Conditions: Healthy Volunteers
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 24
Healthy volunteers: yes

Brief summary:
This study will compare the pharmacokinetics of the Phase 3 simufilam 100 mg oral tablet when taken fasted versus following a high-fat or low-fat meal. Additionally, the Phase 3 oral tablet will be compared to the Phase 2 oral tablet for bioequivalence under fasted conditions.

Detailed description:
This is a single-center, randomized, four-treatment, four-sequence crossover study in healthy volunteers to estimate the effect of food on the pharmacokinetics of simufilam following oral 100 mg Phase 3 oral tablets. Additionally, the relative bioavailability of the Phase 3 100 mg tablet will be compared to the earlier Phase 2 100 mg tablet in the fasted state. A total of twenty four (24) healthy volunteers (12 male and 12 female) will be enrolled into this study. Subjects will be randomly assigned to one of four treatment sequences (6 subjects/sequence).

Arms:
arm 1: This arm received Phase 2 tablet fasted (Period 1), Phase 3 tablet fasted (Period 2), Phase 3 tablet after a high-fat meal (Period 3), and Phase 3 tablet after a low-fat meal (Period 4). arm 2: This arm received Phase 3 tablet after a low-fat meal (Period 1), Phase 2 tablet fasted (Period 2), Phase 3 tablet fasted (Period 3), and Phase 3 tablet after a high-fat meal (Period 4). arm 3: This arm received Phase 3 tablet fasted (Period 1), Phase 3 tablet after a high-fat meal (Period 2), Phase 3 tablet after a low-fat meal (Period 3), and Phase 2 tablet fasted (Period 4). arm 4: This arm received Phase 3 tablet after a high-fat meal (Period 1), Phase 3 tablet after a low-fat meal (Period 2), Phase 2 tablet fasted (Period 3), and Phase 3 tablet fasted (Period 4).

Interventions: intervention 1: simufilam
Intervention descriptions: intervention 1: Simufilam 100 mg oral tablets: the Phase 3 oral tablet for the first 3 arms and the Phase 2 tablet for the 4th arm.

Protocol document:
Prot_000.pdf: 
Cassava Sciences, Inc. 
Clinical Protocol PTI-125-05 
Simufilam, a novel small molecule for AD 
March 5, 2021 
 
Page 1 of 35  
 
 
 
CONFIDENTIAL 
 
 
CLINICAL RESEARCH PROTOCOL 
PROTOCOL PTl-125-05 
 
A Four-way Crossover Food Effect and  
Bioequivalence Pharmacokinetic Study  
of Simufilam in Healthy Volunteers 
 
 
Sponsor:  
 
 
 
  Cassava Sciences, Inc. 
7801 N. Capital of Texas Hwy, Ste. 260 
Austin, TX 78731 
Phone: 512-501-1900 
 
Study Monitor: 
Nadav Friedmann, PhD, MD 
Chief Operating & Medical Officer  
Phone: 925-788-4585 
Email: nfriedmann@cassavasciences.com 
 
Project Manager: 
Lindsay Burns, PhD 
 
SVP, Neuroscience 
 
Phone:   512-501-2484 
 
Email:    lburns@cassavasciences.com 
 
Protocol Date: 
March 5, 2021 
 
 
Confidentiality 
The information contained in this document and all information provided to you related 
to simufilam ("Drug") are the confidential and proprietary information of Cassava 
Sciences, Inc. and except as may be required by federal, state, or local laws or 
regulations, may not be disclosed to others without prior written permission of Cassava 
Sciences. The Principal Investigator may, however, disclose such information to 
supervised individuals working on the Drug, provided such individuals agree to be 
bound to maintain the confidentiality of such Drug information. 




Cassava Sciences, Inc. 
Clinical Protocol PTI-125-05 
Simufilam, a novel small molecule for AD 
March 5, 2021 
 
Page 3 of 35  
 
 
 
CONFIDENTIAL 
 
Cassava Sciences, Inc. 
CLINICAL RESEARCH PROTOCOL 
 
 
 
 
A Four-way Crossover Food Effect and  
Bioequivalence Pharmacokinetic Study  
of Simufilam in Healthy Volunteers 
 
 
 
 
 
Signature of Agreement for Protocol PTI-125-05 
 
 
 
I have read this protocol and agree to conduct the study as outlined herein, in 
accordance with Good Clinical Practice (GCP) and complying with the obligations 
and requirements of clinical investigators and all other requirements listed in 21 
CFR part 312. 
 
 
 
 
 
 
 
 
Principal Investigator Signature 
Date 
 
 
 
 
 
 
Print Principal Investigator Name and Title 


Cassava Sciences, Inc. 
Clinical Protocol PTI-125-05 
Simufilam, a novel small molecule for AD 
March 5, 2021 
 
Page 4 of 35  
 
 
 
CONFIDENTIAL 
Table of Contents 
1. 
LIST OF ABBREVIATIONS .................................................................................... 6 
2. 
INTRODUCTION ................................................................................................... 8 
2.1. Mechanism of action ........................................................................................................ 8 
2.2. Safety pharmacology and toxicology ................................................................................. 8 
2.3. Clinical studies ................................................................................................................ 9 
3. 
STUDY OBJECTIVES .......................................................................................... 12 
4. 
SUMMARY OF STUDY DESIGN ......................................................................... 12 
5. 
SUBJECT SELECTION ....................................................................................... 13 
5.1. Study Population ........................................................................................................... 13 
5.2. Inclusion Criteria ........................................................................................................... 13 
5.3. Exclusion Criteria .......................................................................................................... 13 
5.4. Birth Control ................................................................................................................. 14 
6. 
STUDY DRUG ..................................................................................................... 15 
6.1. Simufilam Physical Description and Preparation .............................................................. 15 
6.1.1. Storage .............................................................................................................. 15 
6.1.2. Drug Accountability ............................................................................................ 15 
6.2. Administration and Dosing Regimen ............................................................................. 15 
6.3. Concomitant Medications ................................................................................................ 16 
6.4. STUDY PROCEDURES ................................................................................................ 16 
6.5. Evaluations by Visit ....................................................................................................... 16 
6.5.1. Screening Period ................................................................................................ 16 
6.5.2. Check-in (Day 0) ................................................................................................ 17 
6.5.3. Treatment Period 1 – Day 1 ............................................................................... 17 
6.5.4. Washout Periods – Days 2, 4 and 6 .................................................................. 18 
6.5.5. Treatment Periods 2, 3 and 4 – Days 3, 5 and 7 ............................................... 18 
6.5.6. Day 8 .................................................................................................................. 19 
6.6. Laboratory Assessments ................................................................................................. 20 
6.6.1. Clinical Laboratory Tests .................................................................................... 20 
6.6.2. Preparation of Plasma Samples for Pharmacokinetic Determination ................ 20 
7. 
EARLY DISCONTINUATION ............................................................................... 20 
8. 
ADVERSE EVENTS/SERIOUS ADVERSE EVENTS ......................................... 21 
8.1. Adverse Events - Definition ............................................................................................ 21 
8.2. Adverse Events - Severity Rating .................................................................................... 22 


Cassava Sciences, Inc. 
Clinical Protocol PTI-125-05 
Simufilam, a novel small molecule for AD 
March 5, 2021 
 
Page 5 of 35  
 
 
 
