Clinical trial NCT04079803
Conditions: Alzheimer Disease
Sponsor: Cassava Sciences, Inc.
Start date: 2019-09-09; Completion date: 2020-03-31
Enrollment: 64 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 2b, Randomized, Double-blind, Placebo-controlled, multiple dose study of PTI-125 in mild-to-moderate Alzheimer's disease patients.

Detailed description:
This is a Phase 2b, Randomized, Double-blind, Placebo-controlled, multiple dose study of PTI-125 in mild-to-moderate Alzheimer's disease patients. A total of sixty (60) patients will be enrolled in the study. Patients will receive Placebo, 50 mg or 100 mg b.i.d. of PTI-125. The objective of this study are to investigate the safety, and biomarkers of PTI-125 following 28-day repeat oral administration.

Arms: arm 1: Subjects administered placebo oral tablets twice daily (BID) arm 2: Subjects administered simufilam (PTI-125) 100 mg oral tablets twice daily (BID) arm 3: Subjects administered simufilam (PTI-125) 50 mg oral tablets twice daily (BID)
Interventions: intervention 1: Placebo oral tablet intervention 2: Simufilam 100 mg tablet intervention 3: Simufilam 50 mg oral tablet
Intervention descriptions: intervention 1: Oral placebo tablet intervention 2: Simufilam 100 mg oral tablet intervention 3: Simufilam 50 mg oral tablet

Protocol documents:
ICF_002.pdf: 
 
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INFORMED CONSENT FORM 
AND 
AUTHORIZATION TO DISCLOSE HEALTH INFORMATION 
 
Sponsor / Study Title: 
  
Cassava Sciences, Inc. / “A Phase 2b, Randomized, 
Double-blind, Placebo-controlled, Multiple Dose, 
Biomarker and Safety Study of PTI-125 in Mild-to-
Moderate Alzheimer’s Disease Patients” 
 
Protocol Number: 
 
PTI-125-02 
 
Principal Investigator: 
(Study Doctor) 
 
«PiFullName» 
 
Telephone: 
 
«IcfPhoneNumber» 
 
Address: 
«PiLocations» 
 
This form is for use in a research study that may involve subjects who may or may not have the 
capacity to consent to take part in the study.  When the subject cannot legally consent to take 
part, pronouns “you” and “your” should be read as referring to the subject rather than the 
person (legally authorized representative) who is signing and dating this form for the subject. 
In cases where the subject’s representative gives consent, the subject should be informed about 
the study to the extent possible given his/her understanding. During the course of the study, if 
the subject regains the capacity to consent, informed consent will be obtained from the subject 
and the subject offered the ability to leave the study if desired. All subjects will be required to 
have a caregiver to assist with taking the study drug and other activities.  
 
INTRODUCTION 
You are being invited to take part in a research study. You must read, sign and date this form 
before you agree to take part in this study. This form will give you more information about 
this study. Please ask as many questions as you need to before you decide if you want to be 
in the study. You should not sign this form if you have any questions that have not been 
answered. 
 
The study doctor is being paid by the sponsor (the company paying for this study) to conduct 
this research study. 
 
You must be honest with the study doctor about your health history or you may harm 
yourself by participating in this study. 
 
The study drug has previously been given to healthy subjects as a single dose and to a few 
Alzheimer’s disease subjects as a repeated, twice daily oral dose for one month. The study 
drug was safe and well tolerated in all subjects.  
 


 
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PURPOSE OF THE STUDY 
The purpose of this study is to measure changes in cognition and biomarkers following 
administration of Cassava Sciences, Inc.’s new investigational drug PTI-125 and to 
determine if there are any side effects associated with the study drug when taken daily for 1 
month. PTI-125 is intended to slow the progression of Alzheimer’s disease as well as provide 
some cognitive recovery.  
 
"Investigational" means the study drug being tested is not approved by the United States 
Food and Drug Administration (FDA) or by any other comparable agency. 
 
A “biomarker” is an indicator that gives information about your health or your response to 
study treatment.  
If you qualify for the study, you will receive PTI-125 or placebo (known throughout this 
form as the “study drug”). You will receive your dose twice a day for 28 days.  
 
This is a blinded study, which means that neither you nor the study doctor will know whether 
you will be taking PTI-125 or a placebo. A placebo is an inactive pill, like a sugar pill. Two-
thirds of the subjects will receive PTI-125, and one-third will receive placebo.  Dependent on 
further data collected by the sponsor company, you may be eligible for a longer study where 
everyone will be given PTI-125 active drug.  
 
HOW LONG WILL THE STUDY LAST AND HOW MANY PEOPLE WILL BE IN 
THE STUDY? 
The study will last about 28 days, excluding the screening period. On the first day of dosing, 
you will stay at the study site for 4 hours after your first dose. You will also be required to 
make follow-up visits to the study site at least six times during the 28 days. About 60 men 
and women who have been diagnosed with mild-to-moderate Alzheimer’s disease, ages 50 
through 85, are expected to be in this study.  
 
WHAT DO I HAVE TO DO TO BE IN THIS STUDY? 
You cannot be in this study if you: 
• Are in another research study or if you have been in any other research study in which 
you received study drug within 3 months of your screening visit.  
• Have been in the previous study of PTI-125 
• Have donated blood within 4 weeks before the first dose of study drug. 
Subject Responsibilities: 
While participating in this research study, you will need to: 
• Be willing and able to follow the study directions and procedures. 
• Tell the study staff about any side effects or problems. 
• Ask questions as you think of them. 
• Tell the study doctor or the study staff if you change your mind about staying in the 
study. 
 
This study involves testing an investigational drug developed by Cassava Sciences, Inc. (the 
Sponsor). We ask subjects to keep information as confidential as possible. This would 


 
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include not sharing details of the study, including requirements for participation, information 
received on the risks and benefits of dosing with this study drug, and symptoms or reactions 
to study drug dosing while enrolled in the study, with persons other than the study staff, your 
family and your healthcare provider. This would also include not disclosing such information 
on social media sites or webpages. 
 
WHAT WILL HAPPEN DURING THE STUDY? 
Screening 
Before the study starts, you will be asked to sign and date this consent form, give your health 
and social history, and tell study staff if you take any over-the-counter or prescription 
medicines, vitamins, or herbs.  
 
The study doctor will do some tests to find out if you can be in the study. These tests include: 
• Physical exam, including vital signs (blood pressure, temperature, heart and breathing 
rates), height and weight   
• An electrocardiogram (ECG) will be taken - this is a recording of the electrical 
activity of your heart 
• Lab tests (blood and urine) 
• Blood test for HIV and hepatitis B and C  
• Urine drug screen 
• Memory testing – Mini Mental State Exam and Cambridge Cognition testing 
• A behavioral/psychological test for suicidal thoughts. If this test is positive, you will 
be referred for appropriate care 
• If you are female and have had your final period less than 24 months ago, or you are 
uncertain when you had your last period, post-menopausal status will be confirmed 
by a blood test 
 
The Screening Visit may take up to 2 hours and 30 minutes of your time. 
 
If you meet certain criteria, you will come back for a lumbar puncture for more tests to 
confirm your diagnosis of Alzheimer’s disease. The lumbar puncture sample will also be 
tested for a neuroinflammation marker (indicating swelling in your brain and/or spinal cord) 
and possibly other cerebrospinal fluid biomarkers.  
 
• You will have a needle placed in your spine to collect a small amount of 
cerebrospinal fluid (Lumbar Puncture).  
• You will have a test for memory  
 
If you qualify for the study, you will return to the study clinic to start the study. You will stay 
in the clinic for about two hours. During this time, you will have blood draws, vital signs, 
and an ECG. You will continue to take study drug each day at home, morning and evening.  
 
You will need to return to the study clinic on the 7th, 14th and 28th days of the study for up to 
2 hours. During these two hours the following testing may be performed:  
• ECG 


 
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• Vital signs 
• Listening to your heart and lungs 
• Blood draws 
• Memory testing 
 
You will return to the clinic once more in the morning of the 28th (last) day of taking the 
study drug for the same testing along with another lumbar puncture. You will also have a 
blood draw very close to the time of your lumbar puncture. You will have more memory 
testing, an ECG and a physical examination. 
 
Study Procedures 
Days 1 and study clinic visits 
The following will be done before taking the first dose:  
• You will be asked questions to be sure that you still qualify for this study. 
• You will be asked about any changes in your health or drugs you have taken since 
your last visit. 
• A study doctor or nurse will take your vital signs (blood pressure, heart rate, 
breathing rate and temperature) and listen to your heart and lungs. 
• You will have a test for memory. 
• You will have a blood draw for an experimental test to confirm your diagnosis and to 
measure biomarkers. 
• You will have a blood draw for clinical laboratory tests. 
 
After your first dose of Study Drug: 
• Standard meals will be given at scheduled times on Day 1 in the study clinic. 
• The level of study drug in your blood will be measured on most study clinic visits. 
About 3/4 teaspoon (4 mL) of blood will be taken. 
• Vital signs (temperature, blood pressure, heart rate and breathing rate) will be 
performed at multiple time points during the study. 
• A study doctor or study nurse will listen to your heart and lungs prior to discharge on 
Day 1 and at every subsequent clinic visit.  
• An electrocardiogram (ECG; a recording of the electrical activity of your heart) will 
be conducted on Day 1 prior to dosing and at all visits except Day 7. 
• Lab tests will be conducted (blood and urine) at all visits.  
• A blood draw (8 mL) to repeat the experimental test to confirm your diagnosis and to 
measure blood-based biomarkers (Days 1, and 28).  
• You will be monitored for any side effects. 
• You will have a behavioral/psychological test, and on Day 28 another test for suicidal 
thoughts. If this test is positive, you will be referred for appropriate care. 
• You will have a blood test for your genotype of the APOE gene. One of these 
genotypes is linked to a higher risk of Alzheimer’s disease. You will not be told the 
results of this test unless you choose. 
  
