Clinical trial NCT03748706
Conditions: Alzheimer Disease
Sponsor: Pain Therapeutics
Start date: 2019-03-07; Completion date: 2019-05-08
Enrollment: 13 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase 2a, multi-center, open-label study of PTI-125 in mild-to-moderate Alzheimer's disease patients.

Detailed description:
This is a Phase 2a, multi-center, open-label study of PTI-125 in mild-to-moderate AD patients, 50-85 years of age. A total of twelve (12) patients will be enrolled into the study. Patients will receive 100 mg b.i.d. of PTI-125. The objectives of this study are to investigate the safety, pharmacokinetics and effect on biomarkers of PTI-125 following 28-day repeat-dose oral administration.

Arms: arm 1: Simufilam (PTI-125) 100 mg oral tablets administered twice daily (BID)
Interventions: intervention 1: PTI-125, 100 mg tablets
Intervention descriptions: intervention 1: PTI-125, 100 mg tablets taken twice a day for 28 days

Protocol documents:
SAP_002.pdf: 
16.1.9 
Documentation of Statistical Methods  
A copy of version 1.0 of the SAP, dated 16 Mar 2020 is provided. 
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Clinical Study Report for Protocol PTI-125-03
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STATISTICAL ANALYSIS PLAN 
Study Title: 
A Phase 2a, Open-label, Multiple Dose, Safety, 
Pharmacokinetic and Biomarker Study of PTI-125 in Mild-to-
moderate Alzheimer’s Disease Subjects 
Study Number: 
PTI-125-03 
Investigational Drug: 
PTl-125 
Indication: 
Treatment of Alzheimer’s disease 
Investigators: 
Multicenter 
IND Number: 
 
EudraCT Number: 
 
Sponsor: 
Cassava Sciences, Inc. 
7801 N. Capital of Texas Hwy, Ste. 260 
Austin, TX 78731 
Plan Version: 
16 March 2020 (1.0) 
Plan Prepared by: 
Inka Leprince, MS 
Statistical Consultant 
PharmaStat, LLC 
 
CONFIDENTIAL 
This document is confidential and property of Cassava Sciences, Inc.  It may not be 
copied or provided to any other party without the express written consent of 
Cassava Sciences, Inc. 
2020 Cassava Sciences, Inc. 
 
 
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SAP Study PTI-125-03 Final 1.0
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STATISTICAL ANALYSIS PLAN
Study PTI-125-03
Final 1.0
A Phase 2a, Open-label, Multiple Dose, Safety, Pharmacokinetic and Biomarker Study of PTI-
125 in Mild-to-moderate Alzheimer’s Disease Subjects
Approval:
__________________________________
______________________
Michael Marsman, PharmD
Date
Consultant, Regulatory Affairs
Cassava Sciences, Inc.
__________________________________
______________________
Elizabeth Li
Date
Project Statistician
PharmaStat, LLC
Michael R 
Marsman
Digitally signed by Michael R 
Marsman 
Date: 2020.03.17 10:32:40 -05'00'
17Mar2020
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Table of Contents 
1 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................................... 5 
2 
REVISION HISTORY........................................................................................................... 7 
3 
RELEVANT DOCUMENTS: PROTOCOL, AMENDMENTS AND CASE REPORT 
FORMS .................................................................................................................................. 7 
4 
PURPOSE OF THE ANALYSIS PLAN ............................................................................... 7 
5 
STUDY OBJECTIVES .......................................................................................................... 8 
6 
STUDY DESIGN................................................................................................................... 8 
 
Overall Study Design .................................................................................................... 8 
 
Assessments ................................................................................................................ 11 
 
Safety Measurements .................................................................................... 11 
 
Pharmacokinetic Measurements .................................................................... 11 
 
Biomarker Measurements .............................................................................. 11 
 
Other Measurements ...................................................................................... 11 
7 
SAMPLE SIZE AND POWER ............................................................................................ 12 
8 
SAFETY ANALYSIS SETS ............................................................................................... 12 
9 
GENERAL CONSIDERATIONS ....................................................................................... 12 
 
Data Summarization and Presentation ........................................................................ 12 
 
Definitions and Derived Variables .............................................................................. 13 
 
Age ................................................................................................................ 13 
 
Body Mass Index ........................................................................................... 13 
 
Study Day ...................................................................................................... 13 
 
Multiple Records at a Time Point .................................................................. 13 
 
Baseline Values ............................................................................................. 13 
 
Treatment-Emergent Adverse Events ........................................................... 14 
 
Concomitant Medications .............................................................................. 14 
10 
STATISTICAL AND ANALYSIS ISSUES ....................................................................... 14 
 
Adjustments for Covariates......................................................................................... 14 
 
Handling Dropouts or Missing Data ........................................................................... 14 
 
Handling of Safety Data.............................................................................................. 14 
 
Adverse Events .............................................................................................. 14 
 
Concomitant Medications .............................................................................. 15 
 
Interim Analyses and Data Monitoring....................................................................... 15 
 
Multicenter Considerations ......................................................................................... 15 
 
Multiple Comparisons, Multiplicity............................................................................ 15 
 
Active-Control Studies................................................................................................ 15 
 
Examination of Subgroups .......................................................................................... 16 
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11 
STUDY SUBJECTS ............................................................................................................ 16 
 
Subject Disposition ..................................................................................................... 16 
 
Protocol Deviations ..................................................................................................... 16 
 
Demographics and Baseline Characteristics ............................................................... 17 
 
Medical History .......................................................................................................... 17 
12 
STUDY DRUG AND OTHER MEDICATIONS ............................................................... 17 
 
Prior and Concomitant Medications ........................................................................... 17 
 
Restricted Medications................................................................................................ 17 
 
Exposure to Study Drug and Study Treatment Compliance ....................................... 17 
13 
SAFETY ANALYSES......................................................................................................... 18 
 
Safety Variables .......................................................................................................... 18 
 
Adverse Events ........................................................................................................... 18 
 
Clinical Laboratory Evaluation ................................................................................... 19 
 
Vital Signs ................................................................................................................... 19 
 
Physical Examination.................................................................................................. 19 
 
12-Lead Electrocardiogram ........................................................................................ 19 
 
Safety Monitoring ....................................................................................................... 19 
14 
EXPLORATORY ANALYSES .......................................................................................... 20 
 
Exploratory Pharmacokinetic Analysis ....................................................................... 20 
 
Exploratory Biomarker Analyses ................................................................................ 20 
 
Exploratory Cognitive/Behavioral Endpoint .............................................................. 20 
15 
CHANGES RELATIVE TO THE PROTOCOL-SPECIFIED ANALYSIS ....................... 21 
16 
References ............................................................................................................................ 21 
 
List of Tables 
Table 1 
Study PTI-125-03 Protocol Schedule of Events (Protocol Version September 18, 
2018) 
.................................................................................................................................... 10 
 
 
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1 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Description 
Aβ 
amyloid beta 
AD 
Alzheimer’s disease 
AE 
adverse event 
ANOVA 
analysis of variance 
ATC 
anatomical/therapeutic/chemical 
AUC 
area under the curve 
BEHAVE-AD 
Behavioral Pathology in Alzheimer’s Disease Rating Scale 
BID 
twice daily 
BLQ 
below the lower limit of quantification 
BMI 
body mass index 
C1/F 
apparent oral clearance 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
confidence interval 
CM 
concomitant medication 
Clast 
concentration of the last quantifiable drug concentration 
Cmax 
maximum plasma concentration 
CSF 
cerebrospinal fluid 
CSR 
clinical study report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CV% 
percent coefficient of variation 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
GLSMR 
geometric least squares mean ratio 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
ICH 
International Council for Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use 
IL-1β 
interleukin 1 beta 
IL-6 
interleukin 6 
IQR 
interquartile range 
LS 
least squares 
λZ 
elimination rate constant 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMSE 
Mini-Mental State Examination 
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Abbreviation 
Description 
mTOR 
mammalian target of rapamycin 
PK 
pharmacokinetic(s) 
PTI-125 
small molecule drug candidate to treat AD 
PTI-125DX 
blood-based diagnostic/biomarker 
SAE 
serious adverse event 
SAF 
safety analysis set 
SAP 
statistical analysis plan 
SD 
standard deviation 
SDTM 
Study Data Tabulation Model 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
TLFs 
tables, listings and figures 
T1/2 
terminal elimination half-life 
Tlast 
time to the last quantifiable concentration 
Tmax 
time to Cmax 
TNFα 
tumor necrosis factor alpha 
Vz/F 
apparent volume of distribution 
YKL40 
chitinase-like protein 1 
 
 
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2 
REVISION HISTORY 
Version 
Date 
Document 
Owner 
Revision Summary 
1.0 
16Mar2020 
Inka Leprince 
First version 
3 
RELEVANT DOCUMENTS: PROTOCOL, AMENDMENTS AND CASE REPORT 
FORMS 
Original Protocol (30 October 2018) 
Amendment #1 (31 October 2018) 
Amendment #2 (05 February 2019) 
 
Case Report Form Version 1.0 (29 November 2018) 
Case Report Form Version 2.0 (11 July 2019) 
 
4 
PURPOSE OF THE ANALYSIS PLAN 
This statistical analysis plan (SAP) pre-specifies the statistical analysis methods for supporting 
the completion of the clinical study report (CSR) of Study PTI-125-03 for investigational 
product PTI-125, a novel drug candidate designed to treat and slow the progression of 
Alzheimer’s disease (AD).  This SAP will be used to analyze the safety data collected during the 
study.  Pharmacokinetic (PK) data and biomarker data will be analyzed by third parties.  
Therefore, the detailed data analysis methods for PK and biomarker will be documented 
separately from this plan.  The planned analyses identified in this SAP may be included in 
regulatory submissions and/or future manuscripts.   
The analysis methods described in this plan are considered a priori, in that they have been 
defined prior to clinical database lock.  Exploratory analyses, which are not defined in this SAP, 
may be performed to support the clinical development program.  Any post-hoc or unplanned 
analyses that are performed for the CSR, but not defined in this SAP, will be documented in the 
CSR.  Changes from the planned analyses stated in the study protocol are described in 
Section 15.  Should the SAP and the protocol be inconsistent with respect to any further planned 
analyses, the language of the SAP is governing.   
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5 
STUDY OBJECTIVES 
The objectives of this study are to investigate the safety, pharmacokinetics and effect on 
biomarkers of PTI-125 following a 28-day repeat-dose oral administration in mild-to-moderate 
AD subjects, 50-85 years of age, within a Mini-Mental State Examination (MMSE) range of 
≥ 16 and ≤ 24.  
6 
STUDY DESIGN 
 