CONFIDENTIAL 
8.3. Adverse  Events  -  Relationship to  Study  Drug ............................................................... 22 
8.4. Serious Adverse Events and Unexpected Adverse Events - Definitions .............................. 22 
8.5. Serious Adverse Events Reporting .................................................................................. 23 
9. 
STATISTICAL CONSIDERATIONS ..................................................................... 24 
9.1. Randomization .............................................................................................................. 24 
9.2. Analysis Populations ...................................................................................................... 24 
9.3. Pharmacokinetic Analysis .............................................................................................. 24 
9.4. Safety Analysis .............................................................................................................. 25 
9.5. Sample Size .................................................................................................................. 26 
10. 
STUDY TERMINATION ....................................................................................... 26 
11. 
DATA COLLECTION, RETENTION AND MONITORING ...................................... 26 
11.1. Case Report Forms ......................................................................................................... 26 
11.2. Availability and Retention of Investigational Records ....................................................... 26 
11.3. Subject Confidentiality ................................................................................................... 27 
11.4. Liability ........................................................................................................................ 27 
11.5. Ethical and Legal Issues ................................................................................................. 27 
11.5.1. Institutional Review Board .................................................................................. 27 
11.6. Informed Consent Form ................................................................................................. 28 
12. 
INVESTIGATOR RESPONSIBILITIES ................................................................. 28 
13. 
References .......................................................................................................... 29 
14. 
Appendix A – Schedule of Activities ..................................................................... 30 
 
 
 
 
 
 
 


Cassava Sciences, Inc. 
Clinical Protocol PTI-125-05 
Simufilam, a small molecule to treat AD 
March 5, 2021 
Page 6 of 30  
 
 
 
CONFIDENTIAL 
1. 
LIST OF ABBREVIATIONS 
α7nAChR  
 
 
α7 nicotinic acetylcholine receptor 
Aβ42 
 
 
 
amyloid beta1-42 
AChEI  
 
 
acetylcholinesterase inhibitor 
AD 
 
 
 
Alzheimer’s disease 
ADAS-cog 
 
 
Alzheimer’s Disease Assessment Scale – cognitive subscale 
ADME 
 
 
absorption, distribution, metabolism, excretion 
AE 
 
 
 
adverse event 
ALT   
 
 
alanine transaminase 
ALP 
 
 
 
alkaline phosphatase 
ANOVA 
 
 
analysis of variance 
AST   
 
 
aspartate transaminase 
AUC  
 
 
area under the curve 
BUN  
 
 
blood urea nitrogen 
CFR 
 
 
 
Code of Federal Regulations 
Cmax  
 
 
maximum plasma concentration 
CRO  
 
 
contract research organization 
CSF 
 
 
 
cerebrospinal fluid 
CSI 
 
 
 
Cassava Sciences, Inc. 
CT 
 
 
 
computed tomography 
ECG  
 
 
electrocardiogram 
CRF 
 
 
 
case report form 
EDTA  
 
 
ethylenediaminetetraacetic acid 
FDA  
 
 
Federal Drug Association 
FIH 
 
 
 
first in human 
FLNA  
 
 
filamin A 
GCP  
 
 
good clinical practice 
GLP 
 
 
 
good laboratory practice 
HBsAg  
 
 
hepatitis B surface antigen 
HCV  
 
 
hepatitis C virus 
HED  
 
 
human equivalent dose 
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 
LOQ  
 
 
limit of quantitation 
MMSE 
 
 
Mini Mental State Evaluation  
NMDAR 
 
 
N-methyl D-aspartate receptor 
NOAEL 
 
 
no observable adverse effect level 


Cassava Sciences, Inc. 
Clinical Protocol PTI-125-05 
Simufilam, a small molecule to treat AD 
March 5, 2021 
Page 7 of 30  
 
 
 
CONFIDENTIAL 
NOEL  
 
 
no observable effect level 
PK 
 
 
 
pharmacokinetics 
SavaDx 
 
 
blood-based diagnostic/biomarker candidate 
RBC  
 
 
red blood cell 
SAE 
 
 
 
serious adverse event 
Simufilam 
 
 
small molecule drug candidate to treat AD 
SOP 
 
 
 
standard operating procedure 
Tmax  
 
 
time to Cmax 
ULN  
 
 
upper limit of normal 
WBC  
 
 
white blood cell 
 
 
 


Cassava Sciences, Inc. 
Clinical Protocol PTI-125-05 
Simufilam, a small molecule to treat AD 
March 5, 2021 
Page 8 of 30  
 
 
 
CONFIDENTIAL 
2. 
INTRODUCTION 
2.1. 
MECHANISM OF ACTION 
Cassava Sciences, Inc. is developing simufilam, a novel drug candidate designed to treat 
and slow the progression of Alzheimer’s disease (AD). Simufilam binds with femtomolar 
affinity to an altered conformation of filamin A (FLNA) that is induced by beta amyloid1-
42 (Aβ42), present in AD brain and critical to the toxicity of Aβ42.1-3 Simufilam binding 
reverses the altered FLNA conformation and restores FLNA’s native shape, preventing 
two toxic signaling cascades of Aβ42. Aβ42, in monomer or small oligomer form, hijacks 
the α7-nicotinic acetylcholine receptor (α7nAChR) and signals via this receptor to 
hyperphosphorylate tau. This signaling requires the recruitment of altered FLNA to this 
receptor. Second, altered FLNA also links to toll-like receptor 4 (TLR4) to allow Aβ42 to 
persistently activate this receptor. Normal FLNA does not associate with either 
α7nAChR or TLR4. In addition to disrupting the normal functions of α7nAChR and tau 
protein, Aβ42’s toxic signaling to hyperphosphorylate tau leads to the signature tangles 
and plaques in AD brain. In two AD mouse models and in postmortem human AD brain 
tissue, simufilam restored function of three receptors that are impaired in AD: the 
α7nAChR, the N-methyl-D-aspartate receptor (NMDAR), and the insulin receptor (IR).2,3 
Simufilam also improved synaptic plasticity and reduced tau hyperphosphorylation, 
amyloid deposits, neurofibrillary tangles and inflammatory cytokine release.2,3 We 
therefore expect simufilam both to improve cognition and to slow AD progression. Both 
mouse models used a dose of 20 mg/kg/day (equivalent to 60 mg/m2/day).  
2.2. 
SAFETY PHARMACOLOGY AND TOXICOLOGY 
A robust nonclinical ADME, safety pharmacology, and general and genetic toxicology 
program has been conducted with simufilam. In vitro metabolic profiling showed 
minimal metabolism across several species including humans. Simufilam was rapidly 
absorbed and eliminated in in vivo studies in rat and dog with nearly 100% oral 
bioavailability, a 2.67-h half-life in dog, dose-proportional PK and no accumulation. 
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.  
 


Cassava Sciences, Inc. 
Clinical Protocol PTI-125-05 
Simufilam, a small molecule to treat AD 
March 5, 2021 
Page 9 of 30  
 
 
 
CONFIDENTIAL 
Simufilam was tested in repeat dose oral toxicity studies in rats and dogs. A 6-month 
repeat dose oral toxicity study in rat (PTI-125-NC-049) used the same doses as a 28-day 
study (50, 500 and 1000 mg/kg/day), which found 500 mg/kg/day to be the no observable 
adverse effect level (NOAEL). In the 6-month study, the toxicological response was 
characterized by decreased body weights and adverse structural and functional alterations 
in the liver of 500 and 1000 mg/kg animals, including increased weight, hepatocellular 
hypertrophy and vacuolation, single/multiple basophilic/ eosinophilic/clear cell focus, 
hepatocellular degeneration, pigmentation, and oval cell hyperplasia. The presence of bile 
pigment was consistent with cholestasis. These findings correlated with changes to the 
clinical chemistry profile, including increased ALP and total/direct bilirubin. Over the 1-
month recovery period, there was complete recovery of the hepatocellular degeneration 
and partial recovery of hepatocellular hypertrophy. The NOAEL from this 6-month study 
was 50 mg/kg/day (equivalent to 300 mg/m2). A second 6-month repeat dose oral toxicity 
study in rat, pending pathology, will more accurately determine the 6-month NOAEL in 
rat. Doses are vehicle and 125 and 250 mg/kg/day.  
In a 9-month toxicity study in dog (PTI-125-NC-050), the no observable effect level 
(NOEL) of simufilam was 25 mg/kg. The 200 mg/kg (high) dose was decreased to 150 at 
1 month due to bodyweight loss thought unsustainable for 9 months. Clinical signs were 
salivation and a few instances of muscle fasciculations. There were no pathology 
findings, but the high dose was considered adverse due to two unexplained deaths. The 
75 mg/kg/day NOAEL provides 38- and 19-fold safety margins by Cmax and AUC, 
respectively, over the 100 mg b.i.d. dose in patients. 
2.3. 
CLINICAL STUDIES 
A first-in-human, double-blind, Single Ascending Dose clinical trial was conducted in 
healthy normal volunteers, age 18-45 with oral dosing solution. Doses were placebo, 50, 
100 and 200 mg (equivalent to 31, 62, and 123 mg/m2, respectively) administered to three 
different groups of volunteers. The study showed dose proportional PK, and there were 
no drug-related adverse events (AEs). 
In a Phase 2a 28-day study, 13 mild-to-moderate AD patients received simufilam 100 mg 
b.i.d. as oral tablets. Patients were MMSE ≥ 16 and ≤ 24, age 50-85, with a CSF total 
tau/Aβ42 ratio ≥ 0.30. A second CSF sample was collected on Day 28, allowing 
assessment of change from baseline in biomarkers using commercial ELISA kits. All 8 
biomarkers that are elevated in AD were significantly reduced from baseline (Fig. 1).4 
Aβ42, which is low in AD, was increased slightly but non-significantly. Reduced 
inflammatory cytokines and YKL-40 indicated reduced neuroinflammation. A reduced 
neurodegenerative drive was suggested by reductions in neurogranin, neurofilament light 
chain, and total tau. The robust reduction in phospho-tau (P-Tau181) confirms the 
mechanism of action of simufilam. Simufilam was safe and well tolerated in all patients. 


