A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel-group, 76-week Study Evaluating the Safety and Efficacy of Two Doses of Simufilam in Subjects With Mild-to-Moderate Alzheimer's Disease
Phase: PHASE3
Conditions: Alzheimer Disease
Sponsor: Cassava Sciences, Inc.

Study Title: A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel-group, 
76-week Study Evaluating the Safety and Efficacy of Two Doses of Simufilam in Subjects 
with Mild-to-Moderate Alzheimer’s Disease 
ClinicalTrials.gov ID: NCT05026177 
 
Protocol Clarification Letter, dated 07-Jun-2024 
Final Protocol, Version 3.0, dated 06-Feb-2023 
Final Protocol, Version 2.0, dated 20-Jul-2021 
Final Protocol, Version 1.0, dated 30-Jun-2021 
Page 1 of 154

 
MMO-125-316 
 
  
 
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-125-06 Study file 
From: 
 Chief Medical Officer 
CC: 
Premier Research 
Date: 07-JUN-2024 
Re: 
Protocol Clarification for Study PTI-125-06, A PHASE 3, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, PARALLEL-GROUP, 76-WEEK STUDY EVALUATING THE SAFETY 
AND EFFICACY OF TWO DOSES OF SIMUFILAM IN SUBJECTS WITH MILD-TO-MODERATE 
ALZHEIMER’S DISEASE 
 
The purpose of this memo for Protocol PTI-125-06, Version 3.0, February 6, 2023, and 
Version 3.0, February 20, 2023 for the Republic of Korea, 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 site’s 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 site’s 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: 
 
Page 2 of 154

 
MMO-125-316 
 
  
 
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 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 | 12:56 CDT
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Cassava Sciences, Inc. 
Clinical Protocol PTI-125-06 
Simufilam (PTI-125) 
FINAL Version 3.0, FEBRUARY 06, 2023 
 
 
 
Page 1 of 59 
 
CONFIDENTIAL 
 
 
 
 
CLINICAL RESEARCH PROTOCOL 
PROTOCOL PTI-125-06 
 
A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
PARALLEL-GROUP, 76-WEEK STUDY EVALUATING THE SAFETY AND 
EFFICACY OF TWO DOSES OF SIMUFILAM 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 
 
 
This clinical study is pending support by NIH grant AG073350 
 
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. 
 
 
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Simufilam (PTI-125) 
FINAL Version 3.0, FEBRUARY 06, 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.  
Changed: This clinical study is supported by NIH grant AG073350.    
Changed to: This clinical study is pending support by NIH grant AG073350. 
 
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. 
 
Clarified that participants in both PET sub-studies will be required to have an MRI during the 
screening period.  
 
 
 
 
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FINAL Version 3.0, FEBRUARY 06, 2023 
 
 
 
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CONFIDENTIAL 
 
 
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 
total tau/Aβ42 ratio (must be ≥ 0.28), or 2) an abnormal qualitative amyloid or tau 
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). 
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CONFIDENTIAL 
 
 
5.3 EXCLUSION CRITERIA 
#2. Clarified that pacemakers are excluded only if not “MRI friendly” 
 
#4. Clarified that upper exclusion for BMI is > 37.5, not 35.0. 
 
#7. 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). 
#10. Clarified as follows: MRI presence of cerebral vascular pathology (including, but not 
limited to, intracerebral hemorrhage, infarct > 1 cm3, > 3 lacunar infarcts, > 10 
microhemorrhages, multifocal or extensive 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). 
#17. Added cancer exclusion: stage 0 melanoma in situ, 
  Added: Other potential exceptions must be discussed with the Medical Monitor.  
#22. Added: Subjects with borderline hypothyroidism may be considered for rescreening after 
consultation with the Medical Monitor.  
#25. 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. 
#26. Added: (Note: borderline elevations in QTcF intervals due to bundle branch block must be 
approved by the Medical Monitor) 
#31. Added memantine: Discontinued AChEI or memantine < 12 weeks prior to randomization. 
#32. 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).  
#33. 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 Study Day 1 4 weeks prior to screening). 
#34. 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 
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CONFIDENTIAL 
 
 
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. 
#36. 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 indications other 
than seizures). 
#37. 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). 
#38. 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 #43) 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: 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, 
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. 
 
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FINAL Version 3.0, FEBRUARY 06, 2023 
 
 
 
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CONFIDENTIAL 
 
 
7.1.1 Screening visit 
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 
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 
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FINAL Version 3.0, FEBRUARY 06, 2023 
 
 
 
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CONFIDENTIAL 
 
 
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. 
 
7.1.2 Sub-studies with PET and Fluid Biomarkers 
Clarified that PET should be scheduled after meeting other entry criteria and that PET subjects 
also need an MRI at screening as follows: 
• Subjects participating in either amyloid or tau PET sub-studies (40 and 50 
subjects/group, respectively) will be scheduled for their first PET scan prior to 
their Baseline Visit (Study Day 1), but after confirmation that the subject meets 
entry criteria based on screening procedures. They will undergo the procedure 
again at Week 76. Individual subjects can potentially participate in both PET 
imaging sub-studies, but consideration must be given to total radiation exposure 
based on the number of PET scans and dose each subject would receive per 
annum. Moreover, PET scans using different tracers must also be acquired at least 
24 hours apart to ensure adequate wash-out of the previous tracer prior to new 
tracer administration. These subjects will also be required to undergo an MRI 
during the screening period to ensure their PET image data can be properly 
analyzed. 
Clarified that PK/plasma biomarker sample collection can be done on Day 1 prior to dose: 
• Subjects participating in the PET sub-studies will also have blood samples drawn 
for assessments of plasma-based biomarkers during the Screening Period and 
again at Weeks 28, 52 and 76 (270 total; 90 subjects/group). Subjects participating 
in the tau PET sub-study will also provide a plasma sample for PK at Weeks 28 
and 76. For subjects participating in the PK and/or plasma biomarker sub-study, 
collection of their baseline blood samples during the Screening Period can be 
taken on Day 1 before administration of their first dose of Study Drug (this may 
help alleviate unnecessary blood sampling or having the subject return to the 
research center for just a blood sample).  
Clarified that coagulation panel or fluoroscopy can be performed prior to LP if routine: 
Subjects participating in an assessment of CSF biomarkers (90 total; 30 subjects/group) will 
undergo lumbar puncture prior to the Baseline Visit (Study Day 1) and again at Week 76. 
Research sites that routinely draw a blood sample for a “coagulation panel” prior to lumbar 
puncture or utilize fluoroscopy during lumbar puncture are permitted to do so. 
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Clinical Protocol PTI-125-06 
Simufilam (PTI-125) 
FINAL Version 3.0, FEBRUARY 06, 2023 
 
 
 
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CONFIDENTIAL 
 
 
7.1.3 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 Sponsor 
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.  
7.1.4 Baseline Visit (Study Day 1) (Dosing Initiation) 
Clarified that Study Day 1 is Baseline Visit. 
Added to eCOA order of administration (also added to 7.1.5, 7.1.6 and 7.1.7):  
• 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 7.1.4, Baseline Visit only): 
• A 12-lead resting ECG (5-min supine; triplicate format) 
Clarified details of ECG in 7.1.5, 7.1.6 and 7.1.7 (all other Visits): 
• A 12-lead resting ECG (5-min supine) 
Added to 7.1.7 (Week 76 / ET visit) only: 
For those 270 subjects participating in the amyloid or tau PET and Plasma Biomarker sub-
studies, collect their Week 76 blood samples (including PK samples for those in the tau PET sub-
study) and schedule their Week 76 scan. Investigators should attempt to schedule a second PET 
scan for those subjects who early terminate after 52 weeks. 
7.1.8 End-of-Study / Early Termination Safety Follow-up 
Added:  This phone call will thus occur Week 77 to 78 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 
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CONFIDENTIAL 
 
 
should be followed and treated by the Investigator until the AE has resolved or stabilized (see 
Section 10.1 – Adverse Events). 
7.1.11 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. 
 
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). 
7.2.4 CSF assays 
Changed as follows: Approximately 5mL of CSF will be collected and split equally into sterile 
polypropylene tubes. Following the instructions within the Laboratory Manual, CSF samples are 
to be frozen (within 30 minutes of collection) and shipped to the central laboratory. CSF samples 
should be split, with approximately 2.5 mL shipped to the central lab (as instructed per lab 
manual). The remaining CSF will be retained at the study site and frozen at -70°C or below until 
instructions are received from the Sponsor.  
CSF samples will be collected during the Screening Period and again at Week 76 for those 
subjects participating in the CSF Biomarker sub-study. We currently plan to assay the following 
biomarkers:  The biomarkers to be assayed will include: 
• Total Tau  
• P-tau181 and/or P-tau217 
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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.  
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 
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CONFIDENTIAL 
 
 
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.  
11.3.3 Other Secondary Analyses 
Clarified that p-tau181 may be p-tau181 and/or p-tau217. 
 
 
 
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Simufilam (PTI-125) 
FINAL Version 3.0, FEBRUARY 06, 2023 
 
 
 
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CONFIDENTIAL 
 
 
  
Cassava Sciences, Inc. 
CLINICAL RESEARCH PROTOCOL 
 
 
 
A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
PARALLEL-GROUP, 76-WEEK STUDY EVALUATING THE SAFETY AND 
EFFICACY OF TWO DOSES OF SIMUFILAM IN SUBJECTS WITH MILD-TO-
MODERATE ALZHEIMER’S DISEASE  
 
 
Approvals: 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
Date 
SVP, Neuroscience 
Cassava Sciences, Inc.  
 