If you leave the study early or are withdrawn the following procedures will be performed:  
• Vital signs (temperature, blood pressure, heart and breathing rates)  


 
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• Physical examination  
• Lab tests (blood and urine)  
• Electrocardiogram (ECG)  
• Memory testing 
• Cerebrospinal fluid (CSF) draw 
 
Blood Samples: 
Blood samples will be taken by single needle-sticks or by a tube that is left in your arm.  You 
cannot choose how the blood is taken. 
 
There will be about 5 blood draws not including 3 blood draws during screening. The total 
amount of blood drawn in the study will be about 68 mL, or less than 1/3 of a cup. For 
comparison, the standard blood donation is about 480 mL (two cups). Additional blood may 
be drawn and additional tests performed for your safety.  
 
HIV AND HEPATITIS TESTING 
As required by the study and if any person is exposed to your blood, you must have your 
blood tested for the hepatitis viruses and for HIV.  HIV is the virus that causes AIDS.  If you 
have a positive HIV or hepatitis test you cannot be in the study. 
 
It may take weeks or months after being infected with HIV for the test to be positive.  The 
HIV test is not always right. 
 
Positive test results may be required to be reported to the State Department of Health.  If you 
have any questions about what information is required to be reported please ask the study 
doctor or study staff. 
 
Although this testing is supposed to be private, this cannot be guaranteed.  For example, it is 
possible for a court of law to get health or study records without your permission. 
 
Additionally, in the unlikely event that a study employee has been exposed to your blood or 
other body fluid either through a needle stick injury, splash incident or contact with broken 
skin (for example, a cut, or a bite), additional samples may be collected to determine and 
confirm whether or not you have a certain infection. Your de-identified results will be 
released to the injured employee, and to the health care provider evaluating and treating that 
employee, to aid the injured employee and the medical provider make decisions regarding 
his/her medical treatment and follow-up care as a result of this on-the-job exposure. 
 
POSSIBLE SIDE EFFECTS AND RISKS  
If you do not understand what any of these side effects mean, please ask the study doctor or 
study staff to explain these terms to you.  
 
Because this study drug is investigational, all its side effects may not be known. There may 
be rare and unknown side effects. Some of these may be life threatening.  
 


 
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In pre-clinical (animal studies) the following side effects were seen:  
• Vomiting  
• Increased salivation  
• Increased blood pressure  
• Weight loss 
• Changes to the size and function of the liver cells 
• Seizure 
 
You must tell the study doctor or study staff about all side effects that you have. If you are 
not honest about your side effects, you may harm yourself by staying in this study. 
 
All drugs may cause allergic reactions in some people. Below is a list of symptoms of an 
allergic reaction: 
• Swelling of the face, lips, throat, and other areas of the skin 
• Difficulty swallowing or breathing 
• Raised, red areas on your skin 
• Skin rash, itching, flaking, or peeling 
 
If you have a side effect of the study drug, such as a skin rash or other visible injury, it might 
be useful to take a digital picture of the affected area to send to the study doctor. By signing 
and dating this consent, you authorize the study doctor or study staff to take such a picture 
and provide it to the sponsor.  Every effort will be made to protect your identity if a 
photograph is necessary. 
 
ADDITIONAL RISKS OR DISCOMFORTS 
Blood Samples (taken by single needle-sticks or by a tube that is left in your arm): 
There may be side effects of having blood drawn such as: 
• Fainting 
• Redness 
• Pain 
• Bruising 
• Bleeding 
• Infection 
• Blood clots, which may cause inflammation, swelling and pain 
• Nerve damage 
 
If you feel faint, tell the study staff right away. 
 
Risks of Using an Intravenous (IV) Catheter for blood draws: 
• Infection 
• Pain 
• Redness 
• Bruising 
• Vein irritation from the fluids or medication being given 


 
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• Local swelling due to IV fluid (saline) accidentally entering the tissue rather than the    
vein 
• Blood clots, which may cause inflammation, swelling and pain 
 
Spinal Tap or Lumbar Puncture: 
Lumbar puncture (spinal tap) is performed in the lower back, in the lumbar region. During 
lumbar puncture, a needle is inserted between two lumbar bones (vertebrae) to remove a 
sample of cerebrospinal fluid — the fluid that surrounds your brain and spinal cord to protect 
them from injury. Side effects may include: 
• Headache 
• Nausea 
• Vomiting  
• Dizziness 
• Back pain or discomfort which may be significant 
• Bleeding at puncture site or rarely into epidural space 
• Infection 
 
You will be given a topical anesthetic to reduce pain from the procedure. There are few risks 
to this anesthetic as it is normally applied, but you may experience mild irritation where the 
anesthetic is applied and/or numbness in places where the anesthetic may be accidentally 
applied. 
 
Electrocardiogram (ECG): 
The ECG test is a recording of the electrical activity of your heart.  The sticky pads used may 
be cold when applied and sometimes cause some discomfort such as redness or itching.  If 
the hair under the patches needs to be shaved, irritation from shaving also could occur. 
 
Reproductive Risks  
Women 
Women in this study will not be of childbearing potential. 
 
Privacy Risks 
If your data are shared with unauthorized users, you may be at risk of loss of the privacy of 
your health data.  This risk is minimized by protections described in the Confidentiality 
section below. 
 
Unknown Risks 
You might have side effects or discomforts that are not listed in this form.  Some side effects 
may not be known yet.  New ones could happen to you.  Tell the study doctor or study staff 
right away if you have any problems. 
 
POSSIBLE BENEFITS OF THE STUDY 
This study is short-term, and as such, is not intended to provide medical benefit. However, if 
the drug appears to benefit subjects, and dependent on further data collected by the sponsor, 
you may be eligible for a longer study where everyone will be given PTI-125 active drug. 


 
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The results of this research study will help guide the development of the study drug and may 
help others.   
 
ALTERNATIVES TO PARTICIPATING IN THE STUDY   
Since this study is for research only, the only other choice would be not to be in the study.   
 
CONFIDENTIALITY  
Your records of being in this study will be kept private except when ordered by law. The 
following people will have access to your study records: 
• The investigator 
• Sponsor company or research institution [including monitor(s) and auditor(s)] 
• The United States Food and Drug Administration (FDA) 
• Other state or federal regulatory agencies 
• Advarra IRB 
 
The Advarra Institutional Review Board (IRB) and accrediting agencies may inspect and 
copy your records, which may have your name on them. Therefore, total confidentiality 
cannot be guaranteed. If the study results are presented at meetings or printed in publications, 
your name will not be used.  
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law.  This Web site will not include information that can identify you.  At 
most, the Web site will include a summary of the results.  You can search this Web site at 
any time. 
 
Certificate of Confidentiality  
This research is covered by a Certificate of Confidentiality from the National Institutes of 
Health. The researchers with this Certificate may not disclose or use information, documents, 
or biospecimens that may identify you in any federal, state, or local civil, criminal, 
administrative, legislative, or other action, suit, or proceeding, or be used as evidence, for 
example, if there is a court subpoena, unless you have consented for this use. Information, 
documents, or biospecimens protected by this Certificate cannot be disclosed to anyone else 
who is not connected with the research except, if there is a federal, state, or local law that 
requires disclosure (see below); if you have consented to the disclosure, including for your 
medical treatment; or if it is used for other scientific research, as allowed by federal 
regulations protecting research subjects. 
 
The Certificate cannot be used to refuse a request for information from personnel of the 
United States federal or state government agency sponsoring the project that is needed for 
auditing or program evaluation by the agency which is funding this project or for information 
that must be disclosed in order to meet the requirements of the federal Food and Drug 
Administration (FDA). You should understand that a Certificate of Confidentiality does not 
prevent you from voluntarily releasing information about yourself or your involvement in 
this research. If you want your research information released to an insurer, medical care 
provider, or any other person not connected with the research, you must provide consent to 
allow the researchers to release it. 


 
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The Certificate of Confidentiality will not be used to prevent disclosure as required by 
federal, state, or local law of, for instance, child abuse or neglect, harm to self or others, and 
communicable diseases.  
 
The Certificate of Confidentiality will not be used to prevent disclosure for any purpose you 
have consented to in this informed consent document. 
 
IN CASE OF STUDY RELATED INJURY 
If you become ill or are injured while you are in the study, get the medical care that you need 
right away. You should inform the healthcare professional treating you that you are 
participating in this study. If you tell the study staff that you think you have been injured then 
they will help you get the care you need.  
 
If you are injured while in this study, you should contact the study doctor as soon as possible 
in person or at the telephone number listed on page one of this consent form. Medical care 
may be obtained in the same way you would ordinarily obtain other medical treatment. If you 
suffer a study-related injury, the reasonable costs of necessary medical treatment of the injury 
will be reimbursed by the study sponsor to the extent these costs are not covered by your 
insurance or other third-party coverage.  No other form of compensation is offered.  A 
study-related injury is a physical injury that is directly caused by the study drug given as 
described in the study protocol or by required study procedures that are not standard of care. 
 
To pay medical expenses, the sponsor will need to know some information about you like 
your name, date of birth, and Medicare Beneficiary Identifier (MBI). This is because the 
sponsor has to check to see if you receive Medicare and if you do, report the payment it 
makes to Medicare.  
 
Please be aware that some insurance plans may not pay for research-related injuries.  You 
should contact your insurance company for more information. 
 
LEGAL RIGHTS 
You will not lose any of your legal rights by signing this consent form, nor will you release 
the sponsor, study doctor, study staff, or study site from liability. 
 
WHOM TO CONTACT ABOUT THIS STUDY 
During the study, if you experience any medical problems, suffer a research-related injury, or 
have questions, concerns or complaints about the study, please contact the study doctor at the 
telephone number listed on the first page of this consent document.  If you seek emergency 
care, or hospitalization is required, alert the treating physician that you are participating in 
this research study.   
 