Overall Study Design 
This is a Phase 2a, multi-center, open-label study.  A total of thirteen (13) subjects were enrolled 
in this study to receive 100 mg PTI-125 twice daily (BID).  Five (5) study centers participated in 
this study.  
Screening Period: Eligible subjects will be screened within 30 days prior to the first 
administration of the study drug (PTI-125).  Eligible subjects will be enrolled into the study if 
they: are 50 to 85 years of age; have a clinical diagnosis of dementia due to possible or probable 
AD; and have a MMSE score of 16 to 24 at screening. The full list of inclusion and exclusion 
criteria can be found in the PTI-125-03 protocol, Section 5.  Once all other inclusion and none of 
the exclusion criteria are met, a cerebrospinal fluid sample will be collected for pre-dose 
biomarkers and for the inclusion criterion of a Tau/Αβ Ratio that indicates AD (i.e., ≥ 0.30).  
Assessments of the Behavioral Pathology in Alzheimer’s Disease Rating Scale (BEHAVE-AD1) 
and Columbia Suicide Severity Rating Scale (C-SSRS) will also be administered during the 
screening period for cognitive/behavioral data. 
Treatment Period: Subjects will receive study drug (PTI-125) on an inpatient basis (i.e., in the 
clinic) on Days 1 and 2.  Subjects will receive study drug on an outpatient basis for the 
remaining 26 days of the 4-week Treatment Period.  The dose of study drug will be fixed for the 
4 weeks of the Treatment Period at 100 mg PTI-125 BID, dispensed as coated tablets to be taken 
orally.  During the 4-week Treatment Period, subjects will attend four study (clinic) visits 
(Days 1, 7, 14, 28) for periodic collection of blood and urine for safety, PK, and biomarker data.  
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Day 28 will include a CSF draw for biomarker data and assessments of the BEHAVE-AD for 
cognitive/behavioral data (see Table 1 for the schedule of assessments). 
Follow-up Period: Subjects will return to the clinic on Day 29 for a Follow-up visit which will 
include PK assessment (24 hours after the last dose of study medication), clinical laboratory 
tests, and other safety assessments. 
The maximum duration of Study PTI-125-03 per subject is expected to be 59 days (i.e., a 
maximum of 30-day Screening Period, a 4-week Treatment Period, and a 1-day Follow-up visit).  
Assessments and procedures for evaluation of safety, PK, and biomarkers will be conducted per 
the protocol-specified schedule (see Table 1 ). 
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Table 1 
Study PTI-125-03 Protocol Schedule of Events (Protocol Version September 18, 2018) 
Study Activity 
Period 
Screening 
Treatment 
Follow-up 
Visit Name 
 
D1 
D2 
D7 
D14 
D28a 
 
Timing 
Days -30 to -1b 
Day 1 
Day 2 
Day 7 
Day 14 
Day 28 
Day 29 
Informed consent 
X 
 
 
 
 
 
 
Demographics and medical history 
X 
 
 
 
 
 
 
Prior/concomitant medications 
X 
 
 
 
 
 
 
ECGc 
X 
X 
X 
X 
X 
 
X 
Vital signsd 
X 
X 
X 
X 
X 
X 
 
Physical examination 
X 
Brief 
Xe 
Xe 
Xe 
 
X 
Clinical laboratory tests (serum chemistry, 
hematology, urinalysis) 
X 
X 
X 
X 
X 
 
X 
MMSE 
X 
 
 
 
 
 
 
HCVm, HBsAg, & HIV screen 
X 
 
 
 
 
 
 
Drug administrationf, g 
 
X 
X 
X 
X 
X 
 
Blood plasma sample collection for PK analysis 
 
X 
X 
X 
X 
X 
X 
Adverse event monitoring 
 
X 
X 
X 
X 
X 
X 
Discharge 
 
 
X 
 
 
 
 
Whole blood draw for biomarkers 
 
X 
 
 
X 
X 
 
BEHAVE-AD  
X 
 
 
 
X 
X 
 
C-SSRS 
X 
 
 
 
 
X 
 
CSF draw 
X 
 
 
 
 
X 
 
BEHAVE-AD = Behavioral Pathology in Alzheimer’s Disease Rating Scale; C-SSRS = Columbia-Suicide Severity Rating Scale; CSF = cerebrospinal fluid; ECG = electrocardiogram, ED = early 
discontinuation; HBsAg = hepatitis B surface antigen; HCVm = hepatitis C virus; HIV = human immunodeficiency virus; MMSE = Mini-Mental State Examination; PK = pharmacokinetic(s). 
Notes: Allowed visit windows are ± 2 days for all study visits during the Treatment. The Follow-up visit will immediately follow the Day 28 visit. 
a. 
Subjects who terminate the study early are required to undergo an Early Discontinuation (ED) Visit with the following procedures to be performed: documentation of the reason for early 
study discontinuation; full physical examination; clinical laboratory tests (biochemistry, hematology, urinalysis); ECG; adverse event collection; blood draw for biomarkers; BEHAVE-AD; 
and CSF draw. 
b. 
Screening Visit must occur within 30 days prior to administration of the study medication. 
c. 
Screening visit ECG will be collected with the subject in a supine position. 
d. 
Vital signs include:  blood pressure, heart rate, respiratory rate, and temperature. 
e. 
Listen to heart and lungs. 
f. 
Administer the first dose of study drug on the morning of Day 1, 1-2 hours before breakfast. On Days 7, 14, and 28, subjects are instructed to take study drug after blood draws. 
g. 
Subjects are instructed to bring all unused study drug to each visit.  Collect all unused study drug at the Day 28 Visit or at the ED Visit.
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Assessments 
Table 1 shows the schedule of events for the study. 
 Safety Measurements 
Safety will be assessed by repeated clinical evaluations including adverse events (AEs), serious 
adverse events (SAEs), vital signs, physical examination, electrocardiograms (ECGs), and 
clinical laboratory tests (serum chemistry, hematology, and urinalysis). 
 Pharmacokinetic Measurements 
Plasma samples will be collected for evaluation of PTI-125 PK.  On Day 1, blood samples for 
PK assessments will be drawn at 20, 40, and 60 minutes and at 1.5, 2, 2.5, 3, 4, 6, 8, 10, and 
12 hours after the first dose of study medication and prior to the second dose. On Day 2, the 
blood sample for the 24 hour PK time point will be drawn.  On study Days 2, 7, 14, and 28, the 
PK samples are to be drawn 30 minutes prior to dosing and will be used for estimation of the 
Cmin parameter.  On Day 28, in addition to the pre-dose sample, post-dose PK samples will be 
obtained at 20, 40, and 60 minutes and at 1.5, 2, 2.5, 3, 4, 6, 8, 10, and 12 hours.  The 24-hour 
PK blood sample will be collected on Day 29.  Other PK parameters, such as Cmax and 
CSF/plasma ratio, will be calculated from the PK concentration data to provide an estimate of the 
extent of accumulation between Day 1 and Day 28.  Pharmacokinetic measurements will be 
analyzed, summarized, and listed separately by a third party. 
 Biomarker Measurements 
The cerebrospinal fluid (CSF) samples will be collected at the second Screening visit and post-
dose on Day 28 to characterize several biomarker assays including: amyloid beta (Aβ), tau, 
phosphorylated tau (ptau), YKL40, IL-6, TNFα, and IL-1β.  Whole blood will be collected on 
Day 1 (pre-dose), Day 14, and Day 28 to characterize PTI-125DX lymphocyte assay, PTI-
125DX plasma assay, and lymphocyte mTOR assays.  Biomarker data will be analyzed 
separately by a third party, but will be listed in subject listings. 
 Other Measurements 
BEHAVE-AD rating scale will be used to assess the behavioral and psychological symptoms of 
dementia.  BEHAVE-AD will be administered on Screening 2, Day 14, and Day 28. 
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7 
SAMPLE SIZE AND POWER 
According to the protocol, the sample size is based on the estimations of intra-subject variability 
for log-transformed data from previous studies of new chemical entities.  No formal statistical 
power calculations were performed. 
8 
SAFETY ANALYSIS SETS 
The safety analysis set (SAF) is defined as all subjects who received any amount of study drug 
(PTI-125).  The safety analysis set will be used to assess safety, biomarkers, and behavioral and 
psychological symptoms of AD. 
9 
GENERAL CONSIDERATIONS 
 
Data Summarization and Presentation 
The safety analysis set will be used for safety analyses as well as analysis for behavioral and 
psychological symptoms of AD.  Subject listings of all analysis data that support summary tables 
and/or figures will be provided.  Extra measurements (such as unscheduled or repeat 
assessments) will not be included in summary tables unless specified otherwise, but will be 
included in the subject listings.  In general, subject listings will be sorted by subject number and 
assessment date (time, and parameter, as applicable).   
For most summary statistics, data will be analyzed and displayed in tabular format.  Unless 
otherwise specified, descriptive statistics for continuous variables will include the number of 
subjects with data to be summarized (n), mean, standard deviation (SD), median, minimum, and 
maximum.  The same number of decimal places as in the observed value will be presented when 
reporting minimum and maximum; 1 additional decimal place than in the observed value will be 
presented when reporting mean and median; and 2 additional decimal places than in the observed 
value will be presented when reporting SD. 
All categorical/qualitative data will be presented using frequency, counts, and percentages.  All 
percentages will be presented to 1 decimal place, unless otherwise specified.  Percentages equal 
to 100 will be presented as 100% and percentages will not be presented for zero frequencies.  
Where individual variable values are missing, categorical data will be summarized based on 
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reduced denominators (i.e., only subjects with available data will be included in the 
denominators).  For summaries of AEs and concomitant medications (CMs), the percentages will 
be based on the number of subjects who received study drug. 
Results of statistical analyses will be reported using summary tables, listings, and figures (TLFs).  
The International Council for Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) numbering convention will be used for all TLFs.  All 
analyses and summaries will be produced using SAS® version 9.4. 
 