Cassava Sciences, Inc. 
Clinical Protocol PTI-125-05 
Simufilam, a small molecule to treat AD 
March 5, 2021 
Page 10 of 30  
 
 
 
CONFIDENTIAL 
Fig. 1   Mean Change from Baseline to Day 28 in CSF biomarkers (±SEM) 
 
Pharmacokinetic analysis indicated minimal accumulation (ratio 1.36, based on overall 
exposure) and consistent clearance and apparent volume of distribution across study days. 
Steady state concentration was achieved by Day 7 and were maintained through Day 28. 
A Phase 2b randomized clinical trial of simufilam 50 or 100 mg tablets or placebo (1:1:1) 
enrolled 64 mild-to-moderate AD patients. Both doses significantly improved eleven CSF 
biomarkers of AD pathology, neurodegeneration, neuroinflammation and blood-brain 
barrier integrity (Fig. 2). CSF biomarker analyses were conducted blind to treatment and 
timepoint by an outside lab. These data suggest disease modification and replicate the 
Phase 2a results in a well-controlled study. 
Fig. 2   Phase 2b Mean Change from Baseline to Day 28 in CSF biomarkers (±SEM) 
 


Cassava Sciences, Inc. 
Clinical Protocol PTI-125-05 
Simufilam, a small molecule to treat AD 
March 5, 2021 
Page 11 of 30  
 
 
 
CONFIDENTIAL 
The secondary endpoints in the Phase 2b trial were two cognitive measures using the 
Cambridge Neuropsychological Test Automated Battery. Patients were assessed on the 
Paired Associate Learning (PAL) test, measuring episodic memory, and a test of spatial 
working memory. The primary outcome measures for each were total errors, with errors 
imputed for more difficult levels not reached in the PAL test. Simufilam produced 
encouraging effect sizes (calculated by Hedge’s g for group sizes of 20), suggesting 
cognitive enhancement (Fig. 3). Effect sizes versus placebo for the test of episodic 
memory were 37% and 23% for the 50 and 100 mg groups, respectively, after removing 
the most and least impaired subjects by baseline score. For spatial working memory, 
effect sizes were 17% and 46% for these respective dose groups. Cognitive enhancement 
by simufilam is supported by preclinical data showing improved function of α7nAChR, 
NMDAR and insulin receptors and improved synaptic plasticity in 3xTg AD mice and in 
postmortem human AD brain tissue. In both Phase 2 clinical trials, simufilam was well 
tolerated and no patients discontinued due to AEs.  
 
Fig. 3   Phase 2b Mean Change from Baseline to Day 28 in Total Errors in Memory Test 
 
To benefit participants of previous one-month studies and to assess longer-term clinical 
safety of simufilam, a 1-year, open-label clinical trial of approximately 100 mild-to-
moderate AD patients is ongoing. All prior patients were eligible, and new patients 
(MMSE 16-26) can enroll. All new patients have a baseline CSF draw, and change in 
biomarkers will be evaluated after 6 or 12 months. Additionally, cognition is being 
assessed with the ADAS-Cog and neuropsychiatric symptoms by the NPI.  


Cassava Sciences, Inc. 
Clinical Protocol PTI-125-05 
Simufilam, a small molecule to treat AD 
March 5, 2021 
Page 12 of 30  
 
 
 
CONFIDENTIAL 
3. 
STUDY OBJECTIVES 
The objectives of this study are 1) to assess the effect of food on the rate and extent of 
absorption of simufilam, and 2) to compare the pharmacokinetic profile of the Phase 3 
formulation of simufilam to that of the earlier Phase 2 formulation. The new Phase 3 
formulation has a higher percentage of active ingredient and is therefore smaller with a 
slightly different shape. 
4. 
SUMMARY OF STUDY DESIGN 
This is a single-center, randomized, four-treatment, four-sequence crossover study in 
healthy volunteers to estimate the effect of food on the PK of simufilam following oral 
dosing of the Phase 3 simufilam 100 mg tablet. Additionally, the relative bioavailability 
of the Phase 3 tablet will be compared to the earlier Phase 2 simufilam 100 mg tablet, 
both in the fasted state. A total of twenty four (24) healthy volunteers (12 male and 12 
female) will be enrolled into this study. Subjects will be randomly assigned to one of four 
treatment sequences (6 subjects/sequence) as shown in Table 6.  
 
 
Table 6   Treatment Sequence  
 
 
 
 
During each 48-h treatment period, subjects will be given a single oral dose of simufilam 
as displayed in Table 6. The administration of each dose of study drug will be separated 
by a 48-hour washout period. PK blood samples will be obtained prior to dosing and at 
specified intervals during the study (0-48 h post-dose for Treatment Periods 1 - 4). The 
observation period for safety will continue through the incarceration period. 
Sequence 
Treatment Period 1 
Treatment Period 2 
Treatment Period 3 
Treatment Period 4 
Fasted 
High 
Low 
Phase 2 
Tablet 
Fasted 
High 
Low 
Phase 2 
Tablet 
Fasted 
High 
Low 
Phase 2 
Tablet 
Fasted 
High 
Low 
Phase 2 
Tablet 
Sequence A 
(n = 6) 
 
 
 
X 
 
 
X 
 
X 
 
 
 
 
X 
 
 
Sequence B 
(n = 6) 
X 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
X 
 
Sequence C 
(n = 6) 
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
Sequence D 
(n = 6) 
 
 
X 
 
 
X 
 
 
 
 
 
X 
X 
 
 
 


Cassava Sciences, Inc. 
Clinical Protocol PTI-125-05 
Simufilam, a small molecule to treat AD 
March 5, 2021 
Page 13 of 30  
 
 
 
CONFIDENTIAL 
5. 
SUBJECT SELECTION 
5.1. 
STUDY POPULATION 
A total of 24 subjects will be enrolled in the study (12 males and 12 females). 
5.2. 
INCLUSION CRITERIA 
Each patient must comply with the following Inclusion Criteria:  
1. Male or female subjects Ages ≥ 18 and ≤ 45 years  
2. BMI of 18 – 30 Kg/m² 
3. Informed consent form (ICF) signed by the subject  
4. General health status acceptable for participation in the study as determined by 
medical history, review of current medication, physical examination, and laboratory 
results  
5. Females must be of non-childbearing potential (defined as surgically sterile [i.e. had a 
bilateral tubal ligation, hysterectomy, or bilateral oophorectomy at least 6 months 
before the first dose of study medication] or postmenopausal with amenorrhea for at 
least 1 year before the first dose of study medication [serum FSH levels consistent 
with postmenopausal status i.e., greater than 40 mIU/mL]) or agree to use  an 
acceptable form of birth control (see Section 5.4) from screening until 14 days after 
study completion.Fluency (oral and written) in English  
6. The patient must agree to comply with the drawing of blood samples for the PK 
assessments, laboratory assessments and plasma biomarkers 
7. The subject is willing and able to remain at the study site for the duration of the study 
5.3. 
EXCLUSION CRITERIA 
Patients meeting any of the following criteria will be excluded from the study: 
1. The subject has any relevant deviations from normal in physical examination, 
electrocardiogram (ECG), or clinical laboratory tests, as evaluated by the investigator. 
2. The subject has had a clinically significant illness within 30 days of this study. 
3. The subject has a history of significant neurological, hepatic, renal, endocrine, 
cardiovascular, gastrointestinal, pulmonary, or metabolic disease. 