 
 
  
 
 
 
 
 
 
 
Date 
Chief Med cal Officer  
Cassava Sciences, Inc. 
06-Feb-2023 | 17:40 CST
06-Feb-2023 | 20:37 CST
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CONFIDENTIAL 
 
 
 
Cassava Sciences, Inc. 
CLINICAL RESEARCH PROTOCOL 
 
 
 
A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
PARALLEL-GROUP, 76-WEEK STUDY EVALUATING THE SAFETY AND 
EFFICACY OF TWO DOSES OF SIMUFILAM IN SUBJECTS WITH MILD-TO-
MODERATE ALZHEIMER’S DISEASE  
 
 
 
Signature of Agreement for Protocol PTI-125-06 
 
 
 
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 
06-Feb-2023 | 15:46 PST
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TABLE OF CONTENTS 
SUMMARY OF PROTOCOL AMENDMENT #1 .............................................................2 
1. 
LIST OF ABBREVIATIONS ..................................................................................17 
2. 
INTRODUCTION ....................................................................................................19 
2.1. Mechanism of Action ............................................................................................................... 19 
2.2. Safety pharmacology and toxicology ....................................................................................... 19 
2.3. Clinical Studies ........................................................................................................................ 20 
3. 
STUDY OBJECTIVES ............................................................................................23 
4. 
SUMMARY OF STUDY DESIGN .........................................................................23 
5. 
SUBJECT SELECTION ..........................................................................................25 
5.1. Study Population ...................................................................................................................... 25 
5.2. Inclusion Criteria ..................................................................................................................... 25 
5.3. Exclusion Criteria .................................................................................................................... 27 
6. 
STUDY DRUG .........................................................................................................31 
6.1. Simufilam Physical Description and Preparation ..................................................................... 31 
6.1.1 
Packaging and Labeling .................................................................................................31 
6.1.2 
Storage ............................................................................................................................32 
6.1.3 
Drug Accountability ........................................................................................................32 
6.2. Administration and Dosing Regimen ....................................................................................... 32 
6.3. Concomitant Medications ........................................................................................................ 32 
7. 
STUDY PROCEDURES .........................................................................................33 
7.1. Evaluations by Visit ................................................................................................................. 33 
7.1.1. Screening Period (No greater than a 60-day duration prior to Study Day 1) .................33 
7.1.2. Sub-studies with PET and Fluid Biomarkers ..................................................................35 
7.1.3. Rescreening of a Subject .................................................................................................35 
7.1.4. Baseline Visit (Study Day 1) (Dosing Initiation) ............................................................36 
7.1.5. Weeks 4, 16, 40 and 64 Follow-up Visits ........................................................................38 
7.1.6. Weeks 28 and 52 Follow-up Visits ..................................................................................38 
7.1.7. Week 76 End-of-Treatment Visit / Early Termination (ET) Visit ....................................39 
7.1.8. End-of-Study / Early Termination Safety Follow-up .......................................................41 
7.1.9. Treatment after Study Completion ..................................................................................41 
7.1.10. Unscheduled Visits and Discontinuation due to AEs ......................................................41 
7.1.11. Stopping Criteria.............................................................................................................41 
7.2. Laboratory Assessments .......................................................................................................... 42 
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7.2.1. Clinical Laboratory Tests ................................................................................................42 
7.2.2. Collection of Whole Blood Samples for ApoE Genotyping .............................................43 
7.2.3. Preparation of Plasma Biomarker and PK Samples from PET Sub-study Participants .......43 
7.2.4. CSF Assays ......................................................................................................................43 
8. 
COGNITIVE AND FUNCTIONAL ASSESSMENTS ...........................................44 
8.1. Mini-Mental State Exam (MMSE) ........................................................................................... 44 
8.2. Clinical Dementia Rating (CDR) ............................................................................................. 44 
8.3. Alzheimer’s Disease Assessment Scale – Cognitive Subscale 12 (ADAS-Cog12) ................. 44 
8.4. Neuropsychiatric Inventory (NPI) ............................................................................................ 44 
8.5. Alzheimer’s Disease Cooperative Study – Activities of Daily Living (ADCS-ADL-AD) ...... 45 
8.6. Columbia-Suicide Severity Rating Scale (C-SSRS) ................................................................ 45 
8.7. Zarit Burden Interview (ZBI) ................................................................................................... 45 
8.8. Geriatric Depression Scale (GDS) ........................................................................................... 45 
8.9. Electronic Capture of Rating Scales......................................................................................... 45 
9. 
EARLY DISCONTINUATION ...............................................................................46 
10. 
ADVERSE EVENTS/SERIOUS ADVERSE EVENTS ..........................................46 
10.1. Adverse Events – Definition ..................................................................................................... 46 
10.2. Adverse Events – Severity Rating ............................................................................................ 47 
10.3. Adverse Events – Relationship to Study Drug ......................................................................... 48 
10.4. Serious Adverse Events and Unexpected Adverse Events – Definitions ................................. 48 
10.5. Serious Adverse Events Reporting ........................................................................................... 49 
11. 
STATISTICAL CONSIDERATIONS .....................................................................50 
11.1. Randomization ......................................................................................................................... 50 
11.2. Analysis Populations ................................................................................................................ 50 
11.3. Statistical Analysis ................................................................................................................... 50 
11.3.1. Primary Efficacy Analysis ...............................................................................................50 
11.3.2 Key Secondary Analysis ..................................................................................................51 
11.3.3 Other Secondary Analyses ..............................................................................................51 
11.4. Safety Analysis ......................................................................................................................... 51 
11.5. Sample Size .............................................................................................................................. 52 
12. 
STUDY TERMINATION ........................................................................................52 
13. 
DATA COLLECTION, RETENTION, AND MONITORING ................................52 
13.1. Case Report Forms ................................................................................................................... 52 
13.2. Availability and Retention of Investigational Records ............................................................ 52 
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13.3. Subject Confidentiality ............................................................................................................ 53 
13.4. Liability .................................................................................................................................... 53 
13.5. Ethical and Legal Issues ........................................................................................................... 53 
13.5.1. Institutional Review Board...............................................................................................53 
13.6. Informed Consent Form ........................................................................................................... 54 
14. 
INVESTIGATOR RESPONSIBILITIES ................................................................54 
15. 
REFERENCES .........................................................................................................56 
16. 
APPENDIX A – SCHEDULE OF ACTIVITIES ....................................................58 
 
LIST OF FIGURES 
 
Figure 1.  Phase 2a Mean Change from Baseline to Day 28 in CSF biomarkers (±SEM) ..... 21 
Figure 2.  Percent Change from Baseline in CSF Biomarkers at 6 Months (±SD) ................ 22 
Figure 3.  Phase 2b Mean Change from Baseline to Day 28 in Total Errors in Memory Test 23 
 
 
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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 
hERG 
 