Definitions and Derived Variables 
 Age 
Age (years) will be calculated as the number of years between date of birth and date of informed 
consent, expressed as an integer. 
 Body Mass Index 
Body mass index (BMI, kg/m2) is derived as weight (kg) / [height (m) × height (m)]. 
 Study Day 
Study Day, which follows the Clinical Data Interchange Standards Consortium (CDISC) Study 
Data Tabulation Model (SDTM) standard, is defined as (Assessment date - date of first study 
drug dosing + 1), where the assessment date is on or after the date of first study drug dosing; 
(Assessment date – date of first study drug dosing), where the assessment date is before the date 
of first study drug dosing.   
 Multiple Records at a Time Point 
For analysis purposes, the mean value of multiple measurements collected at the same position 
(i.e., supine, etc.) on the same visit day and at the same time point will be summarized for the 
corresponding protocol-defined time point.  All collected measurements and the mean values 
will be listed. 
 Baseline Values  
Baseline values are defined as the last non-missing assessment prior to the first dose of study 
drug, unless otherwise specified.   
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 Treatment-Emergent Adverse Events  
Treatment-emergent adverse events (TEAEs) are defined as any AEs, regardless of relationship 
to study drug, that have an onset or worsening in severity on or after the first dose of study drug 
(see also Section 10.3.1).  Related AEs are those reported by investigators as possibly related or 
probably related to the study drug.  Serious TEAEs (SAEs) are defined as described in 
Section 9.4 of the protocol (and are industry standard definitions). 
 Concomitant Medications 
Prior medications are defined as all prescription and over-the-counter medications that were 
taken within 30 days (whether continuing or not) prior to the first dose of study drug.  
Concomitant medications (CM) are defined as all prescription and over-the-counter medications 
that are used concurrently (from Day 1 to Day 28) with the study drug administration.  A CM is 
considered to be any medication that is continued from Screening and continued after the first 
study drug dosing (i.e., a prior medication can also be a CM if it continued after the first dose of 
study drug) or any medication with start dates or stop dates within the Treatment Period. 
10 STATISTICAL AND ANALYSIS ISSUES 
 
Adjustments for Covariates 
There will be no adjustments for covariates.   
 
Handling Dropouts or Missing Data 
Missing data will not be imputed, unless otherwise specified.  Early termination visits will be 
mapped to the next scheduled visit for inclusion in summary tables, where appropriate. 
Every effort will be made by the Sponsor to ensure completeness of data collection.  In the 
subject listing, all collected and all imputed values will be presented. 
 
Handling of Safety Data 
 Adverse Events 
All AE verbatim terms reported on the eCRFs will not be mapped based on Medical Dictionary 
for Regulatory Activities (MedDRA) dictionary.  All AEs will be listed in subject listings. 
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 Concomitant Medications 
For all prior and concomitant medications (as defined in Section 9.2.6), medication verbatim 
terms reported on the eCRFs will be listed in subject listings. 
If start date is missing, the medication will be considered to have started prior to the study and 
will be listed as a prior medication; if a stop date is recorded, the stop date will be used to 
determine whether it is also a CM (and listed accordingly).  If the stop date of any medication is 
missing, then the medication will be treated as ongoing (i.e., a CM).  Unless there is complete 
stop date information sufficient for the determination of "prior" versus "concomitant," 
medications with incomplete start dates (e.g., missing year, etc.) will be identified as 
concomitant if: 
• Day and month are missing and the year is equal to or after the year of the first date of 
study drug dosing;  
• Day is missing and the year is after the year of the first date of study drug dosing;  
• Day is missing and the year is equal to the year of the first date of study drug dosing and 
the month is equal to or after the month of the first date of study drug dosing; or 
• Year is missing. 
 
Interim Analyses and Data Monitoring 
There will be no interim analyses. 
 
Multicenter Considerations 
This trial was conducted at 5 study centers in the United States.  Data from all study centers will 
be pooled for analysis of safety.  Because the number of subjects at each center is likely to be 
small, no analyses will be performed by center. 
 
Multiple Comparisons, Multiplicity 
The analysis results will be presented descriptively.  Since this is an open-label Phase 2a study, 
there is no comparator.  Safety data analyses are exploratory in nature without statistical testing.  
Therefore, there will be no adjustments for multiple comparisons.    
 
Active-Control Studies 
There is no comparator in this study. 
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Examination of Subgroups 
Due to the small sample size, there will be no subgroup analyses. 
11 STUDY SUBJECTS 
 
Subject Disposition 
Enrollment and disposition will be summarized for all subjects.  All enrolled subjects are defined 
as those who received at least one dose of study drug.  The subject disposition summary will 
include: 
• Number of subjects who enrolled in the study 
• Number (%) of subjects in the SAF analysis set 
• Number (%) of subjects who completed the study 
• Number (%) of subjects who prematurely discontinued from the study 
o The primary reason for withdrawal from the study 
A listing of disposition will be provided for all enrolled subjects.  
 
Protocol Deviations 
Protocol deviations will be listed by category (e.g., eligibility criteria, out-of-window visit or 
procedure, etc.; see list below).  All deviations will be identified prior to database lock and will 
be summarized and presented in listing(s); listings will include flags for deviation type 
(important or minor).  Important protocol deviations are defined per ICH E3 guidance 
(https://database.ich.org/sites/default/files/E3_Guideline.pdf).  All deviations will be summarized 
by deviation category and type.  Examples of protocol deviation include, but are not limited to: 
• Investigational product  
• Informed consent  
• Key eligibility criteria  
• SAE reporting procedure was not followed  
• Out-of-window procedure 
• Procedure missed or data not interpretable  
• Missed or out-of-window visit 
• Restricted/prohibited medications  
• Other 
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As of this writing, no protocol deviations were identified by the sponsor. 
 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized for all subjects.  Demographic 
characteristics will include age, sex, race, and ethnicity.  The following baseline characteristics 
will be summarized: baseline weight, height, and BMI.  In addition, the baseline BEHAVE-AD 
score, screening Mini-Mental State Examination score, number of years since diagnosis of AD, 
and Tau/Αβ ratio (> 0.30) will be summarized.  All of the above information will also be listed 
by subject. 
 
Medical History 
Medical history will not be mapped, based on MedDRA dictionary, to preferred terms and 
system organ classes (SOCs).  Medical history will be listed for all subjects by subject 
identification number. 
12 STUDY DRUG AND OTHER MEDICATIONS 
 
Prior and Concomitant Medications 
All prior and concomitant medications will not be mapped, according to the World Health 
Organization Drug Dictionary, to Anatomical/Therapeutic/Chemical class.  All medications will 
be listed by subject identification number. 
 
Restricted Medications 
The concomitant use of restricted medications, as defined in Section 5.3 of the study protocol, if 
any, will be listed separately by subject identification number.   
 
Exposure to Study Drug and Study Treatment Compliance 
Summaries of study drug exposure and compliance will include the total number of tablets 
dispensed, total number of tablets taken, total dose (mg) taken, study drug compliance, and 
duration (days) of exposure during the study treatment period.  Total number of tablets 
dispensed, total number of tablets taken, total number of tablets returned, total number of tablets 
expected to be taken, and compliance percentage are collected in the eCRF. 
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The duration of study drug exposure is defined as the number of days on treatment from the first 
dose of study drug until the last dose of study drug.  Study drug exposure will be summarized 
descriptively.   
The study drug exposure and drug accountability information, including reasons or comments for 
incomplete or missed doses, if available, will be listed in a subject listing.   
13 SAFETY ANALYSES 
One of the study objectives is to assess the safety of PTI-125.  Safety will be evaluated by AEs, 
clinical laboratory test results, vital signs, ECG findings, and physical examinations.  All 
analyses of the safety data will be performed using the SAF analysis set.  All descriptive 
statistics will be presented as described in Section 9. 
 
Safety Variables 
Safety variables include: 
1. AEs, SAEs, and withdrawal of study drug due to an AE 
2. Laboratory test results 
3. Vital signs 
4. Findings from 12-lead ECG 
5. Findings from physical examination 
 
Adverse Events 
• TEAEs are defined in Section 9.2.5.  All reported AEs (including non-TEAEs) will be 
listed.  An overall summary of TEAEs will include the following:All TEAEs 
• TEAEs by worst severity 
• Study drug-related TEAEs 
• Serious TEAEs 
• Study drug-related serious TEAEs 
• TEAEs leading to study drug discontinuation (if any) 
• TEAEs leading to study drug interruption (if any) 
• Deaths (if any) 
The AE listing will include start and stop date of events; reported (verbatim) terms; flags for 
TEAE and SAE; relation to PTI-125; and outcome (resolved, resolved w/sequelae, resolving, not 
resolved, fatal, unknown).  
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Clinical Laboratory Evaluation 
Clinical laboratory test results from laboratories (serum chemistry, hematology, and urinalysis 
[specific gravity and pH]) will be summarized using descriptive statistics at baseline and at each 
scheduled post-baseline time point, unless otherwise specified.  Changes from baseline will also 
be summarized by time point, where available. 
The number and percentage of subjects with any out-of-range chemistry and hematology values 
(i.e., above the laboratory-specified upper limit of normal or below the lower limit of normal) 
will be summarized by time point, where available. 
All laboratory results will be listed with reference ranges and range indicator (Low, High, or 
Clinically Significantly Abnormal). 
 
Vital Signs 
Descriptive statistics for blood pressure, heart rate, respiratory rate, and temperature, including 
baseline values and change from baseline values, will be summarized by time point.  All vital 
signs parameters will be listed.  Abnormal clinically significant findings from vital signs 
evaluations will be listed.   
 
Physical Examination 
Abnormal clinically significant findings from physical examinations are to be reported as 
Medical History or Adverse Events depending on the date of onset.  Abnormal clinically 
significant findings from physical examinations will be listed. 
 
12-Lead Electrocardiogram 
Electrocardiogram (ECG) data, such as clinical interpretation of ECGs, heart rate (HR) values, 
and interval assessments of PR, QRS, RR, QT, and the corrected value of the interval between 
the Q and T waves on the ECG tracing will be listed.  For HR and ECG intervals, descriptive 
statistics for observed values and change from baseline will be presented by time point.   
 
Safety Monitoring  
The Medical Monitor will review safety data on an ongoing basis to identify potential adverse 
safety trends.  The Data Safety Monitoring Board/Data Monitoring Committee will review safety 
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data periodically and determine if dosing may continue.  Details of the Committee safety data 
review can be found in the Data Safety Monitoring Committee charter. 
14 EXPLORATORY ANALYSES 
 
Exploratory Pharmacokinetic Analysis 
All analyses of PK parameters will be performed by a third party vendor, Worldwide Clinical 
Trials Early Phase Services/Bioanalytical Sciences, LLC.  Plasma samples will be collected on 
Day 1, Day 7, Day 14, Day 28 and Day 29. 
 