Cassava Sciences, Inc. 
Clinical Protocol PTI-125-05 
Simufilam, a small molecule to treat AD 
March 5, 2021 
Page 14 of 30  
 
 
 
CONFIDENTIAL 
4. Subject is taking prescription CNS medication. 
5. The subject has used alcohol, grapefruit, grapefruit juice, caffeine or xanthine-
containing products 48 h before dosing or intends to use any of these products during 
the study. 
6. The subject has a history of substance abuse or a current positive ethanol urine test or 
positive urine drug screen. 
7. The subject has a positive serum hepatitis B surface antigen or positive HCV 
antibody test. 
8. The subject has a positive HIV test. 
9. The subject has a current positive urine cotinine test. 
10. The subject has participated in another drug study in the past 30 days. 
11. The subject has donated or lost a significant volume of blood (>450 mL) within 4 
weeks of the study. 
12. The subject is unwilling to reside in the study unit for the duration of the study or to 
cooperate fully with the investigator or site personnel. 
13. Covid-19 infection within the past 3 months 
5.4. 
BIRTH CONTROL 
Subjects will be advised to use one of the following forms of birth control during 
the study: 
• 
Postmenopausal (at least 2 years before dosing) 
• 
Vasectomized partner (at least 6 months before dosing) 
• 
Surgical sterilization (bilateral tubal ligation – tubes tied, hysterectomy – removal of 
the uterus, bilateral oophorectomy – removal of both ovaries) at least 6 months before 
dosing 
• 
Non-surgical permanent sterilization (e.g., Essure® procedure) at least 3 months before 
dosing 
• 
Double barrier (diaphragm with spermicide; condoms with spermicide) 
• 
Intrauterine device (IUD) 
• 
Abstinence (you must agree to use a double barrier method if you become sexually 
active during the study) 
• 
Implanted or intrauterine hormonal contraceptives in use for at least 6 consecutive 
months before study dosing and throughout the study duration 
• 
Oral, patch, or injected contraceptives, or vaginal hormonal device (i.e. NuvaRing®), 
in use for at least 3 consecutive months before study dosing and throughout the study 
duration 


Cassava Sciences, Inc. 
Clinical Protocol PTI-125-05 
Simufilam, a small molecule to treat AD 
March 5, 2021 
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CONFIDENTIAL 
6. 
STUDY DRUG 
6.1. 
SIMUFILAM PHYSICAL DESCRIPTION AND PREPARATION 
Investigational simufilam will be supplied by Cassava Sciences as coated tablets.  
6.1.1. Storage 
Bottles of simufilam 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 
All subjects will receive simufilam as follows: 
 
Treatment 
Period 1 
Day 1* 
Washout 
Day 2 
Treatment 
Period 2 
Day 3* 
Washout  
Day 4 
Treatment 
Period 3 
Day 5* 
Washout  
Day 6 
Treatment 
Period 3 
Day 7* 
Day 8 
1 tablet 
simufilam 
No dose 
1 tablet 
simufilam 
No dose 
1 tablet 
simufilam 
No dose 
1 tablet 
simufilam 
No 
dose 
* Subjects will take the current tablet formulation in a fed or fasted state or the previous Phase 2 
tablet in a fasted state, depending on the sequence group. 
 
When receiving simufilam in a fasted state, subjects will fast for at least 10 h prior to 
dosing. Water will be allowed until 1 h before dosing. The simufilam tablet will be 
administered with 240 mL of water, and no additional water will be allowed until 1 h 
post-dose. No food will be allowed until 4 h post-dose.  
 
Subjects to be administered simufilam in a fed state will consume either a high-fat or 
low-fat breakfast. The high-fat breakfast will consist of two eggs fried in butter, two 
strips of bacon, two slices of toast with butter, 4 oz hash brown potatoes, and 8 oz whole 
milk. The low-fat breakfast will consist of one slice of toast with jelly, l ¼ oz raisin bran 
cereal, one banana, 4 oz skim milk, and 6 oz orange juice. Subjects will be instructed to 


Cassava Sciences, Inc. 
Clinical Protocol PTI-125-05 
Simufilam, a small molecule to treat AD 
March 5, 2021 
Page 16 of 30  
 
 
 
CONFIDENTIAL 
eat the meal within 30 min. The simufilam tablet will be administered 30 min after the 
start of the meal with 240 mL water, and no additional water will be allowed until 1 h 
post-dose. No additional food will be allowed until 4 h post-dose.  
 
6.3. 
CONCOMITANT MEDICATIONS 
Use of non-prescription medication will be prohibited for 48 h before initial drug 
administration and during the study. Use of alcohol, grapefruit, grapefruit juice, and 
caffeine- or xanthine-containing products is also prohibited 48 h before dosing and during 
the study. 
6.4. 
STUDY PROCEDURES 
Appendix A presents the Schedule of Activities. 
Prior to any study-related activities, the ICF must be signed and dated by the subject. The 
format and content of the ICF must be agreed upon by the Principal Investigator(s), the 
appropriate IRB and the Sponsor (or designee). The signed and dated ICF must be 
retained by the Investigator in the subject's file. 
 
6.5. 
EVALUATIONS BY VISIT 
6.5.1. Screening Period 
The following will be completed within 28 days prior to administration of the 
study medication: 
• Informed Consent (written consent must be obtained prior to conducting any 
screening activities) 
• Review of Inclusion and Exclusion Criteria 
• Medical history including review of current medication 
• Physical examination, including measurement of vital signs (after a 3-
minute sitting period), height, weight and BMI 
• A 12-lead ECG 
The following laboratory assessments will be completed at screening. 
• Serum chemistry, hematology, and urinalysis  
• Urine drug screen: amphetamines, barbiturates, benzodiazepines, 
cocaine, opiates, and cannabinoids 


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• Ethanol urine test 
• Urine cotinine 
• HIV test  
• HBsAg, HCV Antibody tests  
 
6.5.2. 
Check-in (Day 0) 
Subjects will check into the clinic on the day prior to dosing, and will remain 
confined to the clinic for the duration of the study. Upon check-in, the following 
assessments will be conducted: 
• Ethanol urine test 
• Urine drug screen/urine cotinine 
• Pregnancy test for females 
• COVID-19 testing (nasopharyngeal swab test) 
• Review of concomitant medication 
• Confirmation of inclusion/exclusion criteria 
 
6.5.3. 
Treatment Period 1 – Day 1 
Note: Study Day 1 is defined as the calendar day the study drug is first administered. 
 
According to each subject’s sequence assignment, subjects to receive the first dose 
fasted will fast for at least 10 h prior to dosing. Water will be allowed until 1 h before 
dosing.  
 
On the morning of Study Day l, prior to dosing, subjects to be administered simufilam 
in a fed state will consume either a high-fat or low-fat breakfast, according to their 
sequence assignment and as described in the Section 6.2 above. The simufilam tablet 
will be administered 30 min after the start of the meal. 
 