 
human ether-a-go-go-related gene 
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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 
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 
were negative. An in vitro specificity screen showed no significant activation or inhibition 
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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). 
In a 28-day phase 2a study (PTI-125-03), 13 subjects with mild-to-moderate AD received 
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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. 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) (Fig. 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 (Fig. 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 
both cognitive tests (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 76-week, repeat-dose oral 
administration in mild-to-moderate AD subjects, 50-87 years of age. Secondary objectives 
are to assess neuropsychiatric symptoms and to replicate the CSF biomarker effects 
observed in the two Phase 2 studies (PTI-125-03 and PTI-125-02) after 76 weeks of 
simufilam treatment. A third objective is to investigate the effect of simufilam treatment 
on plasma biomarkers as well as anatomical correlates of disease progression (brain 
volume [hippocampus, ventricles and whole brain]; amyloid and tau deposition in the 
brain). 
4. 
SUMMARY OF STUDY DESIGN 
In this Phase 3 clinical study, approximately 1,083 subjects with mild-to-moderate AD 
(361 per arm) will receive placebo or 50 mg tablets of simufilam or 100 mg tablets of 
simufilam, twice daily, for 76 weeks. Randomization (1:1:1) 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, 52, 64 and 76.   
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 76).  
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); however, 150 subjects (50 subjects per treatment group) will also undergo repeat 
MRI assessments at Weeks 40 and 76 to assess both long-term safety and drug impact on 
brain volume as noted above. Resting ECGs will be conducted at Baseline (Study Day 1) 
and Weeks 4, 40 and 76. 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 one or more sub-studies 
to assess the impact of simufilam on anatomical and biomarker endpoints, including: 
change from baseline in CSF biomarkers (30 subjects/group), brain volume via MRI (50 
subjects/group), and amyloid and tau PET (40 and 50 subjects/group, respectively). 
Participants in both PET sub-studies will be required to have an MRI during the screening 
period and provide plasma for a biomarker sub-study. Participants in the tau PET sub-study 
will also provide additional plasma for a PK exposure-response analysis. Changes from 
baseline for these imaging and fluid biomarkers represent additional secondary endpoints. 
The ninety subjects (30 per group) in the CSF sub-study will undergo lumbar puncture 
during the Screening Period and again at the Week 76 End-of-Treatment Visit to collect 
CSF biomarkers.  
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. 
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5. 
SUBJECT SELECTION 
5.1. STUDY POPULATION 
Approximately 1,083 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 
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. 
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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). 
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 
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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 
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. A medical condition or treatment with an anticoagulant that would interfere with a 
lumbar puncture for those subjects being considered for participation in the CSF 
biomarker assessment. 
4. BMI < 18.5 or > 37.5  
5. 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. 
6. 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.  
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7. 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). 
8. 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.  
9. Meets DSM-V criteria for alcohol or substance use disorder within 2 years before the 
Screening Period. 
10. 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). 
11. History of transient ischemic attack (TIA) or stroke within 12 months of screening, or 
history of a stroke concurrent with the onset of dementia. 
12. History of seizure within 12 months of screening. 
13. 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. 
14. Onset of dementia secondary to cardiac arrest, surgery with general anesthesia, or 
resuscitation. 
15. 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. 
16. 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. 
17. Malignant tumor within 3 years before screening (except definitively treated squamous 
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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.  
18. Known positive HIV status. 
19. Positive HBsAg or HCV-Ab during screen. 
20. Positive urine drug screen for substances of abuse. 
21. 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. 
22. 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. 
23. 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). 
24. 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. 
25. Clinically significant cardiac arrhythmia or heart block as evidenced by ECG in the 
judgment of the Investigator. 
26. 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) 
27. 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 
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measurement during the Screening Period could be used before excluding a potential 
subject for insufficiently controlled hypertension). 
28. 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). 
29. 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. 
30. Donepezil > 10 mg/day, currently or within 12 weeks of Study Day 1 (randomization).  
31. Discontinued AChEI or memantine < 12 weeks prior to randomization. 
32. Currently or previously prescribed/administered aducanumab, lecanemab or any anti-
amyloid monoclonal antibody, more than two doses.  
33. 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 Study Day 1). 
34. 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.  
35. Immunosuppressants, including systemic corticosteroids, if taken in clinically 
immunosuppressive doses (steroid use for allergy or inflammation is permitted). 
36. 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). 
37. Chronic intake of opioid-containing analgesics at standard doses (use of intermittent or 
low-dose opioids must be approved by the Medical Monitor). 
38. Use of prescribed sedating H1 antihistamines (Note – fexofenadine is the preferred 
non-sedating antihistamine for subjects requiring such medication). 
39. Use of nicotine therapy (all dosage forms including a patch), varenicline (Chantix), or 
similar therapeutic agent within 4 weeks prior to screening. 
40. Loss of a significant volume of blood (> 450 mL) within 4 weeks of randomization. 
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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. This could 
include, for example, excessive marijuana or cannabinoid use. 
6. 
STUDY DRUG 
6.1. SIMUFILAM PHYSICAL DESCRIPTION AND PREPARATION 
Investigational simufilam and matching placebo will be supplied by Cassava as coated 
tablets including 50 and 100 milligram active strengths.  
All remaining unused Study Drug will be returned to the Sponsor or designee. 
6.1.1 Packaging and Labeling 
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.  
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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 50 mg or 100 mg simufilam b.i.d. 
(approximately 361 subjects per treatment group). 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 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, 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 #30 and #31 for additional details regarding 
background medications frequently prescribed to patients with AD]. 
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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 
• 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  
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 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. 
o Subjects participating in the MRI sub-study assessment of brain volume 
(150 total; 50 subjects/group), including the hippocampus, ventricles, and 
whole brain, will have, in addition to the MRI during the Screening Period, 
subsequent MRI scans at Weeks 40 and 76. 
• To remain in the study, subjects who develop COVID-19 (or its variants) or 
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manifest a positive COVID-19 test during the screening period will need 
approval from the Medical Monitor. 
 
7.1.2. Sub-studies with PET and Fluid Biomarkers 
Selected research sites will participate in additional sub-study assessments to determine the 
effect of simufilam on anatomical and biomarker secondary endpoints. 
• Subjects participating in either amyloid or tau PET sub-studies (40 and 50 
subjects/group, respectively) will be scheduled for their first PET scan prior to 
their Baseline Visit (Study Day 1), but after confirmation that the subject meets 
entry criteria based on screening procedures. They will undergo the procedure 
again at Week 76. Individual subjects can potentially participate in both PET 
imaging sub-studies, but consideration must be given to total radiation exposure 
based on the number of PET scans and dose each subject would receive per 
annum. Moreover, PET scans using different tracers must also be acquired at 
least 24 hours apart to ensure adequate wash-out of the previous tracer prior to 
new tracer administration. These subjects will also be required to undergo an 
MRI during the screening period to ensure their PET image data can be properly 
analyzed. 
• Subjects participating in the PET sub-studies will also have blood samples 
drawn for assessments of plasma-based biomarkers during the Screening Period 
and again at Weeks 28, 52 and 76 (270 total; 90 subjects/group). Subjects 
participating in the tau PET sub-study will also provide a plasma sample for PK 
at Weeks 28 and 76. For subjects participating in the PK and/or plasma 
biomarker sub-study, collection of their baseline blood samples during the 
Screening Period can be taken on Day 1 before administration of their first dose 
of Study Drug (this may help alleviate unnecessary blood sampling or having 
the subject return to the research center for just a blood sample).  
• Subjects participating in an assessment of CSF biomarkers (90 total; 30 
subjects/group) will undergo lumbar puncture prior to the Baseline Visit (Study 
Day 1) and again at Week 76. Research sites that routinely draw a blood sample 
for a “coagulation panel” prior to lumbar puncture or utilize fluoroscopy during 
lumbar puncture are permitted to do so. 
7.1.3. 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-
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eligible MMSE (<16), MRI or P-tau results. If screen failure occurs for the following 
reasons, the subject is allowed to rescreen once: 
• 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.  
7.1.4. 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 
• 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. 
• eCOA order of administration 
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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) 
• Clinical laboratory tests (blood and urine) 
• 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. 
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 
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MEMS® cap will be removed from the returned bottle and applied to the newly dispensed 
bottle of Study Drug.  
7.1.5. Weeks 4, 16, 40 and 64 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) 
• Weeks 4 and 40 only: 12-lead resting ECG (5 min supine) 
• Week 40 only: for those 150 subjects participating in the MRI sub-study to 
determine the effect of simufilam on brain volume, schedule their Week 40 
scan. 
7.1.6. Weeks 28 and 52 Follow-up Visits 
Subjects will return to clinic for these scheduled visits within a ± 5-day “window.” On 
the Week 28 Visit, subjects in the tau PET sub-study should come to the clinic before 
taking their a.m. dose and have their PK blood sample collected prior to their dose. 
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• 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 h 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 270 subjects participating in the amyloid or tau PET and Plasma 
Biomarker sub-studies, collect their Week 28 and Week 52 blood samples 
(including PK at Week 28 for those in the tau PET sub-study) 
 
7.1.7. Week 76 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 tau PET sub-study should not take an a.m. (morning) dose of Study Drug 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 
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 
• A 12-lead resting ECG (5 min supine) 
• Clinical laboratory tests (blood and urine) 
• For those 270 subjects participating in the amyloid or tau PET and Plasma 
Biomarker sub-studies, collect their Week 76 blood samples (including PK 
samples for those in the tau PET sub-study) and schedule their Week 76 scan. 
Investigators should attempt to schedule a second PET scan for those subjects 
who early terminate after 52 weeks. 
• For those 150 subjects participating in the MRI sub-study to determine the 
effect of Study Drug on brain volume, schedule their Week 76 scan. 
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• For those 90 subjects participating in the CSF Biomarker sub-study, perform a 
lumbar puncture to collect CSF (5 mL) after all other testing has been 
completed. 
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) 
7.1.8. 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 77 to 78 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). 
 
 
 
7.1.9. Treatment after Study Completion 
The Sponsor plans to initiate an open-label extension study for subjects who have 
completed participation in Study PTI-125-06. Should a subject elect to participate in the 
open-label extension study, the End-of-Study Follow-up (Section 7.1.8) will not be 
conducted. 
 
7.1.10. 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. 
 
 
7.1.11. 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 
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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 (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. 
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• 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 
is 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 the Lab Manual). 
7.2.3. Preparation of Plasma Biomarker and PK Samples from PET Sub-study Participants  
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.  
7.2.4. CSF Assays 
Approximately 5mL of CSF will be collected and split equally into sterile polypropylene 
tubes. Following the instructions within the Laboratory Manual, CSF samples are to be 
frozen (within 30 minutes of collection) and shipped to the central laboratory.  
CSF samples will be collected during the Screening Period and again at Week 76 for those 
subjects participating in the CSF Biomarker sub-study. We currently plan to assay the 
following biomarkers:   
• Total Tau  
• P-tau181 and/or P-tau217 
• Neurogranin 
• sTREM2 
• Amyloid-beta 42 
• Neurofilament light chain 
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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 
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.  
 