An institutional review board (IRB) is an independent committee established to help protect 
the rights of research subjects.  If you have any questions about your rights as a research 
subject, and/or concerns or complaints regarding this research study, contact: 


 
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• By mail: 
Study Subject Adviser 
Advarra IRB 
6940 Columbia Gateway Drive, Suite 110 
Columbia, MD 21046 
• or call toll free:        877-992-4724 
• or by email:              adviser@advarra.com 
 
Please reference the following number when contacting the Study Subject Adviser: 
Pro00037146. 
 
PAYMENT FOR BEING IN THE STUDY 
You may receive up to $XXXX.00 for being in this study.  This money covers the costs for 
time spent at the clinic and is to help cover travel expenses to and from the clinic.  If you 
choose to leave or are withdrawn by the study staff before finishing all study procedures, you 
will be paid a lesser amount that is based on the completed visits made to the clinic. If you 
take study drug, you will be paid as listed below, for each completed visit: 
• $XXX.00 for each clinic visit (4 total) 
 
If you successfully complete the entire study, you will receive up to an additional $XXX.00: 
• $XXX.00 for completion of entire study (all visits) 
 
You will not be paid for the first screening visit.   
 
No other payment will be offered to you.  You will receive your payment within two weeks 
of your final study visit. 
 
You may be required to report the payment received for this study to the Internal Revenue 
Service as taxable income. 
 
VOLUNTEERING TO BE IN THE STUDY 
It is your choice if you want to be in the study.  No one can force you to be in the study. You 
may not want to be in this study or you may leave the study at any time without penalty or 
loss of benefits to which you are otherwise entitled. If you break the study rules you may be 
discontinued from this study.  
 
The study doctor, the sponsor company, Advarra, or the FDA may take you out of the study 
without your permission, at any time, for the following reasons: 
• If you do not follow the study doctor’s instructions  
• If we find out you should not be in the study 
• If the study is stopped 
• If it becomes harmful to your health 
 
If you leave the study or if you are taken out of the study, you may be asked to return for a 
final visit to have some end of study evaluations or tests. If information generated from this 


 
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study is published or presented, your identity will not be revealed. If you leave the study, no 
more information about you will be collected for this study. However, all of the information 
you gave us before you left the study will still be used.  
 
ADDITIONAL COSTS 
There is no cost to you during the study for any of the following: 
• Any study test or study procedure, including physical exam and blood tests 
• Study drug 
 
NEW FINDINGS 
If there is new information or any significant new findings that could relate to your 
willingness to continue participation, we will tell you. You can then decide if you still want 
to be in the study.   
 
AGREEMENT TO BE IN THE STUDY 
This consent form contains important information to help you decide if you want to be in the 
study.  If you have any questions that are not answered in this consent form, ask one of the 
study staff.  
 
Please answer YES or NO to the following questions: 
A. 
Is this document in a language you understand? 
 
 
 
 
 
 
B. 
Do you understand the information in this consent form? 
 
 
 
 
 
C. 
Have you been given enough time to ask questions and talk  
about the study? 
 
 
 
 
 
 
 
 
 
 
D. 
Have all your questions been answered to your satisfaction? 
 
 
 
 
E. 
Do you think you received enough information about the study? 
 
 
 
 
F. 
Do you volunteer to be in this study of your own free will and without  
being pressured by the investigator or study staff?  
 
 
 
 
 
G. 
Do you know that you can leave the study at any time without giving 
a reason and without affecting your health care? 
 
 
 
 
 
 
H. 
Do you know that your health records from this study may be reviewed 
by the sponsor company and by government authorities? 
 
 
 
 
 
I. 
Do you know that you cannot be in another study while you are in  
this study? 
 
 
 
 
 
 
 
 
 
 
 
IF YOU ANSWERED “NO” TO ANY OF THE ABOVE QUESTIONS, OR YOU ARE 
UNABLE TO ANSWER ANY OF THE ABOVE QUESTIONS, YOU SHOULD NOT 
SIGN THIS CONSENT FORM. 


 
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You will be given a signed and dated copy of this consent form to keep. 
 
 
 
 
 
 
Printed Name of Adult Study Subject 
 
 
 
Signature of Adult Study Subject 
Date 
Time (24-hour clock) 
 
 
____________________________________ 
 
 
 
Printed Name of Legally Authorized Representative (if applicable) 
 
 
 
 
Signature of Legally Authorized Representative 
Date 
Time (24-hour clock) 
(if applicable) 
 
 
___________________________________________________________ 
Authority of Legally Authorized Representative to act on behalf of Subject (if applicable) 
 
 
 
 
Printed Name of Person Explaining Consent Form 
 
 
 
 
Signature of Person Explaining Consent Form 
Date  Time (24-hour clock) 
 
 


 
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CAREGIVER ADDENDUM 
 
CAREGIVER PARTICIPATION 
As required by the study, every subject must have a caregiver/study partner to participate 
with them in the study.  A caregiver/study partner is a person who spends sufficient time with 
the study subject so that you can provide certain information.  The caregiver/study partner 
must have the ability to: 
• Observe the subject for any changes in health/possible side effects or cognitive 
function throughout the study. 
• Report and assist with the subject’s compliance with study procedures and 
medications. 
• Accompany the subject to all study visits and procedures (lumbar puncture). 
• Reliably answer interview questions regarding the subject’s medical condition, 
medication use, daily functioning, behaviors, and how he or she feels. 
 
The caregiver/study partner may be compensated for time and travel.  As a caregiver/study 
partner, you will not receive any direct benefit by taking part in this study.  Information from 
this study may also help researchers come up with new tests or medicines in the future to 
help people with Alzheimer’s disease.  
 
Entering a research study is completely voluntary.  Although a caregiver/study partner is 
required for participation, a caregiver/study partner can decide to stop at any time and a 
replacement will need to be identified.  If the caregiver/study partner withdraws from the 
study, you will only be paid for the study visits completed. 
 
If you have any questions about being a caregiver/study partner in this study, you should ask 
the study doctor or study staff. 
 
 
 


 
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AUTHORIZATION TO USE AND DISCLOSE 
PROTECTED HEALTH INFORMATION 
 
If you decide to be in this study, the study doctor and research team will use and 
share health data about you to conduct the study. Health data may include: 
• Your name. 
• Address. 
• Phone number. 
• Date of birth. 
• Medical history. 
• Information from your study visits, including all test results.  
 
Health data may come from your study records or from existing records kept by 
your doctor or other health care workers.  
 
For this study, the research team may share health data about you with 
authorized users. Authorized users may include: 
• Representatives of Cassava Sciences, Inc. 
• Representatives of Advarra IRB (an Institutional Review Board that 
reviews this study). 
• The Food and Drug Administration (FDA) and other US federal and state 
agencies. 
• Government agencies to whom certain diseases (like HIV, hepatitis, and 
STDs) must be reported. 
• Governmental agencies of other countries. 
• Outside individuals and companies, such as laboratories and data storage 
companies, that work with the researchers and sponsor and need to access 
your information to conduct this study. 
• Other research doctors and medical centers participating in this research, 
if applicable.  
• A data safety monitoring board which oversees this research, if 
applicable. 
 
Your health data will be used to conduct and oversee the research, including for 
instance: 
• To see if the study drug works and is safe. 
• To compare the study drug to other drugs. 


 
Cassava Sciences, Inc.  / Protocol Number PTI-125-02 
Page 15 of 16   
 
 
«PiFullName» 
Advarra IRB Approved Version 10 Jul 2019 
Revised «PIApprovalDate» 
 
• For other research activities related to the study drug. 
 
Once your health data has been shared with authorized users, it may no longer 
be protected by federal privacy law and could possibly be used or disclosed in 
ways other than those listed here.  
 
Your permission to use and share health data about you will end in 50 years 
unless you revoke it (take it back) sooner.  
 
You may revoke (take back) your permission to use and share health data about 
you at any time by writing to the study doctor at the address listed on the first 
page of this form. If you do this, you will not be able to stay in this study. No 
new health data that identifies you will be gathered after your written request is 
received. However, health data about you that has already been gathered may 
still be used and given to others as described in this form.  
 
Your right to access your health data in the study records will be suspended 
during the study to keep from changing the study results. When the study is 
over, you can access your study health data. 
 
If you decide not to sign this form, you will not be able to take part in the study. 
 
STATEMENT OF AUTHORIZATION 
I have read this form and its contents were explained. My questions have been 
answered. I voluntarily agree to allow study staff to collect, use and share my 
health data as specified in this form. I will receive a signed and dated copy of 
this form for my records. I am not giving up any of my legal rights by signing 
this form.  
 
__________________________________ 
Printed Name of Adult Subject 
 
 
__________________________________ ___________________________ 
Signature of Adult Subject 
 
 
Date  
Time (24-hour clock) 
 
 
__________________________________  
 
Printed Name of Legally Authorized Representative  
 
 


 
Cassava Sciences, Inc.  / Protocol Number PTI-125-02 
Page 16 of 16   
 
 
«PiFullName» 
Advarra IRB Approved Version 10 Jul 2019 
Revised «PIApprovalDate» 
 
 
__________________________________ ___________________________ 
Signature of Legally Authorized  
Date  
Time (24-hour clock) 
Representative 
 
____________________________________________________________ 
Authority of Legally Authorized Representative to act on behalf of Subject 
 
 
__________________________________ 
Printed Name of the Person Obtaining the  
Authorization 
 
 
__________________________________ ____________________________ 
Signature of the Person Obtaining the  
Date  
Time (24-hour clock) 
Authorization 
 

SAP_003.pdf: 
Study Title: 
A Phase 2b, Randomized, Double-blind, Placebo-controlled, Multiple Dose, Biomarker and 
Safety Study of PTl-125 in Mild-to-moderate Alzheimer’s Disease Patients
(NCT04079803)




















Type text he



























Prot_000.pdf: 
 
Cassava Sciences, Inc. 
Clinical Protocol PTI-125-02 
PTI-125, a small molecule to treat AD 
June 28, 2019 
 
Page 1 of 33 
 
 
 
 
CONFIDENTIAL 
 
 
 
CLINICAL RESEARCH PROTOCOL 
PROTOCOL PTl-125-02 
 
A Phase 2b, Randomized, Double-blind, Placebo-controlled,  
Multiple Dose, Biomarker and Safety Study  
of PTl-125 in Mild-to-moderate Alzheimer’s Disease Patients 
 
 
Sponsor:  
 
 
 
Cassava Sciences, Inc. 
7801 N. Capital of Texas Hwy, Ste. 260 
Austin, TX 78731 
Phone: 
512-501-1900 
 
Study Monitor: 
Nadav Friedmann, PhD, MD 
Chief Operating & Medical Officer  
Phone: 925-788-4585 
Email: nfriedmann@cassavasciences.com 
 
Project Manager 
Michael Marsman, PharmD 
 
Regulatory Affairs and QA 
 
Phone:    512-562-2173 
 
Email:     mmarsman@cassavasciences.com 
 
Protocol Date: 
June 28, 2019 
 
This clinical trial is funded by NIH grant AG060878. 
 
