS-ADL 
Total Score By Visit and Treatment Stratified by Mild (21-
27)/Moderate (<21) AD Status  
14.2.3.4.2 
ITT 
Summary of Change from Baseline to Week 52 in ADCS-ADL 
Total Score By Visit and Treatment Stratified by Mild (21-
27)/Moderate (<21) AD Status : Responder Analysis 
14.2.3.4.3 
ITT 
Summary of Change from Baseline to Week 52 in ADCS-ADL 
Total Score By Visit and Treatment Stratified by Mild (21-
27)/Moderate (<21) AD Status : Time Component Test 
14.2.3.5.1 
ITT 
Summary of Change from Baseline to Week 52 in ADCS-ADL 
Total Score By Visit and Treatment Stratified by Mild (20-
27)/Moderate (<20) AD Status  
14.2.3.5.2 
ITT 
Summary of Change from Baseline to Week 52 in ADCS-ADL 
Total Score By Visit and Treatment Stratified by Mild (20-
27)/Moderate (<20) AD Status : Responder Analysis 
14.2.3.6 
ITT 
Summary of Change from Baseline to Week 52 in ADCS-ADL 
Total Score By Visit and Treatment Stratified by Age 
14.2.3.7 
ITT 
Summary of Change from Baseline to Week 52 in ADCS-ADL 
Total Score by Visit and Treatment Stratified by Gender 
14.2.3.8 
ITT 
Summary of Change from Baseline to Week 52 in ADCS-ADL 
Total Score by Visit and Treatment Stratified by Ethnicity 
14.2.3.9 
ITT 
Summary of Change from Baseline to Week 52 in ADCS-ADL 
Total Score by Visit and Treatment Stratified by Race 
14.2.3.10 
ITT 
Summary of Change from Baseline to Week 52 in ADCS-ADL 
Total Score by Visit and Treatment Stratified by ApoE Genotype 
14.2.3.11 
ITT 
Summary of Change from Baseline to Week 52 in ADCS-ADL 
Total Score by Visit and Treatment Stratified by Baseline Cognitive 
Enhancer Status 
14.2.4.1 
ITT 
Summary of Change from Baseline to Week 52 in iADRS Total 
Score By Visit and Treatment 
14.2.4.2 
ITT-mild 
Summary of Change from Baseline to Week 52 in iADRS Total 
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Score By Visit and Treatment 
14.2.3.4 
ITT 
Summary of Change from Baseline to Week 52 in iADRS Total 
Score By Visit and Treatment Stratified by Mild (21-27)/Moderate 
(<21) AD Status 
14.2.3.5 
ITT 
Summary of Change from Baseline to Week 52 in iADRS Total 
Score By Visit and Treatment Stratified by Mild (20-27)/Moderate 
(<20) AD Status 
14.2.3.6 
ITT 
Summary of Change from Baseline to Week 52 in iADRS Total 
Score By Visit and Treatment Stratified by Age 
14.2.3.7 
ITT 
Summary of Change from Baseline to Week 52 in iADRS Total 
Score By Visit and Treatment Stratified by Gender 
14.2.3.8 
ITT 
Summary of Change from Baseline to Week 52 in iADRS Total 
Score By Visit and Treatment Stratified by Ethnicity 
14.2.3.9 
ITT 
Summary of Change from Baseline to Week 52 in iADRS Total 
Score By Visit and Treatment Stratified by Race 
14.2.3.10 
ITT 
Summary of Change from Baseline to Week 52 in iADRS Total 
Score By Visit and Treatment Stratified by ApoE Genotype 
14.2.3.11 
ITT 
Summary of Change from Baseline to Week 52 in iADRS Total 
Score By Visit and Treatment Stratified by Baseline Cognitive 
Enhancer Status 
14.2.5.1 
ITT 
Summary of Change from Baseline to Week 52 in MMSE Total 
Score By Visit and Treatment 
14.2.5.2 
ITT-mild 
Summary of Change from Baseline to Week 52 in MMSE Total 
Score By Visit and Treatment 
14.2.6.1 
ITT 
Summary of Change from Baseline to Week 52 in CDR-SB Total 
Score by Visit and Treatment 
14.2.6.2 
ITT-mild 
Summary of Change from Baseline to Week 52 in CDR-SB Total 
Score by Visit and Treatment 
14.2.7.1.1 
ITT 
Summary of Change from Baseline to Week 52 in NPI Total Score 
By Visit and Treatment 
14.2.7.1.2 
ITT 
Summary of Change from Baseline to Week 52 in NPI Total Score 
By Visit and Treatment in Subgroup of Individuals with an NPI-10 
Score ≥2 
14.2.7.1.3 
ITT 
Summary of Change from Baseline to Week 52 in NPI Agitation 
and Aggression Domain Scores By Visit and Treatment in 
Subgroup of Individuals with a non-zero Domain Score at Baseline 
14.2.7.1.4 
ITT 
Summary of Change from Baseline to Week 52 in NPI Total Score 
By Visit and Treatment: Responder Analysis 
14.2.7.2.1 
ITT-mild 
Summary of Change from Baseline to Week 52 in NPI Total Score 
By Visit and Treatment 
14.2.7.2.2 
ITT 
Summary of Change from Baseline to Week 52 in NPI Total Score 
By Visit and Treatment Stratified by Mild (21-27)/Moderate (<21) 
AD Status : Responder Analysis 
14.2.7.2.3 
ITT 
Summary of Change from Baseline to Week 52 in NPI Total Score 
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By Visit and Treatment Stratified by Mild (20-27)/Moderate (<20) 
AD Status : Responder Analysis 
14.2.8.1 
ITT 
Summary of Change from Baseline to Week 52 in Zarit Burden 
Index By Visit and Treatment 
14.2.8.2 
ITT-mild 
Summary of Change from Baseline to Week 52 in Zarit Burden 
Index By Visit and Treatment 
14.2.9.1 
ITT 
Summary of Change from Baseline to Week 52 in P-tau 217 By 
Visit and Treatment 
14.2.10.1 
ITT 
Summary of Change from Baseline to Week 52 in GFAP By Visit 
and Treatment 
14.2.11.1 
ITT 
Summary of Change from Baseline to Week 52 in NfL By Visit and 
Treatment 
14.2.12.1 
ITT 
Summary of Change from Baseline to Week 52 in Plasma Total 
Tau by Visit and Treatment 
 
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