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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 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 
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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 7.1.7 – 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 related to Study Drug. Monitoring for AEs will 
start after informed consent has been obtained. Examples include: 
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• 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). 
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: 
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• 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. 
• A persistent or significant disability/incapacity (i.e., a substantial disruption 
of the subject’s ability to carry out normal life functions). 
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•
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. 
In the event of any SAE (other than death), the subject will be instructed to contact the 
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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 (three levels), week (7 levels, corresponding 
to Weeks 4, 16, 28, 40, 52, 64 and 76), 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 
Baseline Visit (Study Day 1) ADAS-Cog12 and ADCS-ADL assessments will represent 
the baseline value for these variables.  
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For each of the two co-primary endpoints, the primary analysis will compare the 100 mg 
group and the placebo group at Week 76 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 Key Secondary Analysis 
If both primary comparisons are statistically significant, then the corresponding 
comparisons at Week 76 for the 50 mg group versus the placebo group will be tested at the 
alpha = 0.05 level of significance (two-sided).  
11.3.3 Other 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 by linear mixed models for repeated measurements, as described above for the 
primary analysis. 
Plasma assays may include P-tau181 and/or P-tau217, SavaDx, neurofilament light chain, 
and other biomarkers. All plasma biomarker data and MRI data measured repeatedly will 
be analyzed by linear mixed models for repeated measurements, as described above for the 
primary analysis. 
CSF biomarker endpoints to be analyzed currently include: 1) neurogranin, 2) 
neurofilament light chain, 3) total tau, 4) P-tau181 and/or P-tau217, 5) sTREM2, and 6) 
Aβ42. Additional CSF biomarkers may be measured. All CSF biomarker data, PET imaging 
data, and CDR-SB will be analyzed using ANCOVA models with treatment group as a 
factor and the baseline value of the corresponding endpoint 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. 
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11.5. SAMPLE SIZE 
Approximately 1,083 subjects will be enrolled in this study. The sample size was 
determined by a power analysis of ADAS-Cog in a similar population over 76 weeks. This 
analysis determined that the comparison between an active arm and placebo requires group 
sizes of 289 to provide 90% power to detect a 45% difference from placebo at 76 weeks, 
based on the use of a two-sided test at the alpha = 0.05 significance level. The power 
calculation assumes a true mean change from baseline for placebo of 6.0 points and a 
standard deviation of 10.0 points. Assuming a drop-out of 20%, each treatment group 
should enroll 361 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 
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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. 
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: 
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• 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. 
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. 
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• 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. 
 
 
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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, Lee K-C, et al. PTI-125 reduces biomarkers of Alzheimer’s 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. 
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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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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 
Week 
64 
Week 76 
ET/ED7 
Safety 
Follow-
up13 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
I/E Criteria 
X 
X 
 
 
 
 
 
 
 
 
Medical & Surgical 
History 
X 
 
 
 
 
 
 
 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical Examination  
X1 
X 
X 
X 
X 
X 
X 
X 
X 
 
Neurologic Examination 
X1 
X 
X 
X 
X 
X 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Resting ECG 
X 
X14 
X 
 
 
X 
 
 
X 
 
Biochemistry, 
Hematology, Urinalysis 
X 
X 
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 
X12 
 
 
 
 
 
 
 
 
 
Genotyping sample 
 
X 
 
 
 
 
 
 
 
 
MRI 
X 
 
 
 
 
X2 
 
 
X2 
 
Plasma Biomarkers 
X3 
 
 
 
X3 
 
X3 
 
X3 
 
Plasma PK 
 
 
 
 
X11 
 
 
 
X11 
 
CSF Biomarkers 
X4 
 
 
 
 
 
 
 
X4 
 
Amyloid PET  
X5 
 
 
 
 
 
 
 
X5 
 
Tau PET  
X6 
 
 
 
 
 
 
 
X6 
 
MMSE 
X 
 
 
 
X 
 
X 
 
X 
 
CDR 
X 
 
 
 
 
 
 
 
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 
Week 
64 
Week 76 
ET/ED7 
Safety 
Follow-
up13 
Geriatric Depression 
Scale 
X 
 
 
 
 
 
 
 
 
 
ADAS-Cog12 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
ADCS-ADL 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
NPI 
 
X 
 
 
X 
 
X 
 
X 
 
ZBI 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
C-SSRS 
X8 
X9 
X9 
X9 
X9 
X9 
X9 
X9 
X9 
 
Drug Dispensation  
 
X10 
X 
X 
X10 
X 
X 
X 
 
 
Drug Accountability 
 
 
X 
X 
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. MRI sub-study subjects only (150 subjects total; 50 subjects/group) 
3. Plasma biomarker sub-study subjects only; these are the same subjects in both PET sub-studies 
(270 subjects total; 90 subjects/group). Collection of blood samples can be taken on Day 1 
prior to administration of first Study Drug dose. 
4. CSF biomarker sub-study subjects only (90 subjects total; 30 subjects/group) 
5. Amyloid PET sub-study subjects only (120 subjects total; 40 subjects/group) 
6. Tau PET sub-study subjects only (150 subjects total; 50 subjects/group) 
7. 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 
8. During the Screening Period, the C-SSRS Baseline/Screening version will be administered 
9. At Study Day 1, as well as all remaining visits, the C-SSRS Since Last Visit version will be 
administered 
10. The first dose of Study Drug is administered at the clinic to all subjects on Study Day 1; for 
tau PET sub-study participants only at the Week 28 visit, administer Study Drug after plasma 
PK sample is collected 
11. Plasma PK sample from tau PET sub-study participants only 
12. Plasma P-tau181 or plasma P-tau217 not required if the subject has evidence for AD 
pathophysiology prior to Screening visit 
13. This phone call will thus occur Week 77 to 78 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. 
14. ECG on Study Day 1 collected in triplicate 
 
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Page 1 of 46 
 
 
 
 
CONFIDENTIAL 
 
 
 
CLINICAL RESEARCH PROTOCOL 
PROTOCOL PTl-125-06 
 
A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
PARALLEL-GROUP, 76-WEEK STUDY EVALUATING THE SAFETY AND 
EFFICACY OF TWO DOSES OF SIMUFILAM 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 
 
 
This clinical study is supported by NIH grant AG073350. 
 
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. 
 
 
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20 July 2021
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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 ..........................................................................................15 
5.1. Study Population ...................................................................................................................... 15 
5.2. Inclusion Criteria ..................................................................................................................... 15 
5.3. Exclusion Criteria .................................................................................................................... 17 
6. 
STUDY DRUG .........................................................................................................21 
6.1. Simufilam Physical Description and Preparation ..................................................................... 21 
6.1.1 
Packaging and Labeling .................................................................................................21 
6.1.2 
Storage ............................................................................................................................21 
6.1.3 
Drug Accountability ........................................................................................................21 
6.2. Administration and Dosing Regimen ....................................................................................... 22 
6.3. Concomitant Medications ........................................................................................................ 22 
7. 
STUDY PROCEDURES .........................................................................................22 
7.1. Evaluations by Visit ................................................................................................................. 22 
7.1.1. Screening Period (No greater than a 60-day duration prior to Study Day 1) .................22 
7.1.2. Sub-studies with PET and fluid biomarkers ....................................................................24 
7.1.3. Rescreening of a Subject .................................................................................................24 
7.1.4. Study Day 1 (Dosing Initiation) ......................................................................................24 
7.1.5. Weeks 4, 16, 40 and 64 Follow-up Visits ........................................................................26 
7.1.6. Weeks 28 and 52 Follow-up Visit ....................................................................................27 
7.1.7. Week 76 End-of-Treatment Visit / Early Termination (ET) Visit ....................................27 
7.1.8. Week 77-78 End-of-Study Follow-up ..............................................................................29 
7.1.9. Treatment after Study Completion ..................................................................................29 
7.1.10. Unscheduled Visits and Discontinuation due to AEs ......................................................29 
7.1.11. Stopping Criteria.............................................................................................................29 
7.2. Laboratory Assessments .......................................................................................................... 30 
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7.2.1. Clinical Laboratory Tests ................................................................................................30 
7.2.2. Collection of Whole Blood Samples for ApoE Genotyping .............................................31 
7.2.3. Preparation of Plasma Biomarker and PK Samples from PET Sub-study Participants .......31 
7.2.4. CSF assays ......................................................................................................................31 
8. 
COGNITIVE AND FUNCTIONAL ASSESSMENTS ...........................................31 
8.1. Mini-Mental State Exam (MMSE) ........................................................................................... 31 
8.2. Clinical Dementia Rating (CDR) ............................................................................................. 32 
8.3. Alzheimer’s Disease Assessment Scale – Cognitive Subscale 12 (ADAS-Cog12) ................. 32 
8.4. Neuropsychiatric Inventory (NPI) ............................................................................................ 32 
8.5. Alzheimer’s Disease Cooperative Study – Activities of Daily Living (ADCS-ADL-AD) ...... 32 
8.6. Columbia-Suicide Severity Rating Scale (C-SSRS) ................................................................ 32 
8.7. Zarit Burden Interview (ZBI) ................................................................................................... 33 
8.8. Geriatric Depression Scale (GDS) ........................................................................................... 33 
8.9. Electronic Capture of Rating Scales......................................................................................... 33 
9. 
EARLY DISCONTINUATION ...............................................................................33 
10. 
ADVERSE EVENTS/SERIOUS ADVERSE EVENTS ..........................................34 
10.1. Adverse Events - Definition ...................................................................................................... 34 
10.2. Adverse Events - Severity Rating ............................................................................................ 35 
10.3. Adverse Events – Relationship to Study Drug ......................................................................... 35 
10.4. Serious Adverse Events and Unexpected Adverse Events - Definitions .................................. 36 
10.5. Serious Adverse Events Reporting ........................................................................................... 37 
11. 
STATISTICAL CONSIDERATIONS .....................................................................37 
11.1. Randomization ......................................................................................................................... 37 
11.2. Analysis Populations ................................................................................................................ 38 
11.3. Statistical Analysis ................................................................................................................... 38 
11.3.1. Primary Efficacy Analysis ...............................................................................................38 
11.3.2 Key Secondary Analysis ..................................................................................................38 
11.3.3 Other Secondary Analyses ..............................................................................................38 
11.4. Safety Analysis ......................................................................................................................... 39 
11.5. Sample Size .............................................................................................................................. 39 
12. 
STUDY TERMINATION ........................................................................................40 
13. 
DATA COLLECTION, RETENTION AND MONITORING .................................40 
13.1. Case Report Forms ................................................................................................................... 40 
13.2. Availability and Retention of Investigational Records ............................................................ 40 
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13.3. Subject Confidentiality ............................................................................................................ 41 
13.4. Liability .................................................................................................................................... 41 
13.5. Ethical and Legal Issues ........................................................................................................... 41 
13.5.1. Institutional Review Board...............................................................................................41 
13.6. Informed Consent Form ........................................................................................................... 42 
14. 
INVESTIGATOR RESPONSIBILITIES ................................................................42 
15. 
REFERENCES .........................................................................................................43 
16. 
APPENDIX A – SCHEDULE OF ACTIVITIES ....................................................45 
 