For all subjects, the following will be conducted in the morning of Study Day 1: 
 
• Blood draw for clinical laboratory tests, chemistry hematology and 
urine sample for urinalysis. 
• Vital signs after a 3-minute sitting period (blood pressure, pulse, 
temperature and respiration rate) within 1 h before dosing 
• Blood sample collection for baseline PK assessment (Time = 0) within 


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1 h before dosing 
 
The simufilam tablet will be administered with 240 mL of water, 30 min after the 
start of the meal (if dosing in a fed state). No additional water will be allowed until 1 
h post-dose. No food will be allowed until 4 h post-dose.  
After dosing, the following assessments will be conducted: 
• Vital signs (blood pressure, pulse and respiration rate) at 
approximately 30 and 90 min, and 4, 8, 12, h post-dose (within 15 min 
of nominal time) 
• Blood samples will be drawn at 20, 40, and 60 min and at 1.5, 2, 2.5, 
3, 4, 6, 8, 10, 12 and 24 h after dosing  for PK assessments (as close as 
possible to nominal time, but within 5 min for timepoints up to 3 h and 
within 15 min thereafter). 
• Adverse event monitoring 
 
All subjects will receive a meal 4 h post-dose. All meals for the first 24 h after dosing 
will be served at a fixed time interval after dose administration, such that meals are 
served in a staggered fashion.  
 
6.5.4. 
Washout Periods – Days 2, 4 and 6  
The following assessments will be conducted: 
• Blood sample collection for PK prior to breakfast 
• Vital signs (blood pressure, temperature, pulse and respiratory rate) at 
approximately 4 and 12 h after the PK sample collection 
• Adverse event monitoring 
 
6.5.5. 
Treatment Periods 2, 3 and 4 – Days 3, 5 and 7 
According to each subject’s sequence assignment, subjects to receive the first dose 
fasted will fast for at least 10 h prior to dosing. Water will be allowed until 1 h before 
dosing.  
 
On the morning of Study Days 3, 5, and 7, prior to dosing, subjects to be administered 
simufilam in a fed state will consume either a high-fat or low-fat breakfast, 
according to their sequence assignment and as described in the Section 6.2 above. 
The simufilam tablet will be administered 30 min after the start of the meal. 
 
The following will be conducted in the morning of Study Days 3, 5, and 7: 


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• Vital signs, within 1 h before dosing (blood pressure, pulse, 
temperature and respiration rate) 
• Blood sample collection for PK assessment, within 1 h before dosing 
(Time = 0) 
 
The simufilam tablet will be administered with 240 mL of water, 30 min after the 
start of the meal (if dosing in a fed state). No additional water will be allowed until 1 
h post-dose. No food will be allowed until 4 h post-dose.  
After dosing, the following assessments will be conducted: 
• Vital signs (blood pressure, pulse and respiration rate) at 
approximately 30 and 90 min, and 4, 8, 12, h post-dose (within 15 min 
of nominal time) 
• Blood samples will be drawn at 20, 40, and 60 min and at 1.5, 2, 2.5, 
3, 4, 6, 8, 10, 12 and 24 h after dosing  for PK assessments (as close as 
possible to nominal time, but within 5 min for timepoints up to 3 h and 
within 15 min thereafter). 
• Adverse event monitoring 
 
All subjects will receive a meal 4 h post-dose. All meals for the first 24 h after dosing 
will be served at a fixed time interval after dose administration, such that meals are 
served in a staggered fashion.  
 
6.5.6. 
Day 8 
The following tests will be performed at Day 8 before discharge: 
• Blood sample collection for PK prior to breakfast 
• Blood draw for clinical laboratory tests, chemistry hematology and 
urine sample for urinalysis 
• Vital signs (blood pressure, temperature, pulse and respiratory rate)  
• Physical examination, excluding height, weight and BMI 
• A 12-lead ECG 
• Adverse event monitoring 
 


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6.6. 
LABORATORY ASSESSMENTS 
6.6.1. 
Clinical Laboratory Tests 
The following clinical laboratory tests will be performed at Screening, at Day 1 time 
0 (pre-dose) and at Day 8 prior to discharge: 
 
• 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), total bilirubin, 
lactose dehydrogenase (LDH) 
• Urinalysis: color, specific gravity, pH, protein, sugar, ketones, occult 
blood 
 
6.6.2. 
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 and placed on ice. Within 30 min of 
collection, the blood will be centrifuged at approximately 1000 X G for 15 min, 
preferably at 4-5°C. Within 30 min of centrifuging, plasma (at least 1.5 mL) will be 
split into two aliquots, transferred to polypropylene tubes and stored at -20°C or 
below until analysis.   
At the end of the study or when advised by Sponsor, PK samples will be shipped 
frozen on dry ice to: Worldwide Clinical Trials Bioanalytical Sciences, 8609 Cross 
Park Drive, Austin, TX 78754 for bioanalytical analysis of simufilam with a validated 
assay. The second set of samples will be shipped when requested by the sponsor. 
7. 
EARLY DISCONTINUATION 
Patients may choose to discontinue study drug or study participation at any time, for 
any reason, and without prejudice. Patients who discontinue may be replaced at the 
discretion of the Sponsor. 
 
The following must be completed and documented in the source documents and CRFs 
for all patients who discontinue the study early: 
• 
The reason for early study discontinuation. 


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• 
Vital signs (blood pressure, temperature, pulse and respiratory rate), full 
physical examination, clinical laboratory tests, ECG, use of concomitant 
medications, and adverse events) should be obtained at discharge prior to 
release. 
8. 
ADVERSE EVENTS/SERIOUS ADVERSE EVENTS  
8.1. 
ADVERSE EVENTS - DEFINITION 
An adverse event (AE) is any undesirable event that occurs to a subject during a 
study, whether or not that event is considered study drug-related. Monitoring for AEs 
will start at dosing. Examples include: 
• Any treatment-emergent signs and symptoms (events that are marked by a 
change from the subject's baseline/entry status [e.g., an increase in severity or 
frequency of pre-existing abnormality or disorder]) 
• All reactions from study drug, an overdose, abuse of drug, withdrawal 
phenomena, sensitivity or toxicity to study drug 
• Apparently unrelated illnesses 
• Injury or accidents (Note: if a medical condition is known to have caused the 
injury or accident, the medical condition and the accident should be reported as 
two separate medical events [e.g., for a fall secondary to dizziness, both 
"dizziness" and "fall" should be recorded separately]) 
• Extensions or exacerbations of symptoms, subjective subject-reported events, 
new clinically significant abnormalities in clinical laboratory, physiological 
testing or physical examination 
 
All AEs, whether or not related to the study drug, must be fully and completely 
documented on the AE page of the CRF and in the subject's clinical chart. 
In the event that a subject is withdrawn from the study because of an AE, it must be 
recorded on the CRF as such. The subject should be followed and treated by the 
Investigator until the abnormal parameter or symptom has resolved or stabilized. 
The Investigator must report all directly observed AEs and all spontaneously 
reported AEs. The Investigator will ask the subject a non-specific question (e.g., 
"Have you noticed anything different since your dose of the study medication?") to 
assess whether any AEs have been experienced since the last assessment. AEs will 
be identified and documented on the AE CRF in appropriate medical terminology. 
The severity and the relationship to the study drug will be determined and reported 
on the CRF (see below). 


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8.2. 
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. 
8.3. 
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. 
8.4. 
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 


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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. 
8.5. 
SERIOUS ADVERSE EVENTS REPORTING 
The reporting of SAEs by the Sponsor to Regulatory Authorities (e.g., FDA) is a 
regulatory requirement. Each Regulatory Agency has established a timetable for 
reporting SAEs based upon established criteria.  Likewise, it is the responsibility 
of the Principal Investigator to report SAEs to their EC/IRB. 
 