Confidentiality 
The information contained in this document and all information provided to you related 
to PTl-125 ("Drug") are the confidential and proprietary information of Cassava 
Sciences, Inc. (CSI) 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 CSI. 
The Principal Investigator may, however, disclose such information to supervised 
individuals working on the Drug, provided such individuals agree to be bound to 
maintain the confidentiality of such Drug information. 




 
Cassava Sciences, Inc. 
Clinical Protocol PTI-125-02 
PTI-125, a novel small molecule for AD 
June 28, 2019 
 
Page 3 of 33 
 
 
 
 
CONFIDENTIAL 
 
 
Cassava Sciences, Inc. 
CLINICAL RESEARCH PROTOCOL 
 
 
 
 
A Phase 2b, Randomized, Double-blind, Placebo-controlled,  
Multiple Dose, Biomarker and Safety Study  
of PTl-125 in Mild-to-moderate AD patients 
 
 
 
 
 
Signature of Agreement for Protocol PTI-125-02 
 
 
 
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. 
 
 
 
 
 
 
 
 
Principal Investigator Signature 
Date 
 
 
 
 
 
 
Print Principal Investigator Name and Title 


 
Cassava Sciences, Inc. 
Clinical Protocol PTI-125-02 
PTI-125, a novel small molecule for AD 
June 28, 2019 
Page 4 of 33 
 
 
 
 
CONFIDENTIAL 
 
Table of Contents 
1. 
List of abbreviations ................................................................................................. 6 
2. 
INTRODUCTION .................................................................................................... 8 
3. 
STUDY OBJECTIVES ............................................................................................. 12 
4. 
SUMMARY OF STUDY DESIGN .......................................................................... 12 
5. 
SUBJECT SELECTION ........................................................................................... 13 
5.1. Study Population ........................................................................................................... 13 
5.2. Inclusion Criteria ........................................................................................................... 13 
5.3. Exclusion Criteria .......................................................................................................... 14 
6. 
STUDY DRUG ...................................................................................................... 17 
6.1. PTI-125 Physical Description and Preparation.................................................................. 17 
6.1.1. Storage ............................................................................................................... 17 
6.1.2. Drug Accountability ............................................................................................ 17 
6.2. Administration and Dosing Regimen .............................................................................. 17 
6.3. Concomitant Medications ................................................................................................. 17 
7. 
STUDY PROCEDURES .......................................................................................... 17 
7.1. Liver chemistry stopping criteria ..................................................................................... 18 
7.2. Evaluations by Visit ....................................................................................................... 18 
7.2.1. Screening Visit 1 (No longer than 30 days prior to Day 1) ................................. 18 
7.2.2. Screening Visit 2 (If all Screening Visit 1 criteria are met) .................................. 19 
7.2.3. Study Day 1 (Dosing Initiation) .......................................................................... 19 
7.2.4. Day 7 Follow-up Visit ......................................................................................... 20 
7.2.5. Day 14 Follow-up Visit ....................................................................................... 20 
7.2.6. Day 28 Follow-up Visit ....................................................................................... 20 
7.2.7. End-of-study Follow-up ...................................................................................... 21 
7.2.8. Unscheduled Visits and Discontinuation due to AEs ......................................... 21 
7.3. Laboratory Assessments ................................................................................................. 21 
7.3.1. Clinical Laboratory Tests .................................................................................... 21 
7.3.2. Preparation of Whole Blood Samples for biomarkers and APOE genotyping ..... 22 
7.3.3. Preparation of Plasma Samples for Pharmacokinetic Determination .................. 22 
7.3.4. CSF assays ........................................................................................................ 22 
8. 
EARLY DISCONTINUATION ................................................................................. 23 
9. 
ADVERSE EVENTS/SERIOUS ADVERSE EVENTS ................................................. 24 
9.1. Adverse Events - Definition ............................................................................................. 24 
9.2. Adverse Events - Severity Rating .................................................................................... 25 


 
Cassava Sciences, Inc. 
Clinical Protocol PTI-125-02 
PTI-125, a novel small molecule for AD 
June 28, 2019 
Page 5 of 33 
 
 
 
 
CONFIDENTIAL 
 
9.3. Adverse  Events  -  Relationship to  Study Drug .................................................................. 25 
9.4. Serious Adverse Events and Unexpected Adverse Events - Definitions ............................... 25 
9.5. Serious Adverse Events Reporting ................................................................................... 26 
10. 
STATISTICAL CONSIDERATIONS ......................................................................... 27 
10.1. Randomization .............................................................................................................. 27 
10.2. Analysis Populations ...................................................................................................... 27 
10.3. Pharmacokinetic Parameters ........................................................................................... 27 
10.4. Statistical Analysis ......................................................................................................... 28 
10.5. Safety Analysis .............................................................................................................. 28 
10.6. Sample Size .................................................................................................................. 28 
11. 
STUDY TERMINATION ......................................................................................... 28 
12. 
DATA COLLECTION, RETENTION AND MONITORING ........................................ 28 
12.1. Case Report Forms ......................................................................................................... 28 
12.2. Availability and Retention of Investigational Records ....................................................... 29 
12.3. Subject Confidentiality ................................................................................................... 29 
12.4. Liability ........................................................................................................................ 29 
12.5. Ethical and Legal Issues ................................................................................................. 30 
12.5.1. Institutional Review Board .................................................................................. 30 
12.6. Informed Consent Form .................................................................................................. 30 
13. 
INVESTIGATOR RESPONSIBILITIES ................................................................... 31 
14. 
REFERENCES ...................................................................................................... 32 
15. 
Appendix A – Schedule of Activities ........................................................................ 33 
 
 
 
 
 
 


Cassava Sciences, Inc. 
Clinical Protocol PTI-125-02 
PTI-125, a small molecule to treat AD 
June 28, 2019 
Page 6 of 33 
 
 
 
 
CONFIDENTIAL 
1. LIST OF ABBREVIATIONS 
7nAChR  
 
 
7 nicotinic acetylcholine receptor 
A42 
 
 
 
amyloid beta1-42 
AChEI  
 
 
acetylcholinesterase inhibitor 
AD 
 
 
 
Alzheimer’s disease 
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 
BUN  
 
 
blood urea nitrogen 
CFR 
 
 
 
Code of Federal Regulations 
Cmax  
 
 
maximum plasma concentration 
CRO  
 
 
contract research organization 
CSF 
 
 
 
cerebrospinal fluid 
CSI 
 
 
 
Cassava Sciences, Inc. 
C-SSRS 
 
 
Columbia-Suicide Severity Rating Scale 
CT 
 
 
 
computed tomography 
DSMB/DMC  
 
Data Safety Monitoring Board/Data Monitoring Committee 
ECG  
 
 
electrocardiogram 
eCRF  
 
 
electronic case report form 
EDTA  
 
 
ethylenediaminetetraacetic acid 
FDA  
 
 
Federal Drug Association 
FIH 
 
 
 
first in human 
FLNA  
 
 
filamin A 
GCP  
 
 
good clinical practice 
GGT   
 
 
gamma glutamyl transpeptidase 
GLP 
 
 
 
good laboratory practice 
HBsAg  
 
 
hepatitis B surface antigen 
HCV  
 
 
hepatitis C virus 
HIV 
 
 
 
human immunodeficiency virus 
hERG  
 
 
human ether-a-go-go-related gene 
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 


Cassava Sciences, Inc. 
Clinical Protocol PTI-125-02 
PTI-125, a small molecule to treat AD 
June 28, 2019 
Page 7 of 33 
 
 
 
 
CONFIDENTIAL 
LOQ  
 
 
limit of quantitation 
MMSE 
 
 
Mini-Mental State Examination 
MRI 
 
 
 
magnetic resonance imaging 
mTOR  
 
 
mammalian target of rapamycin 
NMDAR 
 
 
N-methyl D-aspartate receptor 
NOAEL 
 
 
no observable adverse effect level 
NOEL  
 
 
no observable effect level 
PK 
 
 
 
pharmacokinetics 
PTI-125 
 
 
small molecule drug candidate to treat AD 
PTI-125Dx 
 
 
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  
 
 


Cassava Sciences, Inc. 
Clinical Protocol PTI-125-02 
PTI-125, a small molecule to treat AD 
June 28, 2019 
Page 8 of 33 
 
 
 