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 Test 13 
 
 
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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 
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. 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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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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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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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 76-week, repeat-dose oral 
administration in mild-to-moderate AD subjects, 50-87 years of age. Secondary objectives 
are to assess neuropsychiatric symptoms and to replicate the CSF biomarker effects 
observed in the two Phase 2 studies (PTI-125-03 and PTI-125-02) after 76 weeks of 
simufilam treatment. A third objective is to investigate the effect of simufilam treatment 
on plasma biomarkers as well as anatomical correlates of disease progression (brain 
volume [hippocampus, ventricles and whole brain]; amyloid and tau deposition in the 
brain). 
4. 
SUMMARY OF STUDY DESIGN 
In this Phase 3 clinical study, approximately 1,083 subjects with mild-to-moderate AD 
(361 per arm) will receive placebo or 50 mg tablets of simufilam or 100 mg tablets of 
simufilam, twice daily, for 76 weeks. Randomization (1:1:1) 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 
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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, 52, 64 and 76.   
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 76).  
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, however, 150 subjects (50 subjects 
per treatment group) will also undergo repeat MRI assessments at Weeks 40 and 76 to 
assess both long-term safety and drug impact on brain volume as noted above. ECGs will 
be conducted Day 1 and Weeks 4, 40 and 76. 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 one or more sub-studies 
to assess the impact of simufilam on anatomical and biomarker endpoints, including: 
change from baseline in CSF biomarkers (30 subjects/group), brain volume via MRI (50 
subjects/group), and amyloid and tau PET (40 and 50 subjects/group, respectively). 
Participants in both PET sub-studies will provide plasma for a biomarker sub-study, and 
those in the tau PET sub-study will also provide additional plasma for a PK exposure-
response analysis. Changes from baseline for these imaging and fluid biomarkers represent 
additional secondary endpoints. 
The ninety subjects (30 per group) in the CSF sub-study will undergo lumbar puncture 
during the Screening Period and again at the Week 76 End-of-Treatment Visit to collect 
CSF biomarkers.  
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. 
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5. 
SUBJECT SELECTION 
5.1. STUDY POPULATION 
Approximately 1,083 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 
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. 
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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). 
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 
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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 with a pacemaker 
must be excluded due to the required MRI during screening). 
3. A medical condition or treatment with an anticoagulant that would interfere with a 
lumbar puncture for those subjects being considered for participation in the CSF 
biomarker assessment. 
4. BMI < 18.5 or > 35.0 
5. 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. 
6. 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.  
7. Geriatric Depression Scale (15-item) score > 8. 
8. 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.  
9. Meets DSM-V criteria for alcohol or substance use disorder within 2 years before the 
Screening Period. 
10. MRI presence of cerebral vascular pathology (including, but not limited to, 
hemorrhage, infarct > 1 cm3, or > 3 lacunar infarcts), cerebral contusion, symptomatic 
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subdural hematoma, aneurysm, or space-occupying lesion deemed clinically significant 
in the opinion of the Investigator. 
11. History of transient ischemic attack (TIA) or stroke within 12 months of screening, or 
history of a stroke concurrent with the onset of dementia. 
12. History of seizure within 12 months of screening. 
13. 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. 
14. Onset of dementia secondary to cardiac arrest, surgery with general anesthesia, or 
resuscitation. 
15. 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. 
16. 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. 
17. 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). 
18. Known positive HIV status. 
19. Positive HBsAg or HCV-Ab during screen. 
20. Positive urine drug screen for substances of abuse. 
21. 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. 
22. 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 
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supplementation for hypothyroidism must be on a stable dose for ≥ 3 months before 
screening. 
23. 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). 
24. 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. 
25. History of or current clinically significant cardiac arrhythmia or heart block as 
evidenced by ECG in the judgment of the Investigator. 
26. 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. 
27. 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). 
28. 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). 
29. 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. 
30. Donepezil > 10 mg/day, currently or within 12 weeks of Study Day 1 (randomization).  
31. Discontinued AChEI < 12 weeks prior to randomization. 
32. Administration of aducanumab, either currently or previously prescribed (Note – 
administration of aducanumab at any point during this clinical study is prohibited). 
33. Antipsychotics (Note – low doses are allowed only if given for sleep disturbances, 
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agitation, aggression or dementia-related psychosis, and only if the dose has been stable 
for at least 4 weeks prior to screening). 
34. 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. 
35. Immunosuppressants, including systemic corticosteroids, if taken in clinically 
immunosuppressive doses (steroid use for allergy or inflammation is permitted). 
36. Use of antiepileptic medications if taken for control of seizures (Note – use of 
antiepileptic medications are allowed if used for mood stabilization). 
37. Chronic intake of opioid-containing analgesics. 
38. Use of prescribed sedating H1 antihistamines. 
39. Use of nicotine therapy (all dosage forms including a patch), varenicline (Chantix), or 
similar therapeutic agent within 4 weeks prior to screening. 
40. Loss of a significant volume of blood (> 450 mL) within 4 weeks of randomization. 
41. 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). 
42. Clinically significant abnormalities on screening laboratory tests in the judgment of the 
Investigator. 
43. 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.  
44. 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 and matching placebo will be supplied by Cassava as coated 
tablets including 50 and 100 milligram active strengths.   
All remaining unused simufilam study drug will be returned to the Sponsor or designee. 
6.1.1 Packaging and Labeling 
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 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. 
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6.2. ADMINISTRATION AND DOSING REGIMEN 
Subjects will be randomized to receive placebo, or 50 mg or 100 mg simufilam b.i.d. 
(approximately 361 subjects per treatment group). 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 #30 and #31 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) 
• Medical and surgical history  
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• 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: 
o MMSE  
o CDR  
o Geriatric Depression Scale 
o 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). 
o Subjects participating in the MRI sub-study assessment of brain volume 
(150 total; 50 subjects/group), including the hippocampus, ventricles and 
whole brain, will have, in addition to the MRI during the Screening Period, 
subsequent MRI scans at Weeks 40 and 76. 
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7.1.2. Sub-studies with PET and fluid biomarkers 
Selected research sites will participate in additional sub-study assessments to determine the 
effect of simufilam on anatomical and biomarker secondary endpoints. 
• Subjects participating in either amyloid or tau PET sub-studies (40 and 50 
subjects/group, respectively) will be scheduled for their first PET scan prior to 
Study Day 1; they will undergo the procedure again at Week 76. Individual 
subjects can potentially participate in both PET imaging sub-studies, but 
consideration must be given to total radiation exposure based on the number of 
PET scans and dose each subject would receive per annum. Moreover, PET 
scans using different tracers must also be acquired at least 24 hours apart to 
ensure adequate wash-out of the previous tracer prior to new tracer 
administration. 
• Subjects participating in the PET sub-studies will also have blood samples 
drawn for assessments of plasma-based biomarkers during the Screening Period 
and again at Weeks 28, 52 and 76 (270 total; 90 subjects/group). Subjects 
participating in the tau PET sub-study will also provide a plasma sample for PK 
at Weeks 28 and 76.   
• Subjects participating in an assessment of CSF biomarkers (90 total; 30 
subjects/group) will undergo lumbar puncture prior to Study Day 1 and again at 
Week 76.  
7.1.3. 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, the subject is allowed one rescreen: 
• 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.   
7.1.4. Study Day 1 (Dosing Initiation) 
Subjects will come to the clinic in the morning. Prior to dosing, the following assessments 
will be conducted: 
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• 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) 
• eCOA order of administration: 
o ADAS-Cog12  
o ADCS-ADL 
o NPI 
o ZBI  
o C-SSRS – Since Last Visit version 
• ECG  
• Clinical laboratory tests (blood and urine) 
• 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 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. 
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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.  
7.1.5. Weeks 4, 16, 40 and 64 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 ADAS-Cog12 (whenever possible, within 1 h of the time of day 
administered at the Study Day 1 Visit, and by the same rater) 
o ADCS-ADL 
o ZBI 
o C-SSRS – Since Last Visit version 
• Clinical laboratory tests (blood and urine) 
• Weeks 4 and 40 only: resting ECG 
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• Week 40 only: for those 150 subjects participating in the MRI sub-study to 
determine the effect of simufilam on brain volume, schedule their Week 40 
scan. 
7.1.6. Weeks 28 and 52 Follow-up Visit 
Subjects will return to clinic for these scheduled visits within a ± 5-day “window.” On 
the Week 28 Visit, subjects in the tau PET sub-study should come to the clinic before 
taking their a.m. dose and have their PK 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 ADAS-Cog12 (whenever possible, within 1 h of the time of day 
administered at the Study Day 1 Visit, and by the same rater) 
o ADCS-ADL 
o MMSE 
o NPI 
o ZBI 
o C-SSRS – Since Last Visit version 
• Clinical laboratory tests (blood and urine) 
• For those 270 subjects participating in the amyloid or tau PET and plasma 
biomarker sub-studies, collect their Week 28 and Week 52 blood samples 
(including PK at Week 28 for those in the tau PET sub-study) 
 
7.1.7. Week 76 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 tau PET sub-study should not take an a.m. dose prior to their blood draw. 
• Vital signs (blood pressure [supine], temperature and pulse) 
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• Weight 
• Brief physical and neurologic examination 
• Adverse Event monitoring 
• Use of concomitant medications 
• eCOA order of administration:  
o ADAS-Cog12 (whenever possible, within 1 h of the time of day 
administered at the Study Day 1 Visit, and by the same rater) 
o ADCS-ADL 
o MMSE 
o CDR 
o NPI 
o ZBI 
o C-SSRS – Since Last Visit version 
• Resting ECG 
• Clinical laboratory tests (blood and urine) 
• For those 270 subjects participating in the amyloid or tau PET and plasma 
biomarker sub-studies, collect their Week 76 blood samples (including PK 
samples for those in the tau PET sub-study) and schedule their Week 76 scan. 
• For those 150 subjects participating in the MRI sub-study to determine the 
effect of simufilam on brain volume, schedule their Week 76 scan. 
• For those 90 subjects participating in the CSF biomarker sub-study, perform a 
lumbar puncture to collect CSF (5 mL) after all other testing has been 
completed. 
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) 
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7.1.8. Week 77-78 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. 
 