All SAEs must be reported immediately (within 24 h of learning of the event) by 
telephone to: 
Nadav Friedmann, PhD, MD 
Cassava Sciences, Inc. 
Email: nfriedmann@cassavasciences.com  
Phone:    925-788-4585 
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. 


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March 5, 2021 
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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. 
9. 
STATISTICAL CONSIDERATIONS 
9.1. 
RANDOMIZATION 
Randomized treatments will be assigned by patient numbers in a randomly generated 
numeric sequence. 
9.2. 
ANALYSIS POPULATIONS 
All subjects who receive one dose of study medication will be included in the safety 
analyses. Any subject who did not complete all 4 study periods will be excluded from 
the PK analysis. The PK samples from subjects who drop out early will be analyzed 
and reported in the data listings.   
9.3. 
PHARMACOKINETIC ANALYSIS 
Pharmacokinetic Methods 
Plasma concentration-time data will be analyzed using noncompartmental methods in 
Phoenix™ WinNonlin® (Version 8.1, Certara, L.P.) in conjunction with the internet-
accessible implementation of Pharsight® Knowledgebase ServerTM (PKSO; Version 
4.0.4, Certara, L.P.). Concentration-time data that are below the limit of quantification 
(BLQ) will be treated as zero in the data summarization and descriptive statistics.   
In the pharmacokinetic (PK) analysis, BLQ concentrations will be treated as zero from 
time-zero up to the time at which the first quantifiable concentration will be observed; 
embedded and/or terminal BLQ concentrations will be treated as “missing.” Actual 
sample times relative to the time of dose will be used in the PK analysis. 
The following PK parameters will be calculated (but may not be limited to): 
Cmax 
The maximum concentration determined directly from individual 
concentration-time data 


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Tmax 
Time to reach maximum concentration 
AUClast 
Area under the curve to the time of the last quantifiable 
concentration, calculated using the linear trapezoidal method 
AUCinf 
Area under the curve extrapolated to infinity; calculated as: 
AUCinf = AUClast + Clast/λz 
Clast 
The last quantifiable concentration determined directly from 
individual concentration-time data 
Tlast 
Time of the last quantifiable concentration 
λz 
The observed elimination rate constant; estimated by linear 
regression through at least three data points in the terminal phase 
of the log concentration-time profile 
T1/2 
The observed terminal elimination half-life calculated as: 
z
T
λ
)
2
ln(
2
/
1
=
 
 Note: λz and parameters calculating using λz (AUCinf and T1/2) will be reported only if 
an apparent elimination phase is observed.  
Statistical Procedures 
Natural log transformed AUCinf (if data permit), AUClast, and Cmax, will be analyzed 
using a mixed effect model with sequence, period, and treatment as fixed effects and 
subject within sequence as a random effect. Estimates of the adjusted mean differences 
(Test-Reference) and corresponding 90% confidence intervals (CIs) will be obtained 
from the model.  The adjusted mean differences and 90% CIs for the differences will be 
exponentiated to provide estimates of the ratio of adjusted geometric means 
(Test/Reference) and 90% CIs for the ratios. 
For the food effect assessment, simufilam in the fasted state will be the intended 
reference treatment. The following comparisons will be made: 
High-fat vs. Fasted 
Low-fat vs. Fasted. 
Phase 2 tablet formulation vs. current tablet formulation (both Fasted). 
9.4. 
SAFETY ANALYSIS 
Adverse events reported on case report forms will be mapped to preferred terms and 
organ systems using the MedDRA mapping system. For each preferred term event, 
frequency counts and percentages will be calculated by treatment period. Vital signs 
and clinical laboratory results will be descriptively summarized in terms of change 
from screening values. 


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9.5. 
SAMPLE SIZE 
Twenty-four (24) subjects will be enrolled in this study. Sample size was determined by 
estimating the intrasubject variability for log-transformed data from previous studies of 
simufilam. A sample size of twenty four subjects is expected to provide 80% power to 
obtain 90% confidence intervals for the geometric mean ratios of Cmax and the AUCs. 
10. 
STUDY TERMINATION 
The study will be terminated following completion of the study or at any time at the 
discretion of the Sponsor. 
11. 
DATA COLLECTION, RETENTION AND MONITORING 
11.1. CASE REPORT FORMS 
Case report forms (CRFs) will be provided for each subject. The subjects in the study 
will not be identified by name on any study documents to be collected by the Sponsor 
(or CRO designee), but will be identified by a Study Identification Number and initials.  
All clinical information requested in this protocol will be recorded on the CRFs 
provided by the Sponsor using legible entries with a black ballpoint pen. If an error is 
made, a single line will be drawn through the error and the correct response will be 
written adjacent to the error, and 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. 
11.2. 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 to that 
subject. The Investigator must ensure the reliability and availability of source 
documents from which the information on the CRF was derived. Investigators are 


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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. The Sponsor reserves the right to terminate the study for the 
Investigator's refusal to supply source documentation of work performed in this clinical 
trial.  
11.3. SUBJECT CONFIDENTIALITY 
All reports and subject samples will be identified only by Study Identification Number 
and initials to maintain subject confidentiality. Additional subject confidentiality issues 
(if applicable) are covered in the Clinical Study Agreement. 
11.4. 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. Financial compensation for lost wages, disability or 
discomfort due to the study is not available. 
11.5. 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. 
11.5.1. 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 


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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. 
11.6. INFORMED CONSENT FORM 
The Sponsor (or designee) must review the Investigator's proposed Informed Consent 
Form prior to IRB submission for approval. An IRB-approved copy of the Informed 
Consent Form will be forwarded to the Sponsor. 
The Informed Consent Form documents study-specific information the Investigator 
provides to the subject and the subject's agreement to participate. The Investigator 
explains in plain terms the nature of the study along with the aims, methods, 
anticipated benefits, potential risks, and any discomfort that participation may entail. 
The Informed Consent Form must be signed and dated before the subject enters the 
study. The original Informed Consent Form and any amended Informed Consent 
Form, signed and dated, must be retained in the subject's file at the study site and a 
copy must be given to the subject. 
 
12. 
 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 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. 


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• Maintain adequate records in accordance with ICH, 21 CFR Part 312.62, and 
local laws and have records available for inspection by the Sponsor, FDA, or 
other authorized agency. 
• Promptly report to the IRB and the Sponsor all changes in research activity and 
unanticipated problems involving risks to patients or others (including 
amendments and expedited safety reports). 
• Comply with all other requirements regarding obligations of Clinical 
Investigators and all other pertinent requirements listed in ICH, 21 CFR Part 
312 and local laws. 
 
13. 
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. 
4. 
Wang H-Y, Pei Z, K.-C. Lee K-C, et al. PTI-125 reduces biomarkers of Alzheimer’s disease 
in patients. J Prevent Alzheimer's Disease 2020;7:256-64. 
 


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14. 
 APPENDIX A – SCHEDULE OF ACTIVITIES 
 
PROCEDURE 
SCREENING 
(Days -28 to  
Day -1) 
DAY 0 
CHECK-IN 
DAY 1 
Time = 0 
DAY 2 
4 & 6 
DAY 3 
5 & 7 
DAY 8 
DISCHARGE  
Informed Consent 
X 
 
 
 
 
 
COVID-19 
 
X 
 
 
 
 
Medication and  
medical histories 
X 
X 
 
 
 
 
Ethanol urine test 
X 
X 
 
 
 
 
Urine drug screen/ 
Urine cotinine 
X 
X 
 
 
 
 
Pregnancy test 
 
X 
 
 
 
 
Review of inclusion/ 
exclusion criteria 
X 
X 
 
 
 
 
Drug administration 
 
 
X 
 
X 
 
Physical examination 
X 
 
 
 
 
X 
ECG 
X 
 
 
 
 
X 
Biochemistry,  
hematology, urinalysis 
X 
 
X 
 
 
X 
HCV, HBsAG &  
HIV screen 
X 
 
 
 
 
 