 
CONFIDENTIAL 
 
2. INTRODUCTION 
Cassava Sciences Inc. (CSI) is developing PTI-125, a novel drug candidate designed to 
treat and slow the progression of Alzheimer’s disease (AD). PTI-125 binds with 
femtomolar affinity to an altered conformation of filamin A (FLNA) that is induced by 
beta amyloid1-42 (A42), present in AD brain and critical to the toxicity of A42.1-3 PTI-
125 binding reverses the altered FLNA conformation and restores FLNA’s native shape, 
preventing two toxic signaling cascades of A42. A42, in monomer or small oligomer 
form, hijacks the 7-nicotinic acetylcholine receptor (7nAChR) and signals via this 
receptor to hyperphosphorylate tau, and this signaling requires the recruitment of altered 
FLNA to this receptor. Second, altered FLNA associates with toll-like receptor 4 (TLR4) 
to allow A42 to persistently activate this receptor. Normal FLNA does not associate with 
either 7nAChR or TLR4. In addition to disrupting the normal functions of 7nAChR 
and tau protein, A42’s toxic signaling to hyperphosphorylate tau leads to the signature 
tangles and plaques found in brains of AD patients. In two AD mouse models and in 
postmortem human AD brain tissue, PTI-125 restored function of three receptors that are 
impaired in AD: the 7nAChR, the N-methyl-D-aspartate receptor (NMDAR), and the 
insulin receptor (IR).2,3 PTI-125 also reduced tau hyperphosphorylation, amyloid 
deposits, neurofibrillary tangles and inflammatory cytokine release.2,3 We therefore 
expect PTI-125 to improve memory and to slow or halt AD progression. Both mouse 
models used a dose of 20 mg/kg/day (equivalent to 60 mg/m2/day).  
A robust nonclinical ADME, safety pharmacology, and general and genetic toxicology 
program has been carried out with PTI-125. In vitro metabolic profiling showed minimal 
metabolism across several species including humans. PTI-125 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. 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 were all negative. An in vitro specificity screen showed no 
significant activation or inhibition of a panel of 68 receptors, channels and transporters.  
PTI-125 was tested in single dose and repeat dose oral toxicity studies in rats and dogs. In 
a 28-day repeat dose oral toxicity study followed by a 28-day drug-free recovery period in 
rats (PTI-125-NC-040) with PTI-125 dose levels up to and including 1000 mg/kg/day 
(equivalent to 6,000 mg/m2), toxicity was mainly characterized at 1000 mg/kg/day by a 
decrease in mean body weight, which continued during the recovery period. A diffuse 
cellular hypertrophy of the liver was seen at 1000 mg/kg/day in males and females and 
was interpreted as an adaptive response to the test article. A no-observed-effect-level 


Cassava Sciences, Inc. 
Clinical Protocol PTI-125-02 
PTI-125, a small molecule to treat AD 
June 28, 2019 
Page 9 of 33 
 
 
 
 
CONFIDENTIAL 
(NOEL) could not be determined and the no-observed-adverse-effect-level (NOAEL) was 
determined to be 500 mg/kg/day (equivalent to 3,000 mg/m2). Safety margins based on 
this study are shown in Table 1. 
Table 1.  Safety Margin for a 100 mg b.i.d. Human Dose Based on the 4-week Rat Tox  
a Mean exposure for male and female rats combined on last day of study 
b Mean exposure for patients after 100 mg b.i.d. dose of PTI-125 on Day 28 (CSR PTI-125-03) 
A 28-day repeat dose oral toxicity study in dogs that included a 28-day drug-free recovery 
period used PTI-125 dose levels up to and including 200 mg/kg/day (equivalent to 4,000 
mg/m2). Findings included slight muscle fasciculations in some animals at the high dose 
only, an increase in blood pressure in high dose females, and sporadic alterations in 
clinical chemistry profiles at the high dose. All observations resolved during the recovery 
period. A NOEL could not be determined, and the NOAEL was determined to be 100 
mg/kg/day (equivalent to 2,000 mg/m2). Safety margins based on this study are shown in 
Table 2. 
Table 2.  Safety Margin for a 100 mg b.i.d. Human Dose Based on the 4-week Dog Tox  
a Mean exposure for male and female dogs combined on last day of study 
b Mean exposure for patients after 100 mg b.i.d. dose of PTI-125 on Day 28 (CSR PTI-125-03) 
A subsequent 13-week repeat dose oral toxicity study with a 28-day recovery in dogs used 
doses of 25, 75 and 150 mg/kg/day. The toxicological response was characterized 
primarily by increased incidence of emesis and salivation (sometimes extreme), and 
decreased food consumption in 150 mg/kg animals (reversible). There were occasional 
incidences of muscle fasciculations, and a few isolated incidences of tremors, lying down, 
reluctance to stand, and hypoactivity (generally slight). Based the severity and time 
course of these observations, the NOAEL was established at 150 mg/kg/day. The Day 90 
Cmax at this dose was 70.3 and 71.8 µg/mL in males and females, respectively, and the 
Day 90 AUClast was 456 and 439 h•µg/mL in males and females, respectively. Safety 
NOAEL 
(mg/kg) 
Cmax (ng/mL) 
AUClast (hr*ng/mL) 
Rat-to-Human Ratio  
(Safety Margin) 
Rata 
Humanb 
Rata 
Humanb 
Cmax 
AUC0-24 
500 
44,900 
1,104 
249,000 
8,483 
40.7 
29.4 
NOAEL 
(mg/kg) 
Cmax (ng/mL) 
AUClast (hr*ng/mL) 
Dog-to-Human Ratio  
(Safety Margin) 
Doga 
Humanb 
Doga 
Humanb 
Cmax 
AUC0-24 
100 
49,000 
1,104 
214,000 
8,483 
44.4 
25.2 


Cassava Sciences, Inc. 
Clinical Protocol PTI-125-02 
PTI-125, a small molecule to treat AD 
June 28, 2019 
Page 10 of 33 
 
 
 
 
CONFIDENTIAL 
margins based on this study are shown in Table 3. 
Table 3.  Safety Margin for a 100 mg b.i.d. Human Dose Based on the 13-week Dog Tox  
a Mean exposure for male and female dogs combined on last day of study 
b Mean exposure for patients after 100 mg b.i.d. dose of PTI-125 on Day 28 (CSR PTI-125-03) 
It should be noted that in a 7-day non-GLP dose-range finding study in dogs, convulsions 
(rated “slight”) were observed in one of six animals administered 300 mg/kg/day on Days 
2 and 3. None of the six 1000 mg/kg animals exhibited convulsions. On Day 4, the mid 
(300 mg/kg) and high (1000 mg/kg) doses were reduced to 150 and 200 mg/kg/day, 
respectively.  
A subsequent 6-month repeat dose oral toxicity study in rat (PTI-125-NC-049) used the 
same doses as the 28-day study (50, 500 and 1000 mg/kg/day). The toxicological 
response was characterized by decreased body weights and adverse structural and 
functional alterations in the liver of 500 and 1000 mg/kg animals, including increased 
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. The 
NOAEL from this 6-month study was 50 mg/kg/day (equivalent to 300 mg/m2). Safety 
margins based on this study are shown in Table 4. 
Table 4.  Safety Margin for a 100 mg b.i.d. Human Dose Based on the 6-month Rat Tox  
a Mean exposure for male and female rats combined on last day of study 
b Mean exposure for patients after 100 mg b.i.d. dose of PTI-125 on Day 28 (CSR PTI-125-03) 
A second 6-month repeat dose oral toxicity study in rat has been initiated with the goal of 
determining a more accurate NOAEL. Doses are vehicle and 125 and 250 mg/kg/day.  
NOAEL 
(mg/kg) 
Cmax (ng/mL) 
AUClast (hr*ng/mL) 
Dog-to-Human Ratio  
(Safety Margin) 
Doga 
Humanb 
Doga 
Humanb 
Cmax 
AUC0-24 
150 
71,100 
1,104 
447,000 
8,483 
64.3 
52.7 
NOAEL 
(mg/kg) 
Cmax (ng/mL) 
AUClast (hr*ng/mL) 
Rat-to-Human Ratio  
(Safety Margin) 
Rata 
Humanb 
Rata 
Humanb 
Cmax 
AUC0-24 
50 
6,240 
1,104 
21,200 
8,483 
5.7 
2.5 


Cassava Sciences, Inc. 
Clinical Protocol PTI-125-02 
PTI-125, a small molecule to treat AD 
June 28, 2019 
Page 11 of 33 
 
 
 
 
CONFIDENTIAL 
A 9-month toxicity study in dog has been completed and is awaiting pathology. This 
study started with 200 mg/kg/day as the high dose, which was reduced after 1 month to 
150 mg/kg/day due to a decrease in body weight that was considered unsustainable for 9 
months. Based on clinical signs, clinical chemistry, body weights and food consumption, 
the 150 mg/kg/day dose is estimated to be the NOAEL for this study until pathology is 
complete. 
A first-in-human (FIH) double-blind, Single Ascending Dose clinical trial 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, and there 
were no drug-related adverse events (AEs). 
A 28-day study was conducted with mild-to-moderate AD patients, receiving PTI-125 
100 mg b.i.d. as oral tablets. Key inclusion criteria were MMSE ≥ 16 and ≤ 24, age 50-
85, and a CSF total tau/Aβ42 ratio ≥ 0.30. CSF samples were collected at screening and 
Day 28. Nine CSF biomarkers were analyzed using commercially available ELISA kits. 
PTI-125 was safe and well tolerated in all patients. All 8 biomarkers that are elevated in 
AD were significantly reduced (Table 5 and Figure 1). Aβ42, which is low in AD, was 
increased slightly but non-significantly. Reduced neuroinflammation was indicated by 
reductions in inflammatory cytokines and YKL-40. A reduced neurodegenerative drive 
was suggested by reductions in neurogranin, neurofilament light chain, and total tau. 
Finally, the robust reduction in phospho-tau (pT181) confirms the mechanism of action of 
PTI-125. 
Table 5   Reductions in CSF biomarkers after 28 days PTI-125 (100 mg, b.i.d.) 
 