 
 
7.1.9. Treatment after Study Completion 
The Sponsor plans to initiate an open-label extension study for subjects who have 
completed participation in Study PTI-125-06. Should a subject elect to participate in the 
open-label extension study, the End-of-Study Follow-up (Section 7.1.8) will not be 
conducted. 
 
7.1.10. 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. 
 
 
7.1.11. 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 
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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, 
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. 
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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 Plasma Biomarker and PK Samples from PET Sub-study Participants  
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 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).  
7.2.4. CSF assays 
CSF samples should be split, with approximately 2.5 mL shipped to the central lab (as 
instructed per lab manual). The remaining CSF will be retained at the study site and frozen 
at -70°C or below until instructions are received from the Sponsor. 
CSF samples will be collected during the Screening Period and again at Week 76 for those 
subjects participating in the CSF biomarker sub-study. The biomarkers to be assayed will 
include:  
• Total Tau  
• P-tau181 
• Neurogranin 
• sTREM2 
• Amyloid-beta 42 
• Neurofilament light chain 
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. 
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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 (C-
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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 most clinically relevant reason should be entered on the CRF. 
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• 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 7.1.7 – 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 
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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). 
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 
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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 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 
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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 
 
 
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 
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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 (three levels), week (7 levels, corresponding 
to Weeks 4, 16, 28, 40, 52, 64 and 76), 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 76 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 Key Secondary Analysis 
If both primary comparisons are statistically significant, then the corresponding 
comparisons at Week 76 for the 50 mg group versus the placebo group will be tested at the 
alpha = 0.05 level of significance (two-sided).   
11.3.3 Other 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 
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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 by linear mixed models for repeated measurements, as described above for the 
primary analysis. 
Plasma assays may include P-tau181, SavaDx, neurofilament light chain and other 
biomarkers. All plasma biomarker data and MRI data measured repeatedly will be analyzed 
by linear mixed models for repeated measurements, as described above for the primary 
analysis. 
CSF biomarker endpoints to be analyzed include: 1) neurogranin, 2) neurofilament light 
chain, 3) total tau, 4) P-tau181, 5) sTREM2, and 6) Aβ42. Additional CSF biomarkers may 
be measured. All CSF biomarker data, PET imaging data and CDR-SB will be analyzed 
using ANCOVA models with treatment group as a factor and the baseline value of the 
corresponding endpoint 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 1,083 subjects will be enrolled in this study. The sample size was 
determined by a power analysis of ADAS-Cog in a similar population over 76 weeks. This 
analysis determined that the comparison between an active arm and placebo requires group 
sizes of 289 to provide 90% power to detect a 45% difference from placebo at 76 weeks, 
based on the use of a two-sided test at the alpha = 0.05 significance level. The power 
calculation assumes a true mean change from baseline for placebo of 6.0 points and a 
standard deviation of 10.0 points.  Assuming a drop-out of 20%, each treatment group 
should enroll 361 subjects. 
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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. 
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.  
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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. 
• 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: 
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• 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 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. 
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• 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 
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. 
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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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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 
Week 
64 
Week 76 
ET/ED7 
Week 
77 to 
78 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
I/E Criteria 
X 
X 
 
 
 
 
 
 
 
 
Medical & Med History 
X 
 
 
 
 
 
 
 
 
 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical Examination  
X1 
X 
X 
X 
X 
X 
X 
X 
X 
 
Neurologic Examination 
X1 
X 
X 
X 
X 
X 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
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 
X 
X 
 
Urine Drug Screen 
X 
 
 
 
 
 
 
 
 
 
TSH, free T4, B12, 
HBsAg, HCV-Ab 
X 
 
 
 
 
 
 
 
 
 
HbA1C (diabetic 
subjects only) 
X 
 
 
 
 
 
 
 
 
 
Plasma P-tau181 
X12 
 
 
 
 
 
 
 
 
 
Genotyping sample 
 
X 
 
 
 
 
 
 
 
 
MRI 
X 
 
 
 
 
X2 
 
 
X2 
 
Plasma Biomarkers 
X3 
 
 
 
X3 
 
X3 
 
X3 
 
Plasma PK 
 
 
 
 
X11 
 
 
 
X11 
 
CSF Biomarkers 
X4 
 
 
 
 
 
 
 
X4 
 
Amyloid PET  
X5 
 
 
 
 
 
 
 
X5 
 
Tau PET  
X6 
 
 
 
 
 
 
 
X6 
 
MMSE 
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 
Week 
64 
Week 76 
ET/ED7 
Week 
77 to 
78 
ADAS-Cog12 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
ADCS-ADL 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
CDR 
X 
 
 
 
 
 
 
 
X 
 
NPI 
 
X 
 
 
X 
 
X 
 
X 
 
ZBI 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
C-SSRS 
X8 
X9 
X9 
X9 
X9 
X9 
X9 
X9 
X9 
 
Drug Dispensation  
 
X10 
X 
X 
X10 
X 
X 
X 
 
 
Drug Accountability 
 
 
X 
X 
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. MRI sub-study subjects only (150 subjects total; 50 subjects/group) 
3. Plasma biomarker sub-study subjects only; these are the same subjects in both PET 
sub-studies (270 subjects total; 90 subjects/group) 
4. CSF biomarker sub-study subjects only (90 subjects total; 30 subjects/group) 
5. Amyloid PET sub-study subjects only (120 subjects total; 40 subjects/group) 
6. Tau PET sub-study subjects only (150 subjects total; 50 subjects/group) 
7. 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 
8. During the Screening Period, the C-SSRS Baseline/Screening version will be 
administered 
9. At Study Day 1, as well as all remaining visits, the C-SSRS Since Last Visit version 
will be administered 
10. The first dose of Study Drug is administered at the clinic to all subjects on Study Day 
1; for tau PET sub-study participants only at the Week 28 visit, administer Study Drug 
after plasma PK sample is collected 
11. Plasma PK sample from tau PET sub-study participants only 
12. Plasma P-tau181 not required if the subject has evidence for AD pathophysiology 
prior to screening 
 
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Page 1 of 46 
 
 
 
 
CONFIDENTIAL 
 
 
 
CLINICAL RESEARCH PROTOCOL 
PROTOCOL PTl-125-06 
 
A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
PARALLEL-GROUP, 76-WEEK STUDY EVALUATING THE SAFETY AND 
EFFICACY OF TWO DOSES OF SIMUFILAM 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 
 
 
This clinical study is supported by NIH grant AG073350. 
 
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. 
 
 
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30 June 2021
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Page 3 of 46 
 
 
 
 
CONFIDENTIAL 
 
 
Cassava Sciences, Inc. 
CLINICAL RESEARCH PROTOCOL 
 
 
 
A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 
PARALLEL-GROUP, 76-WEEK STUDY EVALUATING THE SAFETY AND 
EFFICACY OF TWO DOSES OF SIMUFILAM IN SUBJECTS WITH MILD-TO-
MODERATE ALZHEIMER’S DISEASE  
 
 
 
Signature of Agreement for Protocol PTI-125-06 
 
 
 