Exploratory Biomarker Analyses 
All analyses of biomarker variables will be performed by a third party vendor.  Biomarkers will 
be obtained from CSF samples and whole blood samples.  The biomarkers are identified in the 
study protocol for the following assays. 
• CSF samples collected on Screening 2 (pre-dose) and Day 28 
o Tau/Αβ ratio 
o ptau/tau ratio 
o YKL40 
o IL-6, TNFα, and IL-1β 
• Whole blood samples collected Day 1 (pre-dose), Day 14 and Day 28 
o PTI-125DX lymphocyte assay 
o PTI-125DX plasma assay 
o Lymphocyte mTOR assays 
The biomarker data including the above, as well as those that are not identified in the protocol, 
will be listed in subject listings. 
 
Exploratory Cognitive/Behavioral Endpoint 
The cognitive and behavioral endpoint scores of the BEHAVE-AD are used to assess whether 
the behavioral and psychological symptoms of dementia change over time.  The BEHAVE-AD 
will be assessed once at screening and post-baseline on Days 14 and 28.  Reported scores will be 
summarized descriptively by time point.  In addition, mean, SD, 95% CI of mean, and median 
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will be provided by time point for the change from baseline scores.  All data will be listed in a 
subject listing. 
15 CHANGES RELATIVE TO THE PROTOCOL-SPECIFIED ANALYSIS 
The protocol specified the use of repeated measures ANOVA for cognitive/behavioral endpoint 
BEHAVE-AD.  This method will not be used for two reasons: First, there is only one group 
(active treatment group).  Second, the data may not be normally distributed.  Therefore, 
descriptive statistics and 95% CI of the mean will be provided instead. 
The protocol specified that adverse events reported on case report forms will be mapped to 
preferred terms and organ systems using the MedDRA mapping system.  The medication coding 
was not done, due to very small number of events were reported. 
Uric acid was not performed per protocol Section 7.2.1 Clinical Laboratory Test.  Site 04 did not 
collect Uric Acid.  Therefore, uric acid values will be included in the subject listings where 
available.  Additionally, Site 01, Site 03, and Site 05 did not collect In-Patient Day 2 uric acid 
results.  Therefore, uric acid will not be summarized at the In-Patient Day 2 time point. 
16 References 
1. Reisberg et al., “Behavioral symptoms in Alzheimer’s disease: Phenomenology and
treatment.” J. Clin. Psychology. 1987;48: 9-15.
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Clinical Study Report for Protocol PTI-125-03
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Prot_ICF_001.pdf: 
 
Pain Therapeutics, Inc. 
Clinical Protocol PTI-125-03 
PTI-125, A small molecule to treat AD 
CONFIDENTIAL 
 
05 February 2019  
 
 
Page 1 of 48 
 
 
 
Amendment #2 Final 
 
CSF 
Pain Therapeutics, Inc. 
7801 N. Capital of Texas Hwy, Ste. 260 
Austin, TX 78731 
 
CLINICAL RESEARCH PROTOCOL 
PROTOCOL PTl-125-03 
 
A Phase 2a, Open-label, Multiple Dose,  
Safety, Pharmacokinetic and Biomarker Study  
of PTl-125 in Mild-to-moderate Alzheimer’s Disease Patients 
 
Sponsor:  
 
 
 
Pain Therapeutics, 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@paintrials.com 
 
Project Manager 
Michael Marsman, PharmD 
 
Senior Vice President, Regulatory Affairs 
 
Phone:    512-562-2173 
 
Email:     mmarsman@paintrials.com 
 
Protocol Date: 
October 12, 2018 
Amendment #1: 
October 30, 2018 
Amendment #2: 
February 5, 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 Pain 
Therapeutics, Inc. (PTI) 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 PTI. 
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. 


 
Pain Therapeutics, Inc. 
Clinical Protocol PTI-125-03 
PTI-125, A small molecule to treat AD 
CONFIDENTIAL 
 
05 February 2019  
 
 
Page 2 of 48 
 
 
 
Amendment #2 Final 
 
Pain Therapeutics, Inc. 
CLINICAL RESEARCH PROTOCOL 
 
A Phase 2a, Open-label, Multiple Dose,  
Safety, Pharmacokinetic and Biomarker Study  
of PTl-125 in Mild-to-moderate AD patients 
 
SUMMARY OF PROTOCOL AMENDMENT #2 
 
The purpose of protocol amendment #2 is: 
• to reduce the amount of CSF withdrawn during lumbar puncture at 
Screening and on Day 28 
 
Section 7.1.1 – Screening Period 
Changed from: 
If meeting all other criteria: 
• CSF sample collection (10 mL) 
• BEHAVE-AD test  
Changed to: 
If meeting all other criteria: 
• CSF sample collection (5 mL) 
• BEHAVE-AD test 
 
Section 7.1.5 Day 28 Follow-up Visit 
Changed from: CSF sample collection (10 mL) on Study Day 28 will occur 1-2 h after dosing, 
and the nearest plasma PK sample collection will be noted. The CSF samples will be tested for 
PTI-125 levels as well as the Aβ/tau Index, YKL40, inflammatory cytokines and other 
biomarkers. 
Changed to: CSF sample collection (5 mL) on Study Day 28 will occur 1-2 h after dosing, and 
the nearest plasma PK sample collection will be noted. The CSF samples will be tested for PTI-
125 levels as well as the Aβ/tau Index, YKL40, inflammatory cytokines and other biomarkers. 
 
Section 7.2.4 CSF Assays 
Changed from: CSF samples should be split, with 5 mL of all samples shipped to Dr. Wang at 
CUNY and, for Day 28 only, an additional 1 mL shipped to Worldwide Clinical Trials. The 
remaining 4-5 mL will be retained at the study site at -20°C until otherwise informed by the 
Sponsor. All samples will be shipped frozen on dry ice. 
CSF samples (1.0 mL) from Study Day 28 will be shipped to Worldwide Clinical Trials 
Bioanalytical Sciences (8609 Cross Park Drive, Austin, TX 78754) to be assayed for the PTI-
125 analyte using a qualified assay.  


 
Pain Therapeutics, Inc. 
Clinical Protocol PTI-125-03 
PTI-125, A small molecule to treat AD 
CONFIDENTIAL 
 
05 February 2019  
 
 
Page 3 of 48 
 
 
 
Amendment #2 Final 
 
Changed to: CSF samples should be split, with 2.5 mL of all samples shipped to Dr. Wang at 
CUNY and, for Day 28 only, an additional 0.5 mL shipped to Worldwide Clinical Trials. The 
remaining 2.0 mL will be retained at the study site at -20°C until otherwise informed by the 
Sponsor. All samples will be shipped frozen on dry ice. 
CSF samples (0.5 mL) from Study Day 28 will be shipped to Worldwide Clinical Trials 
Bioanalytical Sciences (8609 Cross Park Drive, Austin, TX 78754) to be assayed for the PTI-
125 analyte using a qualified assay.  


 
Pain Therapeutics, Inc. 
Clinical Protocol PTI-125-03 
PTI-125, A small molecule to treat AD 
CONFIDENTIAL 
 
05 February 2019  
 
 
Page 4 of 48 
 
 
 
Amendment #2 Final 
 
 
Pain Therapeutics, Inc. 
CLINICAL RESEARCH PROTOCOL 
 
A Phase 2a, Open-label, Multiple Dose,  
Safety, Pharmacokinetic and Biomarker Study  
of PTl-125 in Mild-to-moderate AD patients 
 
SUMMARY OF PROTOCOL AMENDMENT #1 
 
The purpose of protocol amendment #1 is: 
• to require FSH testing at screening for certain females 
• to add possible FSH test, caregiver information and a caregiver signature to 
the consent form 
 
Section 5.2 – Inclusion Criteria, Number 5 
Changed from: 
If female, postmenopausal for at least 1 year  
Changed to: 
Females should be of non-childbearing potential.  Non-childbearing potential is 
defined as postmenopausal (last natural menses > 24 months) or surgically sterile by 
a documented bilateral tubal ligation or hysterectomy. If last menses < 24 months or 
uncertain, post-menopausal status should be confirmed by serum FSH. 
 
Section 7.1.1 Screening Period  
Changed to add: If female and last natural menses < 24 months or uncertain, post-
menopausal status should be confirmed by serum FSH. 
 
Section 7.1.1 Screening Period  
1. Changed to add: NOTE: For patients determined by C-SSRS to have suicidality 
tendencies, inform the patient’s primary care physician and refer the patient for follow-
up.  
Appendix A– Events Schedule 
Changed to add: Possible FSH test at screening 
 
Appendix B – Informed Consent Document, Page 35  
Changed to add: 
CAREGIVER PARTICIPATION 
As required by the study, every patient 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 


 
Pain Therapeutics, Inc. 
Clinical Protocol PTI-125-03 
PTI-125, A small molecule to treat AD 
CONFIDENTIAL 
 
05 February 2019  
 
 
Page 5 of 48 
 
 
 
Amendment #2 Final 
 
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 (e.g. 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 per the compensation 
table.  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. 
 