Neurogranin 
Neurofilament 
Light Chain 
Total 
Tau 
P-Tau 
(T181) 
Aβ42 
YKL40 
IL-6 
IL-1β 
TNF-α 
Percent
Change 
-32.1% 
-21.5% 
-19.8% 
-34.4% 
4.3% 
-9.4% 
-14.3% 
-11.1% 
-5.1% 
P 
value* 
p < 0.00001 
p < 0.00001 
p < 
0.00001 
p < 
0.00001 
N.S. 
p = 0.043 
p < 
0.00001 
p < 
0.00001 
p < 0.001 
*Screening vs. Day 28, paired t test 
 
 
 
 
 


Cassava Sciences, Inc. 
Clinical Protocol PTI-125-02 
PTI-125, a small molecule to treat AD 
June 28, 2019 
Page 12 of 33 
 
 
 
 
CONFIDENTIAL 
Fig. 1   Mean Change from Baseline to Day 28 in CSF biomarkers (±SEM) 
 
3. STUDY OBJECTIVES 
The objectives of this study are to investigate the safety and effect on biomarkers and 
cognition of PTI-125 following 1-month, repeat-dose oral administration in mild-to-
moderate AD patients, 50-85 years of age, with MMSE  ≥ 16 and ≤ 26. A second 
objective is to replicate the effects on biomarkers shown in the previous open-label 1-
month study (PTI-125-03). A third objective is to investigate a dose-response of PTI-125. 
4. SUMMARY OF STUDY DESIGN 
This is a Phase 2b, multi-center, randomized, double-blind, placebo-controlled, study 
of PTI-125 in mild-to-moderate AD patients, 50-85 years of age. Approximately sixty 
(60) patients will be enrolled into the study and randomized to one of three cohorts. 
Cohorts will receive placebo or PTI-125 at 50 or 100 mg b.i.d. (n=20 per group). 
Placebo or PTI-125 will be administered as coated tablets. 
There will be two screening visits within 30 days of start of the study. Patients meeting 
initial screening criteria, including a Mini-Mental State Examination (MMSE) score ≥ 16 
and ≤ 26 will return for a CSF draw at a second screening visit to confirm that the Aβ/tau 
Index is indicative of AD (final inclusion criterion). This CSF sample will also serve as 
baseline measurement for the YKL40 neuroinflammation and other potential CSF 
biomarker assays. Cambridge Cognition testing will be conducted at the second screening 
visit, Day 1, and at the end of the study. Patients will be assessed for suicidality via the 
Columbia Suicide Severity Scale (C-SSRS) during the first and last visits. 


Cassava Sciences, Inc. 
Clinical Protocol PTI-125-02 
PTI-125, a small molecule to treat AD 
June 28, 2019 
Page 13 of 33 
 
 
 
 
CONFIDENTIAL 
Patients will report to clinic the morning of Day 1. The following will be conducted 
prior to dosing: Cambridge Cognition testing, a full physical exam, an ECG and a blood 
draw for clinical labs and biomarkers (PTI-125Dx and mTOR). After dosing, patients 
will be monitored for adverse events and vital signs will be taken through 4 h. 
Patients will return to the clinic on Days 7, 14 and 28. 
PK blood samples will be obtained prior to the first dose on Day 14 for Cmin values. On 
Day 28, there will be a CSF draw after the last dose, and an additional PK blood sample 
will be obtained after this CSF draw for calculation of CSF/plasma ratio.  
Blood draws for clinical laboratory testing will be performed at screening and on Days 1, 
7, 14 and 28. Safety assessments of vital signs and listening to heart and lungs will be 
conducted at all visits. ECGs will be conducted on Days 7, 14 and 28.  
Blood samples for testing in PTI-125Dx, the companion diagnostic/biomarker, mTOR 
activation and other potential blood-based biomarkers will be drawn on Day 1 and Day 
28. The Day 28 blood sample will also be used for APOE genotyping. A CSF sample 
collection will be performed on Day 28 for neurogranin, neurofilament light chain, total 
tau, pTau (T181), Aβ42, Aβ40, YKL40, IL-6, IL-1β, TNFα and other potential CSF 
biomarker assays as well as bioanalysis of PTI-125. 
An 
independent 
Data 
Safety Monitoring Board/Data Monitoring Committee 
(DSMB/DMC) has been established and will meet periodically to review patient safety 
assessments and determine if dosing may continue. 
5. SUBJECT SELECTION 
5.1. STUDY POPULATION 
Approximately sixty (60) patients will be enrolled in the study (male and female). 
Dropouts may be replaced at the discretion of Sponsor. 
5.2. INCLUSION CRITERIA 
Each patient must comply with the following Inclusion Criteria:  
1. Ages ≥ 50 and ≤ 85 years 
2. Informed consent form (ICF) signed by the subject or legally acceptable 
representative. If a legally acceptable representative signs the ICF, a notation of 
capacity of the subject must be noted. 


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3. Clinical diagnosis of dementia due to possible or probable AD consistent with criteria 
established by a workgroup of the National Institute on Aging and the Alzheimer's 
Disease Association. 
4. MMSE score ≥ 16 and ≤ 26 at screening, OR if > 26, a prior CSF total tau/Aβ42 ratio 
≥ 0.28. (A new CSF draw would be required for analysis of pre-dose biomarkers.) 
5. If female, postmenopausal for at least 1 year 
6. Patient living at home, senior residential setting, or an institutional setting without the 
need for continuous (i.e. 24-h) nursing care 
7. General health status acceptable for participation in the study 
8. Fluency (oral and written) in English or Spanish 
9. If receiving memantine, rivastigmine, galantamine or an AChEI, receiving a stable 
dose for at least 3 months (90 days) before screening and with continuous dosing for 
at least 3 months. If receiving donepezil, receiving any dose lower than 23 mg once 
daily. Multiple medications are allowed. 
10. The patient is a non-smoker for at least 3 years.  
11. The patient or legal representative must agree to comply with the drawing of blood 
samples for the PK assessments, laboratory assessments and PTI-125Dx, and with a 
lumbar puncture and the drawing of CSF samples for biomarker assessments. 
12. The patient has a ratio of total tau/Aβ42 in CSF that indicates AD. This value (total 
tau/Aβ42) will be ≥ 0.28. 
13. Patient has a caregiver or legal representative responsible for administering the drug 
and recording the time. 
5.3. EXCLUSION CRITERIA 
Patients meeting any of the following criteria will be excluded from the study: 
1. Exposure to an experimental drug, experimental biologic or experimental medical 
device within the longer of 5 half-lives or 3 months before screening 
2. Enrollment in the previous PTI-125 trial 
3. A medical condition that would interfere with a lumbar puncture  
4. Residence in a skilled nursing facility and requiring 24 h care. 
5. Clinically significant laboratory test results 


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6. Clinically significant untreated hypothyroidism (if treated, thyroid-stimulating 
hormone level and thyroid supplementation dose must be stable for at least 6 months 
before screening) 
7. Insufficiently controlled diabetes mellitus 
8. Renal insufficiency (serum creatinine > ULN) 
9. Malignant tumor within 3 years before screening (except squamous and basal cell 
carcinoma or cervical carcinoma in situ or localized prostate cancer or localized stage 
1 bladder cancer) 
10. History of ischemic colitis or ischemic enterocolitis 
11. Unstable medical condition that is clinically significant in the judgment of the 
investigator 
12. Alanine transaminase (ALT) or aspartate transaminase (AST) > ULN or total bilirubin 
> ULN.  
13. History of myocardial infarction or unstable angina within 6 months before screening 
14. History of more than 1 myocardial infarction within 5 years before screening 
15. Clinically significant cardiac arrhythmia (including atrial fibrillation), 
cardiomyopathy, or cardiac conduction defect (patients with a pacemaker are 
acceptable) 
16. Symptomatic hypotension, or uncontrolled hypertension  
17. Clinically significant abnormality on screening electrocardiogram (ECG), including 
but not necessarily limited to a confirmed QTc value ≥ 450 msec for males or ≥ 470 
msec for females.  
18. Stroke within 18 months before screening, or history of a stroke concomitant with 
onset of dementia 
19. History of brain tumor or other clinically significant space-occupying lesion on CT or 
MRI 
20. Head trauma with clinically significant loss of consciousness within 12 months before 
screening or concurrent with the onset of dementia 
21. Onset of dementia secondary to cardiac arrest, surgery with general anesthesia, or 
resuscitation 
22. Specific degenerative CNS disease diagnosis other than AD (eg, Huntington's disease, 
Creutzfeld-Jacob disease, Down's syndrome, Frontotemporal Dementia, Parkinson's 
disease) 
23. Wernicke's encephalopathy 


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24. Active acute or chronic CNS infection 
25. Donepezil 23 mg or greater QD currently or within 3 months prior to randomization 
26. Discontinued AChEI < 30 days prior to randomization 
27. Antipsychotics; low doses are allowed only if given for sleep disturbances, agitation 
and/or aggression, and only if the subject has received a stable dose for at least 3 
months before randomization 
28. Tricyclic antidepressants and monoamine oxidase inhibitors; all other antidepressants 
are allowed only if the subject has received a stable dose for at least 3 months before 
randomization 
29. Anxiolytics or sedative-hypnotics, including barbiturates (unless given in low doses 
for benign tremor); low doses of benzodiazepines and zolpidem are allowed only if 
given for insomnia/sleep disturbance, and only if the subject has received a stable 
dose for at least 3 months before randomization 
30. Immunosuppressants, including systemic corticosteroids, if taken in clinically 
immunosuppressive doses (Steroid use for allergy or other inflammation is 
permitted.) 
31. Antiepileptic medications if taken for control of seizures 
32. Chronic intake of opioid-containing analgesics 
33. Sedating H1 antihistamines 
34. Nicotine therapy (all dosage forms including a patch), varenicline (Chantix), or 
similar therapeutic agent within 30 days before screening 
35. Clinically significant illness within 30 days of enrollment  
36. History of significant neurological, hepatic, renal, endocrine, cardiovascular, 
gastrointestinal, pulmonary, or metabolic disease  
37. Positive serum hepatitis B surface antigen (HBsAg) or positive hepatitis C virus HCV 
antibody test at screening  
38. Positive HIV test at screening  
39. Positive urine drug test at screening 
40. Loss of a significant volume of blood (> 450 mL) within 4 weeks prior to the study 
41. Suicidality on C-SSRS at screening 


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6. STUDY DRUG 
6.1. PTI-125 PHYSICAL DESCRIPTION AND PREPARATION 
Investigational PTI-125 and matching placebo will be supplied by CSI as coated tablets 
in 20-count bottles.  
All remaining PTI-125 study drug will be returned to the sponsor or designee. 
6.1.1. Storage 
Bottles of PTI-125 tablets should be stored at controlled room temperature, 20-25º 
C (68-77º F)  and protected from light and moisture. 
 