Adverse events 
 
 
X 
X 
X 
X 
Vital signs 
X 
 
X 
X 
X 
X 
Blood sample collection 
for PK analysis 
 
 
X 
X 
X 
X 

SAP_001.pdf: 
Worldwide Clinical Trials Controlled Quality Management Document 
 
Sponsor: 
Cassava Sciences, Inc 
Protocol Number: 
PTI-125-05 
STATISTICAL ANALYSIS PLAN – PHASE 1 
 
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019 
 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
 
Page 1 of 25 
 
 
Statistical Analysis Plan 
A Four-way Crossover Food Effect and Bioequivalence Pharmacokinetic Study of 
Simufilam in Healthy Volunteers  
 
Protocol Number: PTI-125-05 
Protocol Version: 1.0 / 5 Mar 2021 
 
SAP Version 1.0 
SAP Issue Date: 08-JUN-2021 
SAP Authors 
Kathryn Roupe, PhD 
 Shweta Padmanaban, MS 
 
Previous SAP Versions 
Not Applicable (First Version) 
 
 


Worldwide Clinical Trials Controlled Quality Management Document 
 
Sponsor: 
Cassava Sciences, Inc 
Protocol Number: 
PTI-125-05 
STATISTICAL ANALYSIS PLAN – PHASE 1 
 
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019 
 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
 
Page 2 of 25 
SAP Amendments before database lock 
Version  Issue Date 
Section 
Revision / Addition 
Rationale 
- 
- 
- 
- 
- 
 
 


Worldwide Clinical Trials Controlled Quality Management Document 
 
Sponsor: 
Cassava Sciences, Inc 
Protocol Number: 
PTI-125-05 
STATISTICAL ANALYSIS PLAN – PHASE 1 
 
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019 
 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
 
Page 3 of 25 
Table of Contents 
1 
INTRODUCTION ............................................................................................... 5 
2 
STUDY OBJECTIVES ....................................................................................... 5 
3 
ENDPOINTS ....................................................................................................... 5 
3.1 
Primary Endpoints .......................................................................................................... 5 
4 
SAMPLE SIZE .................................................................................................... 5 
5 
RANDOMIZATION ........................................................................................... 5 
6 
PLANNED ANALYSES ..................................................................................... 6 
6.1 
Analysis Sets ................................................................................................................... 6 
6.1.1 
Randomized Population ............................................................................................ 7 
6.1.2 
Safety Analysis Set ................................................................................................... 7 
6.1.3 
Pharmacokinetic (PK) Population............................................................................. 7 
6.2 
Derived Data ................................................................................................................... 7 
6.2.1 
Treatment Period / Visits .......................................................................................... 7 
6.2.2 
Race........................................................................................................................... 8 
6.2.3 
Baseline ..................................................................................................................... 8 
6.2.4 
Duration / Study Day / Time ..................................................................................... 8 
6.2.5 
Adverse Event ........................................................................................................... 8 
6.2.6 
Conventions for Missing and Partial Dates .............................................................. 9 
6.2.7 
Inexact Values ........................................................................................................... 9 
6.2.8 
Not Done/Missing ..................................................................................................... 9 
6.2.9 
Unscheduled Visits ................................................................................................... 9 
6.2.10 
PK Parameters ........................................................................................................... 9 
6.3 
Conventions .................................................................................................................. 11 
6.3.1 
Decimal Places ........................................................................................................ 12 
6.4 
Subject Disposition ....................................................................................................... 13 
6.5 
Protocol Deviations ....................................................................................................... 13 
6.6 
Demographic and Baseline Characteristics .................................................................. 13 
6.7 
Medical History ............................................................................................................ 14 
6.8 
Prior and Concomitant Medications ............................................................................. 14 
6.9 
Exposure to Study Drug ................................................................................................ 14 
6.10 
Statistical Analysis of PK Data ..................................................................................... 14 
6.11 
Safety Analyses ............................................................................................................. 15 


Worldwide Clinical Trials Controlled Quality Management Document 
 
Sponsor: 
Cassava Sciences, Inc 
Protocol Number: 
PTI-125-05 
STATISTICAL ANALYSIS PLAN – PHASE 1 
 
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019 
 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
 
Page 4 of 25 
6.11.1 
Adverse Events ....................................................................................................... 15 
6.11.2 
Laboratory Data ...................................................................................................... 16 
6.11.3 
Vital Signs ............................................................................................................... 17 
6.11.4 
Electrocardiogram Data .......................................................................................... 17 
6.11.5 
Physical Examination.............................................................................................. 18 
7 
CHANGES TO PLANNED PROTOCOL ANALYSIS ...................................18 
8 
REFERENCES ..................................................................................................19 
9 
LIST OF TABLES, FIGURES AND LISTINGS .............................................20 
 
 
 


Worldwide Clinical Trials Controlled Quality Management Document 
 
Sponsor: 
Cassava Sciences, Inc 
Protocol Number: 
PTI-125-05 
STATISTICAL ANALYSIS PLAN – PHASE 1 
 
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019 
 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
 
Page 5 of 25 
1 INTRODUCTION 
This document details the planned statistical analyses for Cassava Sciences, Inc., protocol “PTl-
125-05” study titled “A Four-way Crossover Food Effect and Bioequivalence Pharmacokinetic 
Study of Simufilam in Healthy Volunteers”. 
The proposed analyses are based on the contents of the final version of the protocol (dated 05-
MAR-2021) 
2 STUDY OBJECTIVES 
The objectives of this study are  
1. to assess the effect of food on the rate and extent of absorption of simufilam 
2. to compare the pharmacokinetic profile of the Phase 3 formulation of simufilam to that of 
the earlier Phase 2 formulation. 
3 ENDPOINTS 
3.1 Primary Endpoints 
 Cmax - The maximum concentration determined directly from individual 
 Tmax - Time to reach maximum concentration 
 AUClast - Area under the curve to the time of the last quantifiable concentration, calculated 
using the linear trapezoidal method 
 AUCinf - Area under the curve extrapolated to infinity 
 Clast - The last quantifiable concentration determined directly from individual 
concentration-time data 
 Tlast - Time of the last quantifiable concentration 
 λz - The observed elimination rate constant; estimated by linear regression through at least 
three data points in the terminal phase of the log concentration-time profile 
 T1/2 - The observed terminal elimination half-life  
 
4 SAMPLE SIZE 
Twenty-four (24) subjects (12 male and 12 female) will be enrolled in this study. Sample size was 
determined by estimating the intrasubject variability for log-transformed data from previous 
studies of simufilam. A sample size of twenty-four subjects is expected to provide 80% power to 
obtain 90% confidence intervals for the geometric mean ratios of Cmax and the AUCs. 
5 RANDOMIZATION 


Worldwide Clinical Trials Controlled Quality Management Document 
 
Sponsor: 
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Protocol Number: 
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STATISTICAL ANALYSIS PLAN – PHASE 1 
 
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019 
 
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Page 6 of 25 
Subjects will be randomly assigned to one of four treatment sequences (6 subjects/sequence) to 
receive a single oral dose of simufilam in each treatment period either under fasted condition or 
low fat fed condition or high fat fed condition or phase 2 tablet as shown in Table 1. 
 
The administration of each dose of study drug will be separated by a 48-hour washout period. PK 
blood samples will be obtained prior to dosing and at specified intervals during the study (0-48 h 
post-dose for Treatment Periods 1 - 4). The observation period for safety will continue through the 
incarceration period. 
Table 1 Treatment Sequences by Period 
Sequence 
Treatment Period -1 
Treatment Period -2 
Treatment Period -3 
Treatment Period -4 
Fasted 
High 
Low 
Phase 2 
Tablet 
Fasted 
High 
Low 
Phase 2 
Tablet 
Fasted 
High 
Low 
Phase 2 
Tablet 
Fasted 
High 
Low 
Phase 2 
Tablet 
Sequence A  
(n = 6) 
 
 
 
X 
 
 
X 
 
X 
 
 
 
 
X 
 
 
Sequence B 
(n = 6) 
X 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
X 
 
Sequence C 
(n = 6) 
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
Sequence D 
(n = 6) 
 
 
X 
 
 
X 
 
 
 
 
 
X 
X 
 
 
 
 
6 PLANNED ANALYSES 
No statistical analysis plan (SAP) prepared in advance of the data can be absolutely definitive and 
the final Clinical Study Report (CSR) may contain additional tables or statistical tests if warranted 
by the data obtained. The justification for any such additional analyses will be fully documented 
in the final CSR. 
6.1 Analysis Sets 
Subjects excluded from the analysis sets and the reason for their exclusion will be listed in 
Appendix 16.2 of the CSR. 