Appendix B – Informed Consent Document, Screening Page 36  
Changed to add: If female and last natural menses < 24 months or uncertain, post-menopausal 
status will be confirmed by serum FSH. 
.  
Appendix B – Informed Consent Document, Page 46  
Changed to add: 
Printed Name of Caregiver/Study Partner 
 
Signature of Caregiver/Study Partner 
Date 
Time (24-hour clock) 
 
 
 
Printed Name of Person Explaining Consent Form 
 
 
 
Signature of Person Explaining Consent Form 
Date  
Time (24-hour clock) 




 
Pain Therapeutics, Inc. 
Clinical Protocol PTI-125-03 
PTI-125, A novel small molecule for AD 
CONFIDENTIAL 
 
05 February 2019  
 
 
Page 7 of 48 
 
 
 
Amendment #2 Final 
 
 
Pain Therapeutics, Inc. 
CLINICAL RESEARCH PROTOCOL 
 
 
 
 
A Phase 2a, Open-label, Multiple Dose, 
Safety, Pharmacokinetic and Biomarker Study 
        of PTl-125 in Mild-to-moderate AD patients 
 
 
 
  
Signature of Agreement for Protocol PTI-125-03 
 
 
 
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 


 
Pain Therapeutics, Inc. 
Clinical Protocol PTI-125-03 
PTI-125, a novel small molecule for AD 
CONFIDENTIAL 
05 February 2019  
 
 
Page 8 of 48 
 
 
 
Amendment #2 Final 
 
Table of Contents 
1. 
List of abbreviations ............................................................................................... 10 
2. 
INTRODUCTION .................................................................................................. 12 
3. 
STUDY OBJECTIVES ............................................................................................. 14 
4. 
SUMMARY OF STUDY DESIGN .......................................................................... 14 
5. 
SUBJECT SELECTION ........................................................................................... 15 
5.1. Study Population ........................................................................................................... 15 
5.2. Inclusion Criteria ........................................................................................................... 15 
5.3. Exclusion Criteria .......................................................................................................... 16 
6. 
STUDY DRUG ...................................................................................................... 18 
6.1. PTI-125 Physical Description and Preparation.................................................................. 18 
6.1.1. Storage ............................................................................................................... 18 
6.1.2. Drug Accountability ............................................................................................ 18 
6.2. Administration and Dosing Regimen .............................................................................. 18 
6.3. Concomitant Medications ................................................................................................. 18 
7. 
STUDY PROCEDURES .......................................................................................... 18 
7.1. Evaluations by Visit ....................................................................................................... 19 
7.1.1. Screening Period ................................................................................................ 19 
7.1.2. Study Days 1-2 (In-patient) ................................................................................ 20 
7.1.3. Day 7 Follow-up Visit ......................................................................................... 21 
7.1.4. Day 14 Follow-up Visit ....................................................................................... 21 
7.1.5. Day 28 Follow-up Visit ....................................................................................... 22 
7.1.6. Day 29 Follow-up Visit ....................................................................................... 23 
7.2. Laboratory Assessments ................................................................................................. 23 
7.2.1. Clinical Laboratory Tests .................................................................................... 23 
7.2.2. Preparation of Whole Blood Samples for PTI-125DX and mTOR ....................... 23 
7.2.3. Preparation of Plasma Samples for Pharmacokinetic Determination .................. 24 
7.2.4. CSF assays ........................................................................................................ 24 
8. 
EARLY DISCONTINUATION ................................................................................. 24 
9. 
ADVERSE EVENTS/SERIOUS ADVERSE EVENTS ................................................. 25 
9.1. Adverse Events - Definition ............................................................................................. 25 
9.2. Adverse Events - Severity Rating .................................................................................... 26 
9.3. Adverse  Events  -  Relationship to  Study Drug .................................................................. 26 
9.4. Serious Adverse Events and Unexpected Adverse Events - Definitions ............................... 27 
9.5. Serious Adverse Events Reporting ................................................................................... 27 


 
Pain Therapeutics, Inc. 
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PTI-125, a novel small molecule for AD 
CONFIDENTIAL 
05 February 2019  
 
 
Page 9 of 48 
 
 
 
Amendment #2 Final 
 
10. 
STATISTICAL CONSIDERATIONS ......................................................................... 28 
10.1. Analysis Populations ...................................................................................................... 28 
10.2. Pharmacokinetic Parameters ........................................................................................... 28 
10.3. Statistical Analysis ......................................................................................................... 29 
10.4. Safety Analysis .............................................................................................................. 29 
10.5. Sample Size .................................................................................................................. 30 
11. 
STUDY TERMINATION ......................................................................................... 30 
12. 
DATA COLLECTION, RETENTION AND MONITORING ........................................ 30 
12.1. Case Report Forms ......................................................................................................... 30 
12.2. Availability and Retention of Investigational Records ....................................................... 30 
12.3. Subject Confidentiality ................................................................................................... 31 
12.4. Liability ........................................................................................................................ 31 
12.5. Ethical and Legal Issues ................................................................................................. 31 
12.5.1. Institutional Review Board .................................................................................. 31 
12.6. Informed Consent Form .................................................................................................. 32 
13. 
INVESTIGATOR RESPONSIBILITIES ................................................................... 32 
14. 
REFERENCES ...................................................................................................... 33 
15. 
Appendix A ........................................................................................................... 34 
16. 
Appendix B ........................................................................................................... 35 
 


Pain Therapeutics, Inc. 
Clinical Protocol PTI-125-03 
PTI-125, A small molecule to treat AD 
CONFIDENTIAL 
05 February 2019  
 
Page 10 of 48 
 
 
 
 
Amendment #2 Final 
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 
ANOVA 
 
 
analysis of variance 
AST   
 
 
aspartate transaminase 
AUC  
 
 
area under the curve 
BEHAVE-AD  
 
behavioral pathology in Alzheimer’s disease rating scale 
BUN  
 
 
blood urea nitrogen 
CFR 
 
 
 
Code of Federal Regulations 
Cmax  
 
 
maximum plasma concentration 
CRF 
 
 
 
case report form 
CRO  
 
 
contract research organization 
CSF 
 
 
 
cerebrospinal fluid 
C-SSRS 
 
 
Columbia-Suicide Severity Rating Scale 
CT 
 
 
 
computed tomography 
DSMB/DMC  
 
Data Safety Monitoring Board/Data Monitoring Committee 
ECG  
 
 
electrocardiogram 
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 
LOQ  
 
 
limit of quantitation 


Pain Therapeutics, Inc. 
Clinical Protocol PTI-125-03 
PTI-125, A small molecule to treat AD 
CONFIDENTIAL 
05 February 2019  
 
Page 11 of 48 
 
 
 
 
Amendment #2 Final 
MATE1 
 
 
multidrug and toxin extrusion protein 1 
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 
OTC  
 
 
over-the-counter 
PK 
 
 
 
pharmacokinetics 
PTI 
 
 
 
Pain Therapeutics, Inc. 
PTI-125 
 
 
small molecule drug candidate to treat AD 
PTI-125DX 
 
 
blood-based diagnostic/biomarker 
QS 
 
 
 
quantity sufficient 
RBC  
 
 
red blood cell 
SAD  
 
 
single ascending dose 
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  
 
 


Pain Therapeutics, Inc. 
Clinical Protocol PTI-125-03 
PTI-125, A small molecule to treat AD 
CONFIDENTIAL 
05 February 2019  
 
Page 12 of 48 
 
 
 
 
Amendment #2 Final 
 
2. INTRODUCTION 
Pain Therapeutics Inc. (PTI) 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 aberrantly 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 20-22 mg/kg/day (equivalent to 60 and 66 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 general toxicity studies in rats and 
dogs. In a 28-day repeat dose oral general toxicity study followed by a 28-day drug-free 
recovery period in rats, 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. There were no other adverse 


Pain Therapeutics, Inc. 
Clinical Protocol PTI-125-03 
PTI-125, A small molecule to treat AD 
CONFIDENTIAL 
05 February 2019  
 
Page 13 of 48 
 
 
 
 
Amendment #2 Final 
effects and all biologically significant findings noted during the dosing period were 
resolved at the end of the 28-day recovery period. A no-observed-effect-level (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).  
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).  
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.  
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. On Day 4, this dose was reduced to 150 mg/kg/day, and the high dose, 1000 
mg/kg/day, was reduced to 200 mg/kg/day. Convulsions were not observed in the 
1000/200 mg/kg/day animals.  
A first-in-human (FIH) Single Ascending Dose (SAD) clinical trial was conducted in 
healthy normal volunteers, age 18-45 with oral dosing solution. Doses were 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). 
This study in mild-to-moderate AD patients will use a 100 mg b.i.d. dose, based on dog-
to-human dose exposure scaling between both 28-day and 13-week repeat dose oral 
toxicity studies in dog and the exposure levels from the SAD study in volunteers. Safety 
margins of the human exposure levels from 50, 100 and 200 mg by Cmax over the NOAEL 
in the 13-week dog study were 55-fold for the 200 mg dose and ≥125-fold for the 100 mg 
dose by Cmax or AUC0-last. Additionally, an accumulation ratio using elimination rate 
constants from the SAD study predicted minimal accumulation with b.i.d. dosing. 


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3. STUDY OBJECTIVES 
The objectives of this study are to investigate the safety, pharmacokinetics and effect on 
biomarkers of PTI-125 following 28-day repeat-dose oral administration in mild-to-
moderate AD patients, 50-85 years of age, within an MMSE range of ≥ 16 and ≤ 24. 
4. SUMMARY OF STUDY DESIGN 
This is a Phase 2a, multi-center, open-label study of PTI-125 in mild-to-moderate AD 
patients, 50-85 years of age. A total of twelve (12) patients will be enrolled into the 
study. Patients will receive 100 mg b.i.d. of PTI-125. 
The study includes a screening period (Day -30 to Day -1). Patients meeting initial 
screening criteria, including a Mini-Mental State Examination (MMSE) score ≥ 16 and ≤ 
24 will subsequently undergo 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. The BEHAVE-AD psychological test and the Columbia Suicide 
Severity Rating Scale (C-SSRS) will be administered during this second screening visit, 
and on Day 28 (and for BEHAVE-AD, also on Day 14).  
Patients will report to clinic on Study Day 1 and will return for visits on Days 7, 14, 28 
and 29.  
PK blood samples will be obtained prior to the first and last doses (Day 1 and Day 28) 
and at timepoints through 24 h after the first and last dose. Additional PK blood samples 
will be obtained prior to the first dose on Days 7 and 14 for Cmin values. PK parameters 
will be calculated using non-compartmental analysis.  
Clinical laboratory testing (blood and urine) will be performed at screening, prior to 
dosing on Day 1, and on Days 7, 14 and 29. Safety assessments of vital signs and 
listening to heart and lungs and ECGs will also be conducted on Days 7 and 14. Baseline 
and final ECGs will be conducted on Day 1 (pre-dose) and on Day 29, respectively. 
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 (pre-dose), 
Day 14 and Day 28. A CSF sample collection will be performed on Day 28 for Aβ/tau, 
YKL40 and other potential CSF biomarker assays as well as bioanalysis of PTI-125. 
An 
independent 
Data Safety Monitoring Board/Data Monitoring Committee 
(DSMB/DMC) will be established and will meet periodically to review patient safety 
assessments and determine if dosing may continue. 