6.1.2. Drug Accountability 
The Investigator will be responsible for monitoring the receipt, storage, dispensing 
and accounting of all study medications according to site SOPs. All invoices of 
study medication shipments 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 
Patients will be randomized to receive placebo (20 patients) or 50 mg PTI-125 b.i.d. (20 
patients) or 100 mg PTI-125 b.i.d. (20 patients). Study drug should be taken 1-2 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 3 months. 
7. STUDY PROCEDURES 
Appendix A presents the Schedule of Activities. 
Prior to any study-related activities, the Informed Consent Form must be signed and 
dated by the patient or legal representative and the caregiver. The format and content of 
the Informed Consent Form must be agreed upon by the Principal Investigator(s), the 
appropriate IRB and the Sponsor (or designee). The signed and dated Informed 
Consent Form must be retained by the Investigator in the subject's file. 


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7.1. LIVER CHEMISTRY STOPPING CRITERIA 
Liver chemistry threshold stopping criteria have been designed to assure patient safety 
and to evaluate liver event etiology during administration of Study Drug. 
Administration of Study Drug will be discontinued if any of the following liver 
chemistry stopping criteria occurs: 
 
• ALT or AST ≥ 2.5 x ULN.  
• ALT or AST ≥ 2 x ULN and total bilirubin ≥ 2 x ULN. Note: Serum bilirubin 
fractionation should be performed if total bilirubin is ≥ 2 x ULN. 
• ALT or AST ≥ 2 x ULN if associated with appearance or worsening of a rash 
or hepatitis symptoms (fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash or eosinophilia).  
• ALP or GGT ≥ 2.5 x ULN. 
 
In the event of discontinuation due to liver abnormalities, the patient will be 
appropriately investigated to determine the potential cause. 
 
7.2. EVALUATIONS BY VISIT 
Follow-up visits can be scheduled +/- two (2) days from the actual Study Day number. Please 
notify Sponsor of changes so that the biomarker lab is aware of whole blood sample shipments. 
 
7.2.1. Screening Visit 1 (No longer than 30 days prior to Day 1) 
The following will be completed in the first screening visit: 
• Informed Consent.  
• Review of Inclusion and Exclusion Criteria 
• Medical history 
• Review of concomitant medications 
• MMSE evaluation 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
• Physical examination, including measurement of vital signs (blood pressure, 
temperature, pulse and respiratory rate), height, weight  
• A 12-lead ECG (5-min supine) 
• Laboratory assessments, including serum chemistry, hematology, 
urinalysis, and screens for HCV, HIV and HBsAg. 
• Urine drug screen. 


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7.2.2. Screening Visit 2 (If all Screening Visit 1 criteria are met) 
• Cambridge Cognition testing (conducted prior to CSF collection) 
• CSF sample collection (5 mL)  
CSF total tau/Aβ42 criterion  (~1-week turnaround) must be met prior to Day 1. 
7.2.3. Study Day 1 (Dosing Initiation) 
Patients will come to the clinic in the morning. Prior to dosing, the following 
assessments will be conducted: 
• 
Confirmation of inclusion/exclusion criteria 
• Review of concomitant medications 
• Vital signs (blood pressure, temperature, pulse and respiratory rate). 
• Listen to heart and lungs 
• Cambridge Cognition testing; the average of this result and that of the 
second screening visit will be taken as the baseline value. 
• 
Blood sample collection for clinical laboratory tests 
• Blood sample collection for PTI-125Dx and mTOR assessments (8 mL 
total) 
• 
ECG 
Patients will be administered Study Drug at least 1 h before or after a meal. The 
patient will be discharged 2 h later with their supply of Study Drug.   
After dose on Study Day 1, the following assessments will be conducted: 
• Vital signs (blood pressure, temperature, pulse and respiratory rate) at 
approximately 30 min, and 1 and 2 h post-dose.  
• Adverse event monitoring 
Clinic personnel will monitor the patients for the occurrence of any adverse events 
until patients are discharged from the clinic. Upon investigator judgment, patients 
will be discharged from the clinic with their supply of study drug until the next visit. 
The caregiver will be instructed to administer study drug twice daily at least 1 h 
before or after a meal. A dose can be up to 4 h late, but if a dose is missed, the next 
dose should NOT be doubled.  
For all follow-up visits, patients will come to the clinic in the morning and will be instructed 
not to take their morning dose prior to coming to the clinic.  


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7.2.4. Day 7 Follow-up Visit 
Patients will return to clinic on Study Day 7 before taking their morning dose. 
On the morning of Study Day 7, within 30 min prior to dosing, the following 
assessments will be conducted: 
• 
Blood sample collection for PK assessment (for Cmin) 
• Clinical laboratory tests (blood and urine) 
After dose, the following will be conducted: 
• Vital signs (blood pressure, temperature, pulse and respiratory rate) 
• Listen to heart and lungs 
• Adverse event monitoring 
7.2.5. Day 14 Follow-up Visit 
Patients will return to clinic on Study Day 14 before taking their morning dose. 
On the morning of Study Day 14, within 30 min prior to dosing, the following 
assessments will be conducted: 
• 
Blood sample collection for PK assessment (for Cmin) 
• Clinical laboratory tests (blood and urine) 
After dose, the following will be conducted: 
• Vital signs (blood pressure, temperature, pulse and respiratory rate) 
• Listen to heart and lungs 
• Adverse event monitoring 
• ECG 
7.2.6. Day 28 Follow-up Visit 
Patients will return to the clinic in the morning on Study Day 28 and take their 
morning dose upon arrival. 
After dose on Study Day 28, the following assessments will be conducted: 
• Vital signs (blood pressure, temperature, pulse and respiratory rate)  
• Adverse event monitoring 


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• Cambridge Cognition testing 
• MMSE 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
• ECG 
• CSF sample collection (time post-dose to be recorded) 
• 
Blood sample collection for PK (time post-dose to be recorded) 
• Clinical laboratory tests (blood and urine) 
• Blood sample collection for PTI-125Dx, mTOR and other biomarkers      
(8 mL total) 
CSF sample collection (5 mL) on Study Day 28 will occur 1-2 h after dosing and after 
the MMSE and Cambridge Cognition testing have been completed. These samples 
will be tested for PTI-125 levels as well as the Aβ/tau Index, YKL40, inflammatory 
cytokines and other biomarkers.  
 
Blood sample collection for PK assessment on Study Day 28 should be taken as soon 
after the CSF draw as possible to allow CSF to plasma ratio to be calculated. 
 
7.2.7. End-of-study Follow-up  
Patient will receive a follow-up phone call 7-14 days after the last dose. If needed, a 
follow-up clinic visit will be scheduled. 
 
7.2.8. 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 patient from study drug, the Sponsor will be notified immediately. 
Restarting the patient on study drug will be a mutual decision by the investigator and 
the Sponsor. 
 
7.3. LABORATORY ASSESSMENTS 
7.3.1. Clinical Laboratory Tests 
The following clinical laboratory tests will be performed at screening, Day 1 pre-dose, 
and at follow-up visits on Day 7, 14, and 28: 
 
• Hematology:  white blood cell (WBC) count with differential, red blood 
cell (RBC) count, hemoglobin, hematocrit, platelet count. 


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• Serum Chemistry:  glucose, sodium, potassium, chloride, bicarbonate, 
calcium, phosphate, blood urea nitrogen (BUN), total bilirubin, 
creatinine, cholesterol, triglycerides, 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. 
 
7.3.2. Preparation of Whole Blood Samples for biomarkers and APOE genotyping 
Blood samples to be assessed in blood-based (lymphocytes or plasma) biomarkers, 
e.g. PTI-125Dx and mTOR, or genotyping (8 mL total) will be drawn into a 
Vacutainer® tube containing K2EDTA. Collection will occur on Days 1 and 28. 
The tubes will be placed immediately on wet ice or in a refrigerator and shipped as 
whole blood, unfrozen, with cold gel packs (2-8°C) within 24 h to: Dr. Hoau-Yan 
Wang, CUNY School of Medicine, SOM CDI 3370, 85 St. Nicolas Terrace, New 
York, NY 10027. Do not freeze, do not ship with dry ice, and do not ship whole 
blood samples on Friday. 
7.3.3. Preparation of Plasma Samples for Pharmacokinetic Determination  
At each blood collection for PK, blood samples (4 mL) will be drawn into a 
Vacutainer® 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 (at least 1.5 mL) 
will be split into two aliquots, transferred to polypropylene tubes and stored at 
approximately -20°C or below until analysis.  
At the end of the study or when advised by Sponsor, PK samples will be shipped 
frozen on dry ice to: Worldwide Clinical Trials Bioanalytical Sciences, 8609 Cross 
Park Drive, Austin, TX 78754 for bioanalytical analysis of PTI-125 with a validated 
assay. The second set of samples will be shipped separately once receipt of the first 
set is confirmed. One sample from each placebo subject will be analyzed. The 
timepoint will be selected to be near the Cmax.  
 
7.3.4. CSF assays 
CSF samples should be split, with 2.5 mL shipped to Dr. Wang at CUNY and, for 
Day 28 only, an additional 0.5 mL shipped to Worldwide Clinical Trials (WCT). This 
0.5 mL sample will be assayed for the PTI-125 analyte at WCT using a qualified 
assay.  The remaining 2.5 or 2 mL will be retained at the study site frozen at -20°C or 
below until informed by the Sponsor. 