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 ..........................................................................................15 
5.1. Study Population ...................................................................................................................... 15 
5.2. Inclusion Criteria ..................................................................................................................... 15 
5.3. Exclusion Criteria .................................................................................................................... 17 
6. 
STUDY DRUG .........................................................................................................21 
6.1. Simufilam Physical Description and Preparation ..................................................................... 21 
6.1.1 
Packaging and Labeling ................................................................................................ 21 
6.1.2 
Storage ........................................................................................................................... 21 
6.1.3 
Drug Accountability ....................................................................................................... 21 
6.2. Administration and Dosing Regimen ....................................................................................... 22 
6.3. Concomitant Medications ........................................................................................................ 22 
7. 
STUDY PROCEDURES .........................................................................................22 
7.1. Evaluations by Visit ................................................................................................................. 22 
7.1.1. Screening Period (No greater than a 60-day duration prior to Study Day 1) ................ 22 
7.1.2. Sub-studies with PET and fluid biomarkers ................................................................... 23 
7.1.3. Rescreening of a Subject ................................................................................................ 24 
7.1.4. Study Day 1 (Dosing Initiation) ..................................................................................... 24 
7.1.5. Weeks 4, 16, 40 and 64 Follow-up Visits ....................................................................... 26 
7.1.6. Weeks 28 and 52 Follow-up Visit ................................................................................... 27 
7.1.7. Week 76 End-of-Treatment Visit / Early Termination (ET) Visit ................................... 27 
7.1.8. Week 77-78 End-of-Study Follow-up ............................................................................. 28 
7.1.9. Treatment after Study Completion ................................................................................. 28 
7.1.10. Unscheduled Visits and Discontinuation due to AEs ..................................................... 29 
7.1.11. Stopping Criteria ............................................................................................................ 29 
7.2. Laboratory Assessments .......................................................................................................... 30 
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7.2.1. Clinical Laboratory Tests ............................................................................................... 30 
7.2.2. Collection of Whole Blood Samples for ApoE Genotyping ............................................ 30 
7.2.3. Preparation of Plasma Biomarker and PK Samples from PET Sub-study Participants ...... 30 
7.2.4. CSF assays ..................................................................................................................... 31 
8. 
COGNITIVE AND FUNCTIONAL ASSESSMENTS ...........................................31 
8.1. Mini-Mental State Exam (MMSE) ........................................................................................... 31 
8.2. Clinical Dementia Rating (CDR) ............................................................................................. 31 
8.3. Alzheimer’s Disease Assessment Scale – Cognitive Subscale 12 (ADAS-Cog12) ................. 32 
8.4. Neuropsychiatric Inventory (NPI) ............................................................................................ 32 
8.5. Alzheimer’s Disease Cooperative Study – Activities of Daily Living (ADCS-ADL-AD) ...... 32 
8.6. Columbia-Suicide Severity Rating Scale (C-SSRS) ................................................................ 32 
8.7. Zarit Burden Interview (ZBI) ................................................................................................... 32 
8.8. Geriatric Depression Scale (GDS) ........................................................................................... 32 
8.9. Electronic Capture of Rating Scales......................................................................................... 33 
9. 
EARLY DISCONTINUATION ...............................................................................33 
10. 
ADVERSE EVENTS/SERIOUS ADVERSE EVENTS ..........................................34 
10.1. Adverse Events - Definition ...................................................................................................... 34 
10.2. Adverse Events - Severity Rating ............................................................................................ 35 
10.3. Adverse Events – Relationship to Study Drug ......................................................................... 35 
10.4. Serious Adverse Events and Unexpected Adverse Events - Definitions .................................. 35 
10.5. Serious Adverse Events Reporting ........................................................................................... 36 
11. 
STATISTICAL CONSIDERATIONS .....................................................................37 
11.1. Randomization ......................................................................................................................... 37 
11.2. Analysis Populations ................................................................................................................ 37 
11.3. Statistical Analysis ................................................................................................................... 38 
11.3.1. Primary Efficacy Analysis .............................................................................................. 38 
11.3.2 Key Secondary Analysis ................................................................................................. 38 
11.3.3 Other Secondary Analyses ............................................................................................. 38 
11.4. Safety Analysis ......................................................................................................................... 39 
11.5. Sample Size .............................................................................................................................. 39 
12. 
STUDY TERMINATION ........................................................................................39 
13. 
DATA COLLECTION, RETENTION AND MONITORING .................................39 
13.1. Case Report Forms ................................................................................................................... 39 
13.2. Availability and Retention of Investigational Records ............................................................ 40 
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13.3. Subject Confidentiality ............................................................................................................ 40 
13.4. Liability .................................................................................................................................... 40 
13.5. Ethical and Legal Issues ........................................................................................................... 41 
13.5.1. Institutional Review Board .............................................................................................. 41 
13.6. Informed Consent Form ........................................................................................................... 41 
14. 
INVESTIGATOR RESPONSIBILITIES ................................................................42 
15. 
REFERENCES .........................................................................................................43 
16. 
APPENDIX A – SCHEDULE OF ACTIVITIES ....................................................45 
 
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 Test 13 
 
 
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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 
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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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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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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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 76-week, repeat-dose oral 
administration in mild-to-moderate AD subjects, 50-87 years of age. Secondary objectives 
are to assess neuropsychiatric symptoms and to replicate the CSF biomarker effects 
observed in the two Phase 2 studies (PTI-125-03 and PTI-125-02) after 76 weeks of 
simufilam treatment. A third objective is to investigate the effect of simufilam treatment 
on plasma biomarkers as well as anatomical correlates of disease progression (brain 
volume [hippocampus, ventricles and whole brain]; amyloid and tau deposition in the 
brain). 
4. 
SUMMARY OF STUDY DESIGN 
In this Phase 3 clinical study, approximately 1,083 subjects with mild-to-moderate AD 
(361 per arm) will receive placebo or 50 mg tablets of simufilam or 100 mg tablets of 
simufilam, twice daily, for 76 weeks. Randomization (1:1:1) 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 
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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, 52, 64 and 76.   
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 76).  
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, however, 150 subjects (50 subjects 
per treatment group) will also undergo repeat MRI assessments at Weeks 40 and 76 to 
assess both long-term safety and drug impact on brain volume as noted above. ECGs will 
be conducted Day 1 and Weeks 4, 40 and 76. 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 one or more sub-studies 
to assess the impact of simufilam on anatomical and biomarker endpoints, including: 
change from baseline in CSF biomarkers (30 subjects/group), brain volume via MRI (50 
subjects/group), and amyloid and tau PET (40 and 50 subjects/group, respectively). 
Participants in both PET sub-studies will provide plasma for a biomarker sub-study, and 
those in the tau PET sub-study will also provide additional plasma for a PK exposure-
response analysis. Changes from baseline for these imaging and fluid biomarkers represent 
additional secondary endpoints. 
The ninety subjects (30 per group) in the CSF sub-study will undergo lumbar puncture 
during the Screening Period and again at the Week 76 End-of-Treatment Visit to collect 
CSF biomarkers.  
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. 
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5. 
SUBJECT SELECTION 
5.1. STUDY POPULATION 
Approximately 1,083 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 
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. 
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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). 
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 
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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 with a pacemaker 
must be excluded due to the required MRI during screening). 
3. A medical condition or treatment with an anticoagulant that would interfere with a 
lumbar puncture for those subjects being considered for participation in the CSF 
biomarker assessment. 
4. BMI < 18.5 or > 35.0 
5. 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. 
6. 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.  
7. Geriatric Depression Scale (15-item) score > 8. 
8. 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.  
9. Meets DSM-V criteria for alcohol or substance use disorder within 2 years before the 
Screening Period. 
10. MRI presence of cerebral vascular pathology (including, but not limited to, 
hemorrhage, infarct > 1 cm3, or > 3 lacunar infarcts), cerebral contusion, symptomatic 
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subdural hematoma, aneurysm, or space-occupying lesion deemed clinically significant 
in the opinion of the Investigator. 
11. History of transient ischemic attack (TIA) or stroke within 12 months of screening, or 
history of a stroke concurrent with the onset of dementia. 
12. History of seizure within 12 months of screening. 
13. 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. 
14. Onset of dementia secondary to cardiac arrest, surgery with general anesthesia, or 
resuscitation. 
15. 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. 
16. 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. 
17. 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). 
18. Known positive HIV status. 
19. Positive HBsAg or HCV-Ab during screen. 
20. Positive urine drug screen for substances of abuse. 
21. 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. 
22. 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 
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supplementation for hypothyroidism must be on a stable dose for ≥ 3 months before 
screening. 
23. 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). 
24. 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. 
25. History of or current clinically significant cardiac arrhythmia or heart block as 
evidenced by ECG in the judgment of the Investigator. 
26. 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. 
27. 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). 
28. 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). 
29. 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. 
30. Donepezil > 10 mg/day, currently or within 12 weeks of Study Day 1 (randomization).  
31. Discontinued AChEI < 12 weeks prior to randomization. 
32. Administration of aducanumab, either currently or previously prescribed (Note – 
administration of aducanumab at any point during this clinical study is prohibited). 
33. Antipsychotics (Note – low doses are allowed only if given for sleep disturbances, 
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agitation, aggression or dementia-related psychosis, and only if the dose has been stable 
for at least 4 weeks prior to screening). 
34. 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. 
35. Immunosuppressants, including systemic corticosteroids, if taken in clinically 
immunosuppressive doses (steroid use for allergy or inflammation is permitted). 
36. Use of antiepileptic medications if taken for control of seizures (Note – use of 
antiepileptic medications are allowed if used for mood stabilization). 
37. Chronic intake of opioid-containing analgesics. 
38. Use of prescribed sedating H1 antihistamines. 
39. Use of nicotine therapy (all dosage forms including a patch), varenicline (Chantix), or 
similar therapeutic agent within 4 weeks prior to screening. 
40. Loss of a significant volume of blood (> 450 mL) within 4 weeks of randomization. 
41. 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). 
42. Clinically significant abnormalities on screening laboratory tests in the judgment of the 
Investigator. 
43. 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.  
44. 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 and matching placebo will be supplied by Cassava as coated 
tablets including 50 and 100 milligram active strengths.   
All remaining unused simufilam study drug will be returned to the Sponsor or designee. 
6.1.1 Packaging and Labeling 
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 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. 
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6.2. ADMINISTRATION AND DOSING REGIMEN 
Subjects will be randomized to receive placebo, or 50 mg or 100 mg simufilam b.i.d. 
(approximately 361 subjects per treatment group). 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 #30 and #31 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) 
• Medical and surgical history  
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• 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: 
o MMSE  
o CDR  
o Geriatric Depression Scale 
o 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). 
o Subjects participating in the MRI sub-study assessment of brain volume 
(150 total; 50 subjects/group), including the hippocampus, ventricles and 
whole brain, will have, in addition to the MRI during the Screening Period, 
subsequent MRI scans at Weeks 40 and 76. 
7.1.2. Sub-studies with PET and fluid biomarkers 
Selected research sites will participate in additional sub-study assessments to determine the 
effect of simufilam on anatomical and biomarker secondary endpoints. 
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• Subjects participating in either amyloid or tau PET sub-studies (40 and 50 
subjects/group, respectively) will be scheduled for their first PET scan prior to 
Study Day 1; they will undergo the procedure again at Week 76. Individual 
subjects can potentially participate in both PET imaging sub-studies, but 
consideration must be given to total radiation exposure based on the number of 
PET scans and dose each subject would receive per annum. Moreover, PET 
scans using different tracers must also be acquired at least 24 hours apart to 
ensure adequate wash-out of the previous tracer prior to new tracer 
administration. 
• Subjects participating in the PET sub-studies will also have blood samples 
drawn for assessments of plasma-based biomarkers during the Screening Period 
and again at Weeks 28, 52 and 76 (≈ 270 total; ≈ 90 subjects/group). Subjects 
participating in the tau PET sub-study will also provide a plasma sample for PK 
at Weeks 28 and 76.   
• Subjects participating in an assessment of CSF biomarkers (90 total; 30 
subjects/group) will undergo lumbar puncture prior to Study Day 1 and again at 
Week 76.  
7.1.3. 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, the subject is allowed one rescreen: 
• 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.   
7.1.4. 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 
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• 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) 
• eCOA order of administration: 
o ADAS-Cog12  
o ADCS-ADL 
o NPI 
o ZBI  
o C-SSRS – Since Last Visit version 
• ECG  
• Clinical laboratory tests (blood and urine) 
• 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 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 
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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.  
7.1.5. Weeks 4, 16, 40 and 64 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 ADAS-Cog12 (whenever possible, within 1 h of the time of day 
administered at the Study Day 1 Visit, and by the same rater) 
o ADCS-ADL 
o ZBI 
o C-SSRS – Since Last Visit version 
• Clinical laboratory tests (blood and urine) 
• Weeks 4 and 40 only: resting ECG 
• Week 40 only: for those 150 subjects participating in the MRI sub-study to 
determine the effect of simufilam on brain volume, schedule their Week 40 
scan. 
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7.1.6. Weeks 28 and 52 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:  
o ADAS-Cog12 (whenever possible, within 1 h of the time of day 
administered at the Study Day 1 Visit, and by the same rater) 
o ADCS-ADL 
o MMSE 
o NPI 
o ZBI 
o C-SSRS – Since Last Visit version 
• Clinical laboratory tests (blood and urine) 
• For those 270 subjects participating in the amyloid or tau PET and plasma 
biomarker sub-studies, collect their Week 28 and Week 52 blood samples 
(including PK at Week 28 for those in the tau PET sub-study) 
 