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Clinical Protocol PTI-125-03 
PTI-125, A small molecule to treat AD 
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05 February 2019  
 
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5. SUBJECT SELECTION 
5.1. STUDY POPULATION 
A total of twelve (12) patients will be enrolled in the study (male and female).  
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. 
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 ≤ 24 at screening 
5. If female and last natural menses < 24 months or uncertain, post-
menopausal status should be confirmed by serum FSH. 
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.  
10. The patient is a non-smoker for at least 12 months.  
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 an Aβ/tau Index in CSF that indicates AD. This value (total tau/Aβ42) 
will be ≥ 0.30. 
13. Patient has a caregiver or legal representative responsible for administering the drug 
and recording the time. 


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05 February 2019  
 
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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. Residence in a skilled nursing facility 
3. Clinically significant laboratory test results 
4. Clinically significant untreated hypothyroidism (if treated, thyroid-stimulating 
hormone level and thyroid supplementation dose must be stable for at least 6 months 
before screening) 
5. Insufficiently controlled diabetes mellitus or requiring insulin 
6. Renal insufficiency (serum creatinine >2.0 mg/dL) 
7. 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) 
8. History of ischemic colitis or ischemic enterocolitis 
9. Unstable medical condition that is clinically significant in the judgment of the 
investigator 
10. Alanine transaminase (ALT) or aspartate transaminase (AST) >2 times the upper limit 
of normal or total bilirubin greater than the ULN.  
11. History of myocardial infarction or unstable angina within 6 months before screening 
12. History of more than 1 myocardial infarction within 5 years before screening 
13. Clinically significant cardiac arrhythmia (including atrial fibrillation), 
cardiomyopathy, or cardiac conduction defect (patients with a pacemaker are 
acceptable) 
14. Symptomatic hypotension, or uncontrolled hypertension  
15. 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.  
16. Stroke within 18 months before screening, or history of a stroke concomitant with 
onset of dementia 
17. History of brain tumor or other clinically significant space-occupying lesion on CT or 
MRI 


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18. Head trauma with clinically significant loss of consciousness within 12 months before 
screening or concurrent with the onset of dementia 
19. Onset of dementia secondary to cardiac arrest, surgery with general anesthesia, or 
resuscitation 
20. Specific degenerative CNS disease diagnosis other than AD (eg, Huntington's disease, 
Creutzfeld-Jacob disease, Down's syndrome, Frontotemporal Dementia, Parkinson's 
disease) 
21. Wernicke's encephalopathy 
22. Active acute or chronic CNS infection 
23. Donepezil 23 mg or greater QD currently or within 3 months prior to enrollment in 
the study 
24. Discontinued AChEI < 30 days prior to enrollment in the study 
25. 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 enrollment in the study 
26. 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 
enrollment in the study 
27. 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 enrollment in the study 
28. Peripherally acting drugs with effects on cholinergic transmission 
29. Immunosuppressants, including systemic corticosteroids, if taken in clinically 
immunosuppressive doses (Steroid use for allergy or other inflammation is 
permitted.) 
30. Antiepileptic medications if taken for control of seizures 
31. Chronic intake of opioid-containing analgesics 
32. Sedating H1 antihistamines 
33. Nicotine therapy (all dosage forms including a patch), varenicline (Chantix), or 
similar therapeutic agent within 30 days before screening 
34. Clinically significant illness within 30 days of enrollment  
35. History of significant neurological, hepatic, renal, endocrine, cardiovascular, 
gastrointestinal, pulmonary, or metabolic disease  


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05 February 2019  
 
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36. Positive serum hepatitis B surface antigen (HBsAg) or positive hepatitis C virus HCV 
antibody test at screening  
37. Positive HIV test at screening  
38. Loss of a significant volume of blood (> 450 mL) within 4 weeks prior to the study 
39. Metformin or cimetidine. PTI-125 is a marginal/weak inhibitor of the multidrug and 
toxin extrusion protein 1 (MATE1) transporter. 
6. STUDY DRUG 
6.1. PTI-125 PHYSICAL DESCRIPTION AND PREPARATION 
Investigational PTI-125 will be supplied by PTI 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 receive 100 mg PTI-125 b.i.d. 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. 


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PTI-125, A small molecule to treat AD 
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05 February 2019  
 
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Amendment #2 Final 
Prior to any study-related activities, the Informed Consent Form must be signed and 
dated by the patient or legal representative. 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). Appendix B contains a sample Informed Consent 
for this study. The signed and dated Informed Consent Form must be retained by the 
Investigator in the subject's file. 
7.1. EVALUATIONS BY VISIT 
7.1.1. Screening Period 
The following will be completed within 30 days prior to administration of the 
study medication: 
• Informed Consent. If Informed Consent is signed by a legally authorized 
representative, patient capacity must be noted. 
• Review of Inclusion and Exclusion Criteria 
• Medical history 
• Review of concomitant medications 
• 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. 
• MMSE evaluation  
• If female, negative FSH test if >60 years and last natural menses 
was < 24 months prior to screening 
If meeting all other criteria: 
• CSF sample collection (5 mL) 
• BEHAVE-AD test 
2. Columbia Suicide Severity Rating Scale (C-SSRS) NOTE: For patients determined 
by C-SSRS to have suicidality tendencies, inform the patient’s primary care physician 
and refer the patient for follow-up.  
 


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7.1.2. Study Days 1-2 (In-patient) 
Note:  Study Day 1  is defined as the day of dosing initiation. Clinic visits on Study 
days 7, 14 and 28 can occur +/- 2 days of the designated day. The clinic visit on Day 
29 will immediately follow the Day 28 visit. 
 
Patients will come to the clinic the morning of Study Day 1. Within 1 h prior to 
dosing, the following assessments will be conducted:  
• 
Confirmation of inclusion/exclusion criteria 
• Review of concomitant medications 
• Brief physical examination 
• ECG 
• Blood drawn for PTI-125DX and mTOR assessments (8 mL whole blood) 
• 
Blood sample collection for baseline PK assessment (Sample Time=0) 
• 
Clinical laboratory tests (blood and urine) 
Patients will be administered 100 mg PTI-125 b.i.d. 1-2 h before breakfast.  
After the first dose on Study Day 1, the following assessments will be conducted: 
• Vital signs (blood pressure, temperature, pulse and respiratory rate) at 
approximately 10 and 30 min, and 1, 2, 4, 8 and 12 h post-dose.  
• Blood samples will be drawn at 20, 40, and 60 min and at 1.5, 2, 2.5, 3, 
4, 6, 8, 10 and 12 h after the first dose for PK assessments. Please note 
that the 12 h PK samples will be collected prior to the second dose. 
• Adverse event monitoring 
After the second dose on Study Day 1 (administered 12 h after the first), the following 
assessments will be conducted: 
• 
Vital signs (blood pressure, temperature, pulse and respiratory rate) at 30 
min, 1 and 2 h after this second dose. 
On the morning of Study Day 2, 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 on Study Day 2, the following assessments will be conducted: 


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Clinical Protocol PTI-125-03 
PTI-125, A small molecule to treat AD 
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05 February 2019  
 
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• Vital signs (blood pressure, temperature, pulse and respiratory rate) 
• Listen to heart and lungs  
• Adverse event monitoring 
• ECG  
            Should procedures occur at the same nominal timepoint, collection of the PK 
assessment will take priority. All other procedures will be performed within a 
sufficient +/- window for logistical purposes.  
 
Clinic personnel will monitor the patients for the occurrence of any adverse events 
until patients are discharged from the clinic. Patients will be discharged from the 
clinic on Day 2 upon investigator judgment. They will leave with their bottle of Study 
Drug and be instructed to take one tablet each morning and evening, 1-2 h before or 
after a meal. 
For 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. They will be instructed to bring 
their bottle of Study Drug for each visit and will receive a new bottle on Day 7 and two new 
bottles on Day 14.  
7.1.3. Day 7 Follow-up Visit 
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 assessments will be conducted: 
• Vital signs (blood pressure, temperature, pulse and respiratory rate) 
• Listen to heart and lungs 
• ECG 
• Adverse event monitoring 
7.1.4. Day 14 Follow-up Visit 
Patients will return to clinic the morning of Study Day 14 for the assessments listed 
below. 
On the morning of Study Day 14, within 30 min prior to dosing, the following 
assessments will be conducted: 


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Clinical Protocol PTI-125-03 
PTI-125, A small molecule to treat AD 
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05 February 2019  
 
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• 
Blood sample collection for PK assessment (for Cmin) 
• 
Blood sample collection for PTI-125DX, mTOR and other biomarkers 
• Clinical laboratory tests (blood and urine) 
After dose, the following assessments will be conducted: 
• Vital signs (blood pressure, temperature, pulse and respiratory rate) 
• Listen to heart and lungs 
• Adverse event monitoring 
• ECG 
• BEHAVE-AD test 
7.1.5. Day 28 Follow-up Visit 
Patients will return to the clinic on Study Day 28, prior to the morning dose, which 
will be the LAST dose of the study. 
On the morning of Study Day 28, within 30 min prior to dosing, the following 
assessments will be conducted: 
• 
Blood sample collection for PK assessment (Sample Time=0) 
• 
Blood sample collection for PTI-125DX, mTOR and other biomarkers 
After dose on Study Day 28, the following assessments will also be conducted: 
• Vital signs (blood pressure, temperature, pulse and respiratory rate)  
• Blood samples will be drawn at 20, 40, and 60 min and 1.5, 2, 2.5, 3, 4, 
6, 8, 10 and 12 h after the single dose on Day 28 for PK assessments.  
• CSF draw 
• Adverse event monitoring 
• BEHAVE-AD test 
Columbia Suicide Severity Rating Scale (C-SSRS)  NOTE: For patients determined 
by C-SSRS to have suicidality tendencies, inform the patient’s primary care physician 
and refer the patient for follow-up.  
CSF sample collection (5 mL) on Study Day 28 will occur 1-2 h after dosing, and the 
nearest plasma PK sample collection will be noted. The CSF samples will be tested 
for PTI-125 levels as well as the Aβ/tau Index, YKL40, inflammatory cytokines and 
other biomarkers. 