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CSF will be collected into 5 ml Screw-Cap LoBind Eppendorf® tubes 
(# 0030122356). When dividing into aliquots, the same tubes can be used or a 2 ml 
Sarstedt® Screw Cap Micro Tube Protein Low Binding (#72.694.600). CSF 
samples will be collected at the second screening visit and on Study Day 28.   
The samples collected at screening and on Study Day 28 will be shipped frozen on 
dry ice (Monday – Wednesday) to Dr. Hoau-Yan Wang, CUNY School of Medicine, 
SOM CDI 3370, 85 St. Nicolas Terrace, New York, NY 10027 to be tested in 
biomarker assays including: 
• Abeta 
• Tau, ptau 
• YKL40 
• IL-6, TNFα and IL-1β 
• Neurogranin 
• Neurofilament light chain 
CSF samples collected at screening should be shipped to Dr. Wang upon collection; 
all Day 28 CSF samples can be held until end of study and shipped together per 
Sponsor instructions (2 mL samples), or for the 0.5 mL samples, to WCT along with 
plasma PK samples in one shipment. 
8. EARLY DISCONTINUATION 
Patients may choose to discontinue study drug or study participation at any time, for 
any reason, and without prejudice. Patients who discontinue may be replaced at the 
discretion of Sponsor. 
 
The following must be completed and documented in the source documents and CRFs 
for all patients who discontinue the study early: 
• 
The reason for early study discontinuation. 
• 
Vital signs (blood pressure, temperature, pulse and respiratory rate), full physical 
examination, clinical laboratory tests, ECG, use of concomitant medications, and 
adverse events) should be obtained at discharge prior to release. 
• 
Blood draw for PTI-125Dx, mTOR and other biomarkers 
• 
MMSE  
• 
Cambridge Cognition testing if not performed within the last 3 days 


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• 
CSF draw for biomarkers 
9. ADVERSE EVENTS/SERIOUS ADVERSE EVENTS  
9.1. 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 on the AE CRF in appropriate medical terminology. The 
severity and the relationship to the study drug will be determined and reported on the 
CRF (see below). 


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9.2. 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 Adverse Event CRF. 
9.3. 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 the study drug belongs to; 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 Adverse Event eCRF. 
9.4. 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 


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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 only listed 
elevated hepatic enzymes or hepatitis. 
Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by 
virtue of greater specificity) if the Investigator's Brochure only listed cerebral 
vascular accidents. 
9.5. 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 their EC/IRB. 
 
All SAEs must be reported immediately (within 24 h of learning of the event) by 
telephone to: 
 
Nadav Friedmann, PhD, MD 
Cassava Sciences, Inc. 
Email: nfriedmann@cassavasciences.com 
Phone:    925-788-4585 


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Do not delay reporting a suspected SAE to obtain additional information.  Any 
additional information, if collected, can be reported to the Sponsor as a follow-up 
to the initial report. 
A completed SAE report form must be faxed within five working days to the 
medical monitor. SAEs must also be reported to the responsible EC/IRB 
immediately. 
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 EC/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 patients experiencing an 
SAE will be seen by a Principal Investigator or designee as soon as feasible 
following the report of an SAE. 
10. STATISTICAL CONSIDERATIONS 
10.1. RANDOMIZATION 
Randomized treatments will be assigned by patient numbers in a randomly generated 
numeric sequence. 
The randomization code will not be revealed to study patients, investigators, clinical 
staff or study monitors until all patients 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 on the case report form, and the medical monitor must 
be informed as soon as possible. 
10.2. ANALYSIS POPULATIONS 
All patients who receive study medication will be included in analyses for safety, 
biomarkers and cognition.  
10.3. PHARMACOKINETIC PARAMETERS 
The only plasma PK parameters to be collected from this study are the Cmin values from 
blood samples taken prior to dosing on Days 7 and 14 and the sample on Day 28 


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collected just after the CSF draw. 
 
A CSF to plasma ratio will be determined using the Day 28 CSF and plasma samples. 
10.4. STATISTICAL ANALYSIS 
CSF biomarker endpoints to be analyzed include: 1) neurogranin, 2) neurofilament light 
chain, 3) total tau, 4) pTau (T181), 5) Aβ42, 6) YKL40, 7) IL-6, 8) TNFα, and 9) IL-1β. 
Plasma and lymphocyte assays include 1) PTI-125Dx lymphocyte assay, 2) PTI-125Dx 
plasma assay and 3) mTOR assay. CSF biomarkers may also be measured in plasma. 
All biomarker data will be analyzed by a two-tailed paired t test or other appropriate 
statistics. 
 
Although not powered for efficacy, the Cambridge Cognition tests will be analyzed by 
repeated measures ANOVA or other appropriate statistics. 
 
10.5. 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. 
10.6. SAMPLE SIZE 
Sixty (60) patients will be enrolled in this study. Sample size was determined by 
estimating the intrasubject variability for log-transformed data from previous studies 
of new chemical entities (NCEs). 
11. STUDY TERMINATION 
The study will be terminated following completion of the study or at any time at the 
discretion of the Sponsor. 
12. DATA COLLECTION, RETENTION AND MONITORING 
12.1. CASE REPORT FORMS 
Electronic case report forms (eCRFs) will be used for each subject. The patients 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 patient number. 


Cassava Sciences, Inc. 
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All clinical information requested in this protocol will be recorded in the eCRFs 
provided by CSI.  Case report forms must be completed within 48 hours of a patient’s 
visit. In case of error, the correction will be noted, initialed and dated. 
eCRFs must be reviewed and verified for accuracy and signed-off by the Principal 
Investigator before collection by the Sponsor (or CRO designee). Paper source 
documents, if used, will remain at the Investigator's site at the completion of the 
study. 
12.2. 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 eCRFs, 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 Informed Consent Form and all source 
documentation related to that subject. The Investigator must ensure the reliability and 
availability of source documents for the eCRF. 
Investigators are required to maintain all study documentation until notification by 
CSI that any records may be discarded. 
The Investigator is responsible for maintaining adequate case histories in each 
subject's source records.  
12.3. SUBJECT CONFIDENTIALITY 
All reports and subject samples will be identified only by the assigned patient number 
and initials to maintain subject confidentiality. Additional subject confidentiality 
issues (if applicable) are covered in the Clinical Trial Agreement. 
12.4. 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 use of the study drug, the 
Sponsor will reimburse for reasonable physician fees and medical expenses 
necessary for treatment of only the bodily injury which 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 


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Clinical Protocol PTI-125-02 
PTI-125, a small molecule to treat AD 
June 28, 2019 
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compensation of any type will be provided by the Sponsor. Compensation for lost 
wages, disability or discomfort due to the study is not available. 
12.5. 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. 
12.5.1. Institutional Review Board 
The protocol and Informed Consent Form 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 IRB approval must be provided to the Sponsor. Investigators are 
responsible for the following: 
• Obtaining IRB approval of the protocol, Informed Consent Form, and any 
advertisements to recruit patients and IRB approval of any protocol 
amendments and Informed Consent Form revisions before implementing the 
changes. 
• Providing the IRB with any required information before or during the study. 
• Submitting progress reports to the IRB, as required, requesting additional 
review and approval, as needed; and providing copies of all relevant IRB 
communications to the Sponsor. 
• Notifying the IRB within 15 calendar days of all SAEs and unexpected AEs 
related to study medications reported by the Sponsor to the Investigator. 
12.6. INFORMED CONSENT FORM 
The Sponsor (or designee) must review the Investigator's proposed Informed Consent 
Form prior to IRB submission for approval. An IRB-approved copy of the Informed 
Consent Form will be forwarded to the Sponsor. 
The Informed Consent Form 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 Informed Consent Form must be signed and dated before the subject enters the 
study. The original Informed Consent Form and any amended Informed Consent 
Form, signed and dated, must be retained in the subject's file at the study site and a 
copy must be given to the subject. 


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PTI-125, a small molecule to treat AD 
June 28, 2019 
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13.  INVESTIGATOR RESPONSIBILITIES 
The Investigator agrees to: 
• Conduct the study in accordance with the protocol, except to protect the safety, 
rights, or welfare of patients. 
• Personally conduct or supervise the study. 
• Ensure that requirements for obtaining informed consent and EC/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. 
• Ensure that EC/IRB complies with requirements of ICH, 21 CFR Part 56, and 
local laws and will be responsible for initial and continuing review and approval 
of the clinical study. 
• Promptly report to the EC/IRB and the Sponsor all changes in research activity and 
unanticipated problems involving risks to patients 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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14. REFERENCES 
1. 
Burns LH, Wang H-Y. Altered filamin A enables amyloid beta-induced tau 
hyperphosphorylation and neuroinflammation in Alzheimer’s disease. Neuroimmunol 
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. 
Neurobiol 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. J Neurosci 
2012;32:9773-84. 


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June 28, 2019 
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15.  APPENDIX A – SCHEDULE OF ACTIVITIES 
 
PROCEDURE 
SCREEN 1  
(Days -29 to 
Day -1) 
SCREEN 2  
(Days -28 
to Day 0) 
DAY 1 
Time=0 
DAY  
7 
DAY 
14 
DAY 
28 
Informed consent 
X 
 
 
 
 
 
Medical and medication 
histories 
X 
 
X 
 
 
 
ECG  
X 
 
X 
 
X 
X 
Vital signs 
X 
 
X 
X 
X 
X 
Physical examination 
X 
 
* 
* 
* 
X 
FSH Test** 
X 
 
 
 
 
 
Biochemistry, hematology, 
urinalysis 
X 
 
X 
X 
X 
X 
MMSE  
X 
 
 
 
 
X 
HCV, HBsAg & HIV screen 
X 
 
 
 
 
 
Urine drug screen 
X 
 
 
 
 
 
Drug administration 
 
 
X 
X 
X 
X 
Blood sample collection for 
PK analysis 
 
 
 
X 
X 
X 
Adverse Events 
 
 
X 
X 
X 
X 
Blood draw for biomarkers 
and one time only, APOE 
genotyping 
 
 
X 
 
 
X 
Cambridge Cognition testing 
 
X 
X 
 
 
X 
C-SSRS 
X 
 
 
 
 
X 
CSF draw 
 
X 
 
 
 
X 
* Listen to heart and lungs      ** If female and last natural menses < 24 months or uncertain