7.1.7. Week 76 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 
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• eCOA order of administration:  
o ADAS-Cog12 (whenever possible, within 1 h of the time of day 
administered at the Study Day 1 Visit, and by the same rater) 
o ADCS-ADL 
o MMSE 
o CDR 
o NPI 
o ZBI 
o C-SSRS – Since Last Visit version 
• Resting ECG 
• Clinical laboratory tests (blood and urine) 
• For those 270 subjects participating in the amyloid or tau PET and plasma 
biomarker sub-studies, collect their Week 76 blood samples (including PK 
samples for those in the tau PET sub-study) and schedule their Week 76 scan. 
• For those 150 subjects participating in the MRI sub-study to determine the 
effect of simufilam on brain volume, schedule their Week 76 scan. 
• For those 90 subjects participating in the CSF biomarker sub-study, perform a 
lumbar puncture to collect CSF (5 mL) after all other testing has been 
completed. 
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) 
7.1.8. Week 77-78 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. 
 
 
 
7.1.9. Treatment after Study Completion 
The Sponsor plans to initiate an open-label extension study for subjects who have 
completed participation in Study PTI-125-06. Should a subject elect to participate in the 
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open-label extension study, the End-of-Study Follow-up (Section 7.1.8) will not be 
conducted. 
 
7.1.10. 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. 
 
 
7.1.11. 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. 
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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, 
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 Plasma Biomarker and PK Samples from PET Sub-study Participants  
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 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).  
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7.2.4. CSF assays 
CSF samples should be split, with approximately 2.5 mL shipped to the central lab (as 
instructed per lab manual). The remaining CSF will be retained at the study site and frozen 
at -70°C or below until instructions are received from the Sponsor. 
CSF samples will be collected during the Screening Period and again at Week 76 for those 
subjects participating in the CSF biomarker sub-study. The biomarkers to be assayed will 
include:  
• Total Tau  
• P-tau181 
• Neurogranin 
• sTREM2 
• Amyloid-beta 42 
• Neurofilament light chain 
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 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.  
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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 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 
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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 7.1.7 – 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: 
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• 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 reporting 
SAEs based upon established criteria.  Likewise, it is the responsibility of the Principal 
Investigator to report SAEs to the IRB. 
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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 (three levels), week (7 levels, corresponding 
to Weeks 4, 16, 28, 40, 52, 64 and 76), 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 76 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 Key Secondary Analysis 
If both primary comparisons are statistically significant, then the corresponding 
comparisons at Week 76 for the 50 mg group versus the placebo group will be tested at the 
alpha = 0.05 level of significance (two-sided).   
11.3.3 Other 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 by linear mixed models for repeated measurements, as described above for the 
primary analysis. 
Plasma assays may include P-tau181, SavaDx, neurofilament light chain and other 
biomarkers. All plasma biomarker data and MRI data measured repeatedly will be analyzed 
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by linear mixed models for repeated measurements, as described above for the primary 
analysis. 
CSF biomarker endpoints to be analyzed include: 1) neurogranin, 2) neurofilament light 
chain, 3) total tau, 4) P-tau181, 5) sTREM2, and 6) Aβ42. Additional CSF biomarkers may 
be measured. All CSF biomarker data, PET imaging data and CDR-SB will be analyzed 
using ANCOVA models with treatment group as a factor and the baseline value of the 
corresponding endpoint 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 1,083 subjects will be enrolled in this study. The sample size was 
determined by a power analysis of ADAS-Cog in a similar population over 76 weeks. This 
analysis determined that the comparison between an active arm and placebo requires group 
sizes of 289 to provide 90% power to detect a 45% difference from placebo at 76 weeks, 
based on the use of a two-sided test at the alpha = 0.05 significance level. The power 
calculation assumes a true mean change from baseline for placebo of 6.0 points and a 
standard deviation of 10.0 points.  Assuming a drop-out of 20%, each treatment group 
should enroll 361 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 
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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. 
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. 
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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. 
• 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 
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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 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. 
 
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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 
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 
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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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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 
Week 
64 
Week 76 
ET/ED7 
Week 
77 to 
78 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
I/E Criteria 
X 
X 
 
 
 
 
 
 
 
 
Medical & Med History 
X 
 
 
 
 
 
 
 
 
 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical Examination  
X1 
X 
X 
X 
X 
X 
X 
X 
X 
 
Neurologic Examination 
X1 
X 
X 
X 
X 
X 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
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 
X 
X 
 
Urine Drug Screen 
X 
 
 
 
 
 
 
 
 
 
TSH, free T4, B12, 
HBsAg, HCV-Ab 
X 
 
 
 
 
 
 
 
 
 
Plasma P-tau181 
X12 
 
 
 
 
 
 
 
 
 
Genotyping sample 
 
X 
 
 
 
 
 
 
 
 
MRI 
X 
 
 
 
 
X2 
 
 
X2 
 
Plasma Biomarkers 
X3 
 
 
 
X3,11 
 
X3 
 
X3,11 
 
CSF Biomarkers 
X4 
 
 
 
 
 
 
 
X4 
 
Amyloid PET  
X5 
 
 
 
 
 
 
 
X5 
 
Tau PET  
X6 
 
 
 
 
 
 
 
X6 
 
MMSE 
X 
 
 
 
X 
 
X 
 
X 
 
ADAS-Cog12 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
ADCS-ADL 
 
X 
X 
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 
Week 
64 
Week 76 
ET/ED7 
Week 
77 to 
78 
CDR 
X 
 
 
 
 
 
 
 
X 
 
NPI 
 
X 
 
 
X 
 
X 
 
X 
 
ZBI 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
C-SSRS 
X8 
X9 
X9 
X9 
X9 
X9 
X9 
X9 
X9 
 
Drug Dispensation  
 
X10 
X 
X 
X 
X 
X 
X 
 
 
Drug Accountability 
 
 
X 
X 
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. MRI sub-study subjects only (150 subjects total; 50 subjects/group) 
3. Plasma biomarker sub-study subjects only; these are the same subjects in both PET 
sub-studies (270 subjects total; 90 subjects/group) 
4. CSF biomarker sub-study subjects only (90 subjects total; 30 subjects/group) 
5. Amyloid PET sub-study subjects only (120 subjects total; 40 subjects/group) 
6. Tau PET sub-study subjects only (150 subjects total; 50 subjects/group) 
7. 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 
8. During the Screening Period, the C-SSRS Baseline/Screening version will be 
administered 
9. At Study Day 1, as well as all remaining visits, the C-SSRS Since Last Visit version 
will be administered 
10. The first dose of Study Drug is administered at the clinic 
11. Plasma PK sample from tau PET sub-study participants 
12. Plasma P-tau181 not required if the subject has evidence for AD pathophysiology 
prior to screening 
 
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