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PTI-125, A small molecule to treat AD 
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05 February 2019  
 
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Should procedures occur at the same nominal timepoint, collection of the plasma PK 
assessment will take priority. All other procedures will be performed within a 
sufficient +/- window for logistical purposes.  
All meals will be served at standard meal times. Patients can leave the clinic after the 
12-h blood draw and will return prior to the 24-h blood draw on Day 29. 
7.1.6. Day 29 Follow-up Visit 
On Study Day 29, patients will return to the clinic for the following assessments: 
• 
Blood sample collection for PK assessment (24 h after the last dose) 
• Clinical laboratory tests (blood and urine) 
• ECG 
• Full physical exam 
7.2. LABORATORY ASSESSMENTS 
7.2.1. Clinical Laboratory Tests 
The following clinical laboratory tests will be performed at screening, Day 1 pre-dose, 
Day 2 and at follow-up visits on Day 7, 14 and 29: 
 
• Hematology:  white blood cell (WBC) count with differential, red blood 
cell (RBC) count, hemoglobin, hematocrit, platelet count. 
• Serum Chemistry:  glucose, sodium, potassium, chloride, bicarbonate, 
blood urea nitrogen (BUN), creatinine, uric acid, phosphorus, calcium, 
total 
protein, albumin, 
globulin, 
alkaline 
phosphatase, 
alanine 
transaminase (ALT), aspartate transaminase (AST), gamma glutamyl 
transpeptidase (GGT), total bilirubin, lactose dehydrogenase (LDH). 
• Urinalysis: color, specific gravity, pH, protein, sugar, ketones, occult 
blood, creatinine clearance calculation by Cockcroft-Gault equation. 
 
7.2.2. Preparation of Whole Blood Samples for PTI-125DX and mTOR 
Blood samples to be assessed in the PTI-125DX assay and the mTOR assay (8 mL 
total) will be drawn into a Vacutainer® tube containing K2EDTA. Collection will 
occur on Days 1 (pre-dose), 14 and 28. The tubes will be placed immediately on 
ice and shipped AS WHOLE BLOOD at 2-8°C within 24-48 h to: Dr. Hoau-Yan 
Wang, CUNY School of Medicine, SOM CDI 3370, 85 St. Nicolas Terrace, New 
York, NY 10031. 


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PTI-125, A small molecule to treat AD 
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05 February 2019  
 
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7.2.3. 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 
minutes between 4-5°C. Within 30 minutes 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, 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.   
 
7.2.4. CSF assays 
CSF samples should be split, with 2.5 mL of all samples shipped to Dr. Wang at 
CUNY and, for Day 28 only, an additional 0.5 mL shipped to Worldwide Clinical 
Trials. The remaining 2.0 mL will be retained at the study site at -20°C until otherwise 
informed by the Sponsor. All samples will be shipped frozen on dry ice. 
The samples will be collected using polypropylene screw-cap tubes (e.g. Sarstedt® 13 
ml, 101 x 16.5 mm tubes) at the second screening visit and on Study Day 28. Samples 
shipped to Dr. Hoau-Yan Wang, (CUNY School of Medicine, SOM CDI 3370, 85 St. 
Nicolas Terrace, New York, NY 10031) will be tested in several biomarker assays 
including: 
• Abeta 
• Tau, ptau 
• YKL40 
• IL-6, TNFα and IL-1β 
CSF samples (0.5 mL) from Study Day 28 will be shipped to Worldwide Clinical 
Trials Bioanalytical Sciences (8609 Cross Park Drive, Austin, TX 78754) to be 
assayed for the PTI-125 analyte using a qualified assay.  
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 will not be replaced. 
The following must be completed and documented in the source documents and CRFs 
for all patients who discontinue the study early: 


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• 
The reason for early study discontinuation. 
• 
Full physical examination  
• 
Clinical laboratory tests (blood and urine)  
• 
ECG  
• 
Adverse events 
• 
Blood draw for PTI-125DX and other biomarkers 
• 
BEHAVE-AD 
• 
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 Case Report Form (CRF) and in the subject's 
clinical chart. 
In the event that a subject is withdrawn from the study because of an AE, it must be 
recorded on the CRF as such. The subject should be followed and treated by the 
Investigator until the abnormal parameter or symptom has resolved or stabilized. 


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The Investigator must report all directly observed AEs and all spontaneously reported 
AEs. The Investigator will ask the subject a non-specific question (e.g., "Have you 
noticed anything different since your dose of the study medication?") to assess 
whether any AEs have been experienced since the last assessment. AEs will be 
identified and documented 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). 
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 CRF. 


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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 
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) to: 


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Nadav Friedmann, PhD, MD 
Pain Therapeutics, Inc.  
Email: nfriedmann@paintrials.com 
Phone:    925-788-4585 
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. ANALYSIS POPULATIONS 
All patients who receive study medication will be included in safety analyses. All 
patients who have sufficient data for PK analysis will be included in the PK analysis 
population.  
10.2. PHARMACOKINETIC PARAMETERS 
Plasma PK parameters for PTI-125 will be calculated using non-compartmental 
methods in WinNonlin. The peak drug concentration (Cmax), the time to peak drug 
concentration (Tmax), Tlast and Clast, the time to and concentration of the last quantifiable 
drug concentration, will be obtained directly from the data without interpolation The 
following parameters will be calculated: the elimination rate constant (z), the terminal 
elimination half-life (T1/2), the AUC from time zero to the time of the last quantifiable 
concentration (AUClast), the AUC from time zero extrapolated to infinity (AUCinf), and 
the percentage of AUCinf based on extrapolation (AUCextrap(%)), Cl/F, the apparent oral 
clearance, and Vz/F, apparent volume of distribution. Accumulation will be estimated 
based by the ratios of the AUC on the last day of dosing to the corresponding AUC the 


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first day of dosing. Time to steady state may be estimated, if possible, based on Cmin 
blood samples taken on Days 7, 14, and 28, prior to the first dose of the day. 
In the PK analysis, below limit of quantitation (BLQ) concentrations will be treated as 
zero from time-zero up to the time at which the first quantifiable concentration was 
observed; embedded and/or terminal BLQ concentrations will be treated as “missing”. 
Full precision concentration data (not rounded to three significant figures) and actual 
sample times will be used for all pharmacokinetic and statistical analyses. Nominal 
sampling times will be used to prepare concentration versus time profiles. 
 
CSF concentrations of PTI-125 will be measured using a qualified assay. A CSF to 
plasma ratio will be determined if possible, using the nearest plasma timepoint. 
10.3. STATISTICAL ANALYSIS 
Comparison of the PK parameters Cmax, AUClast, and AUCinf (if possible) for PTI-125 
between the first and last Day of dosing will be done using an analysis of variance 
(ANOVA) model with factors for subject and day as the classification variables, 
using the natural logarithms of the data. Confidence intervals (90%) will be constructed 
for the ratios of the last Day and first Day of dosing for both parameters using the log-
transformed data and the two-one-sided t-tests procedure. The point estimates and 
confidence intervals will be exponentiated back to the original scale. The point estimate 
for Cmax will provide an estimate of the extent of accumulation between the first and 
last Day of dosing. 
 
Biomarker endpoints to be analyzed include: 1) the CSF Aβ/tau Index, 2) CSF ptau/tau, 
3) CSF YKL40 4) CSF IL-6, TNFα and IL-1β 5) PTI-125DX lymphocyte assay, and 6) 
PTI-125DX plasma assay, and 7) a lymphocyte mTOR assay. These data will be 
analyzed by repeated measures ANOVA. 
 
Although not powered for efficacy, cognitive/behavioral endpoint to be analyzed will be 
the BEHAVE-AD to assess behavioral/psychological symptoms of dementia. These 
data will also be analyzed by repeated measures ANOVA. 
 
10.4. SAFETY ANALYSIS 
Adverse events reported on case report forms will be mapped to preferred terms and 
organ systems using the MedDRA mapping system. Vital signs and clinical 
laboratory results will be descriptively summarized in terms of change from 
screening values. 


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10.5. SAMPLE SIZE 
Twelve (12) 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 
Case report forms (CRFs) will be provided 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. 
All clinical information requested in this protocol will be recorded in the CRFs 
provided by PTI. In case of error, the correction will be noted, initialed and dated. 
CRFs must be reviewed and verified for accuracy by the Principal Investigator and 
signed-off before collection by the Sponsor (or CRO designee). A copy of the CRF 
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 CRFs, 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 CRF. 
Investigators are required to maintain all study documentation until notification by 
PTI that any records may be discarded. 
The Investigator is responsible for maintaining adequate case histories in each 
subject's source records.  


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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 Study 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 
Compensation of any type will be provided by the study 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. 


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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 is 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. 
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 


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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. 
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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15.  APPENDIX A 
Events Schedule 
PROCEDURE 
SCREENING  
(Days -29 to 
Day 0) 
DAY  
1 
DAY 
2 
DAY 
7 
DAY 
14 
DAY 
28  
DAY 
29 
Informed consent 
X 
 
 
 
 
 
 
Medical and 
medication 
histories 
X 
 
 
 
 
 
 
ECG  
X 
X 
X 
X 
X 
 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
 
Physical 
examination 
X 
Brief 
* 
* 
* 
 
X 
FSH Test ** 
X 
 
 
 
 
 
 
Biochemistry, 
hematology, 
urinalysis 
X 
X 
X 
X 
X 
 
X 
MMSE  
X 
 
 
 
 
 
 
HCV, HBsAg & 
HIV screen 
X 
 
 
 
 
 
 
Drug 
administration 
 
X 
X 
X 
X 
X 
 
Blood sample 
collection for PK 
analysis 
 
X 
X 
X 
X 
X 
X 
Adverse events 
 
X 
X 
X 
X 
X 
X 
Discharge 
 
 
X 
 
 
 
 
Blood draw PTI-
125DX, mTOR 
 
X 
 
 
X 
X 
 
Behave AD 
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, post-menopausal 
status should be confirmed by serum FSH. 


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16. APPENDIX B 
 
INFORMED CONSENT DOCUMENT 
AGREEMENT TO BE IN A RESEARCH STUDY 
 
NAME OF SPONSOR COMPANY: 
Pain Therapeutics, Inc. 
 
PROTOCOL NUMBER AND TITLE OF STUDY: PTI-125-02: 
“A Phase 2a, Open-label, Multiple Dose,  
Safety, Pharmacokinetic and Biomarker Study  
of PTI-125 in Mild-to-Moderate AD patients” 
 
NAME OF PERSON IN CHARGE OF THE RESEARCH  
STUDY (STUDY DOCTOR/INVESTIGATOR):  M.D. 
 
TELEPHONE NUMBER(S), DAYTIME:               (Monday-Friday, 8:00 a.m.-5:00 p.m.) 
AFTER HOURS: 
  
 
INTRODUCTION 
You are being invited to volunteer for a medical research study. You must read and sign 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 investigator is being paid by the sponsor (the company paying for this study) to conduct 
this research study. 
 
You must be honest with the investigator about your health history or you may harm yourself by 
participating in this study. 
 
The study drug has previously been given to healthy volunteers as ONE SINGLE DOSE. 
There were no drug-related side effects. THIS IS THE FIRST STUDY IN WHICH THE 
STUDY DRUG IS BEING GIVEN AS A REPEATED, DAILY DOSE. 
 
PURPOSE OF THE STUDY 
In this document, you may see the terms “medication”, “treatment”, and “treatment period”; 
these are terms used in research studies as mentioned above.  This does not mean that you 
will be receiving medical treatment for any condition. These terms apply to the 


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investigational study drug and parts of the study where you will be receiving this 
investigational product. 
 
The purpose of this study is to measure the blood levels of Pain Therapeutics, Inc.’s new 
investigational drug PTI-125, and to determine if there are any side effects associated with 
the drug when taken daily for a 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). 
 
If you qualify for the study, you will receive PTI-125 (investigational product). You will 
receive your dose twice a day for 28 days.  
 
This is an open-label study, which means that all patient participants will be taking PTI-125.   
 
 
HOW LONG THE STUDY WILL LAST AND HOW MANY PEOPLE WILL BE IN 
THE STUDY 
The study will last about 28 days, excluding the screening period, and involve 1 night at 
the facility. You will also be required to make follow-up visits to the facility at least four 
times during the 28 days. About 12 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.  
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 donated blood within 4 weeks before the first dose of study formulation 
 
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 investigator or the study staff if you change your mind about staying in the study. 
 
This study involves testing an investigational drug developed by the sponsor. We ask patients 
to keep information as confidential as possible. This would 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 


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enrolled in the study, with persons other than the clinic staff, your family and your healthcare 
provider. This would also include not disclosing such information on social media sites or 
webpages. 
 CAREGIVER PARTICIPATION 
As required by the study, every patient 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 (e.g. 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. 
 
WHAT WILL HAPPEN DURING THE STUDY 
Screening 
 
Before the study starts, you will be asked to sign 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 investigator 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   


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• 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  
• Memory testing – Mini Mental State Exam 
• 
If female and last natural menses < 24 months or uncertain, post-menopausal status should 
be confirmed by serum FSH. 
 
The Screening Visit may take up to 2 hours and 30 minutes of your time. 
 
• If you meet the criteria above, 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 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).  
 
If you qualify for the study, you will return to the clinic to start the study. You will need to 
stay in the clinic the first night after receiving study drug (active or placebo) and part of the 
following day before being discharged from the clinic. 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 clinic on the 7th and 14th days of the 
study for up to 2 hours. During these two hours the following testing may be performed: 
ECG, vital signs, listening to your heart and lungs, blood draws and some 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 and a 
blood draw 12 hours after your last dose. You will return the next morning for one final 
blood draw, 24 hours after your last dose, an ECG and a physical examination. 
 
Study Procedures 
 
In-clinic Periods (Days 1-2) and 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 
• You will have a brief physical exam including vital signs (blood pressure, heart rate, 
breathing rate and temperature)  
• You will have a behavioral/psychological test and a test for suicidal thoughts 
• You will have a blood draw for an experimental test to confirm your diagnosis and to 
measure other biomarkers such as mTOR. 
• You will have a blood draw for clinical laboratory tests. 


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After your first dose of Study Drug: 
• Standard meals will be given at scheduled times during your stay in the clinic 
• The level of study drug in your blood will be measured. About 3/4 teaspoon (4 mL) of 
blood will be taken during your stay in the study clinic at different timepoints during the 
days. 
• Vital Signs (temperature, blood pressure, heart rate and breathing rate) will be performed 
at multiple time points during the study. 
• A doctor or nurse will listen to your heart and lungs prior to discharge on Day 2 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, on Day 2 prior to discharge and at subsequent clinic 
visits on Days 14 and 29.  
• Lab tests will be conducted (blood and urine).  
• A blood draw to repeat the experimental test to confirm your diagnosis and to measure 
other blood-based biomarkers such as mTOR (Days 14 and 28). 
• A blood draw to determine your APOE genotype will be performed. You can choose not 
to know the results of this test.  
• You will be monitored for any side effects. 
• You will have a behavioral/psychological test and a test for suicidal thoughts. 
  
If you leave the study early or are withdrawn the following procedures will be performed:  
• Vital Signs (temperature, blood pressure, heart and breathing rates)  
• Physical examination  
• Lab tests (blood and urine)  
• Electrocardiogram (ECG)  
• Memory testing 
• 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 36 blood draws not including 3 blood draws during screening. The total 
amount of blood drawn in the study will be about 154 mL, or about 2/3 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. 


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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 
investigator 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 (i.e., cut, 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 investigator or 
study staff to explain these terms to you.  
 
Because this 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.  
  
In pre-clinical (animal studies) the following side effects were seen:  
• Vomiting  
• Increased salvation  
• Increased blood pressure  
• Weight loss 
• Changes to the size of the liver cells 
 
You must tell the investigator 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 
 


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If you have a side effect of the 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 sponsor. By signing 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 
• 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 
• bleeding at puncture site or rarely into epidural space 
 


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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. 
 
Men  
It is unknown if the drug used in this study may harm an unborn child.  You should not have 
sexual intercourse or you or your partner should use a method of birth control that is 
acceptable to you, the study doctor, and the sponsor during the study.  If you think that you 
have gotten a woman pregnant, you must tell the study doctor at once. If your partner gets 
pregnant during the study, she will be asked to sign a release of information form to allow 
your study doctor to contact her obstetrician to collect updates on the progress of the 
pregnancy and its outcome. The study doctor will make this information available to the 
study sponsor for safety monitoring follow-up. 
 
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 not intended to provide medical benefit to the participants. 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 


Pain Therapeutics, Inc. 
Clinical Protocol PTI-125-03 
PTI-125, A small molecule to treat AD 
CONFIDENTIAL 
05 February 2019  
 
Page 43 of 48 
 
 
 
 
Amendment #2 Final 
• Advarra IRB 
 
The Institutional Review Board (IRB), Advarra 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.  
IN CASE OF STUDY RELATED INJURY 
If you are injured while in this study, you should contact the study investigator 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 medical procedures that are 
required by the study and that are not standard of care. 
 
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. 
CONTACT INFORMATION 
If you have questions, concerns, or complaints about this study or to report a study related 
injury, contact: 
 
 
 
If you feel this emergency may be life-threatening, call 911. 
 
If you are unable to reach anyone at the number(s) listed above and you require 
immediate (life threatening) medical attention, please go to the nearest emergency 
room. 
 
If you do not want to talk to the investigator or study staff, if you have concerns or 
complaints about the research, or to ask questions about your rights as a study subject you may 
contact Advarra.  Advarra’s policy indicates that all concerns/complaints are to be submitted in 
writing for review at a convened IRB meeting to: 
 


Pain Therapeutics, Inc. 
Clinical Protocol PTI-125-03 
PTI-125, A small molecule to treat AD 
CONFIDENTIAL 
05 February 2019  
 
Page 44 of 48 
 
 
 
 
Amendment #2 Final 
 
 
                    Mailing Address:            OR            Website: 
Chairperson 
Advarra IRB 
6940 Columbia Gateway Drive, 
Suite 110 
Columbia, MD 21046 
 
 
https://www.advarra.com/contact-
us/ 
 
If you are unable to provide your concerns/complaints in writing or if this is an emergency 
situation regarding subject safety, contact Advarra at: 
 
410-884-2900 
between 8 a.m. and 5 p.m. Eastern Time  
Advarra has approved the information in this consent form and has given approval for the 
investigator to do the study. This does not mean Advarra has approved your being in the 
study.  You must consider the information in this consent form for yourself and decide if you 
want to be in this study. 
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 overnight stay (up to 3 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 screening visit.   
 
Should you be required to stay additional time in the research unit for safety follow up you 
will be compensated for your time based on the overnight compensation of $150.00 per 
overnight.  
 
No other payment will be offered to you.  You will receive your payment within two weeks 
of your final study visit. 
 


Pain Therapeutics, Inc. 
Clinical Protocol PTI-125-03 
PTI-125, A small molecule to treat AD 
CONFIDENTIAL 
05 February 2019  
 
Page 45 of 48 
 
 
 
 
Amendment #2 Final 
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 investigator, 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 investigator’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 
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 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.   
THE REASON FOR INSTITUTIONAL REVIEW BOARDS AND INFORMED 
CONSENT 
What is a consent form? 
The informed consent document contains information required by federal regulations.  The 
informed consent document must be approved by an Institutional Review Board (IRB). 
 
What is an Institutional Review Board (IRB)? 


Pain Therapeutics, Inc. 
Clinical Protocol PTI-125-03 
PTI-125, A small molecule to treat AD 
CONFIDENTIAL 
05 February 2019  
 
Page 46 of 48 
 
 
 
 
Amendment #2 Final 
An Institutional Review Board (IRB) is a group of people that reviews research studies.  The 
main goal of this review is to protect the rights and well-being of the patients participating in 
research studies. 
 
Advarra, the IRB for this study 
Advarra is an IRB whose board members provide IRB services worldwide. 
 
To meet requirements of the law, the Advarra Boards currently include:  
• Doctors  
• Pharmacists  
• Nurses  
• Toxicologists (people who study the harmful effects of chemicals)  
• Other specialists 
• Others who do not have a background in science/medicine 
 


Pain Therapeutics, Inc. 
Clinical Protocol PTI-125-03 
PTI-125, A small molecule to treat AD 
CONFIDENTIAL 
05 February 2019  
 
Page 47 of 48 
 
 
 
 
Amendment #2 Final 
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? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Pain Therapeutics, Inc. 
Clinical Protocol PTI-125-03 
PTI-125, A small molecule to treat AD 
CONFIDENTIAL 
05 February 2019  
 
Page 48 of 48 
 
 
 
 
Amendment #2 Final 
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. 
 
 
You will be given a signed and dated copy of this consent form to keep. 
 
 
 
You and your caregiver 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 Person Explaining Consent Form 
 
 
 
 
Signature of Person Explaining Consent Form 
Date  
Time (24-hour clock) 
 
 
 
Printed Name of Caregiver/Study Partner 
 
 
Signature of Caregiver/Study Partner 
Date 
Time (24-hour clock) 
 
  
 
 
Printed Name of Person Explaining Consent Form 
 
 
 
 
Signature of Person Explaining Consent Form 
Date  
Time (24-hour clock)