Worldwide Clinical Trials Controlled Quality Management Document 
 
Sponsor: 
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Protocol Number: 
PTI-125-05 
STATISTICAL ANALYSIS PLAN – PHASE 1 
 
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019 
 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
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Page 7 of 25 
6.1.1 
Randomized Population 
The Randomized Population is defined as all subjects who were randomized irrespective of 
receiving study drug. 
6.1.2 
Safety Analysis Set 
The Safety Population is defined as all subjects who receive one dose of study medication. 
6.1.3 
Pharmacokinetic (PK) Population 
The PK Population will include all evaluable subjects that complete all 4 periods of the study. 
Concentrations from subjects who drop out early will be analyzed and reported in the 
concentration-time listing only. 
6.2 Derived Data 
This section describes the derivations required for statistical analysis. Unless otherwise stated, 
variables derived in the source data will not be re-calculated. 
6.2.1 
Treatment Period / Visits   
Each visit as per study schedule will be mapped to treatment period and analysis visit for 
summary tables as given below. Listings will reflect actual period and visit as defined in 
protocol. 
 
Collected visit 
Treatment Period 
Analysis visit 
Screening 
- 
Screening 
DAY 0 Check-in 
- 
Check-in 
DAY 1 
Period 1 
Day 1 
DAY 2 
Period 1 
Day 2 
DAY 3 
Period 2 
Day 3 
DAY 4 
Period 2 
Day 4 
DAY 5 
Period 3 
Day 5 
DAY 6 
Period 3 
Day 6 
DAY 7 
Period 4 
Day 7 
DAY 8 
Period 4 
EOS / ET 
Early Termination 
Subject’s last treatment period 
EOS / ET 
 


Worldwide Clinical Trials Controlled Quality Management Document 
 
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Protocol Number: 
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STATISTICAL ANALYSIS PLAN – PHASE 1 
 
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Page 8 of 25 
6.2.2 
Race 
Where more than one race category has been selected for a subject, these race categories will be 
combined into a single category labeled “Multiple Race” in the summary tables. The listings will 
reflect the original selected categories.  
6.2.3 
Baseline 
Baseline is defined as the last non-missing value (either scheduled, unscheduled or repeat) before 
the subject receives the first dose of study drug.  
For variables that will be summarized by treatment, the baseline for each period is defined as the 
last non-missing value (either scheduled, unscheduled or repeat) that is collected before dosing of 
respective period. 
6.2.4 
Duration / Study Day / Time  
Study day will be calculated as the number of days from first dose of study drug.  
 date of event – date of first dose of study drug + 1, for events on or after first dose  
 date of event – date of first dose of study drug, for events before first dose   
6.2.5 
Adverse Event 
A treatment emergent adverse event (TEAE) is defined as an AE that emerges during treatment, 
having been absent pretreatment, or worsens relative to the pretreatment state. The following rules 
will be used to assign a TEAE to a treatment group: 
 A TEAE will be assigned to the treatment received immediately before onset. 
 
Any TEAE reported within the washout period between doses will be attributed to the 
previous treatment.  
 
If a TEAE started in one treatment period and continued to subsequent periods, the event 
will be counted in period which AE started. 
If a TEAE is missing relationship, it is assumed to be ‘probably related’ to the study drug for 
analysis purposes. Maximum severity will be assumed for an AE with missing severity. Adverse 
events that are reported as ‘possibly’ or ‘probably’ related will be considered as Related and events 
that are ‘unlikely’ related will be considered as Not Related. 


Worldwide Clinical Trials Controlled Quality Management Document 
 
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Protocol Number: 
PTI-125-05 
STATISTICAL ANALYSIS PLAN – PHASE 1 
 
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Governing QMD: Worldwide-SOP-ST-001 
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Page 9 of 25 
If a subject has multiple occurrences of same SOC and PT within a treatment period, then 
maximum severity and closest relationship will be separately flagged. 
6.2.6 
Conventions for Missing and Partial Dates 
It is not expected that there will be any missing dates, however in the rare case that an Adverse 
Event (AE) start date or time is missing and it is unclear whether the AE is treatment emergent or 
not then a conservative approach will be taken and it will be assumed that the AE occurred after 
first dosing.  
All dates presented in the individual subject listings will be as recorded on the Electronic Case 
Report Form (eCRF).  
6.2.7 
Inexact Values 
In the case where a safety laboratory variable is recorded as “> x”, “≥ x”, “< x” or “≤ x”, a value 
of x will be taken for analysis purposes. 
6.2.8 
Not Done/Missing 
For safety assessments where shift summaries are required, records will be imputed for all 
subjects who received IMP in the respective period in all scheduled visits and marked as ‘Not 
Done/Missing’ if either the subjects did not attend the visit, or discontinued or had missing 
assessment at the respective visit 
6.2.9 
Unscheduled Visits 
Only scheduled post-baseline laboratory and vital signs values will be tabulated. Post-baseline 
repeat / unscheduled assessments will be disregarded, although these post-baseline assessments 
will be listed in the relevant appendices to the CSR.  
6.2.10 
PK Parameters 
Concentration-time data for simufilam will be analyzed using noncompartmental methods in 
Phoenix™ WinNonlin® (Version 8.1 or higher, Certara, L.P.) in conjunction with the internet-
accessible implementation of Pharsight® Knowledgebase ServerTM (PKSO; Version 4.0.4, 
Certara, L.P.). Concentrations that are below the limit of quantification (BLQ) will be treated as 
zero in the data summarization and descriptive statistics. 


Worldwide Clinical Trials Controlled Quality Management Document 
 
Sponsor: 
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Protocol Number: 
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STATISTICAL ANALYSIS PLAN – PHASE 1 
 
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This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
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Page 10 of 25 
Blood samples for PK samples for the determination of simufilam will be collected at pre-dose 
(0), and at 0.333 (20 min), 0.667 (40 min), 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours post-
dose, for each treatment period.  
Mean plasma concentration-time data will be presented graphically on both linear and semi-log 
scales using nominal time. Spaghetti plots and individual plots will be presented on both linear 
and semi-log scales using actual time. The following plots will be created: 
1) Mean plot: Phase 3 Simufilam Tablet Fasted, Low-fat, and High-fat 
2) Mean plot: Phase 2 Simufilam Tablet Fasted, Phase 3 Simufilam Fasted 
3) All Subject plot: All subjects in one plot per Treatment 
4) Individual Subject plot: Phase 3 Simufilam Tablet Fasted, Low-fat, and High-fat plotted 
together for each subject 
5) Individual Subject plot: Phase 2 Simufilam Tablet Fasted, Phase 3 Simufilam Fasted 
plotted together for each subject 
Individual plasma concentrations from subjects that were excluded from the PK Analysis 
Population will be listed in Concentration Listings. 
Concentration-time data for simufilam in plasma will be analyzed using non-compartmental 
methods. The following descriptive statistics will be presented by treatment and nominal time: 
sample size (N), arithmetic mean, standard deviation (SD), coefficient of variation (CV%), 
minimum, median, and maximum. 
In the PK analysis, BLQ concentrations will be treated as zero from time-zero up to the time at 
which the first quantifiable concentration is observed; embedded and terminal BLQ 
concentrations will be treated as “missing”. Actual time relative to dosing will be used in the PK 
analysis. 
The following PK parameters will be calculated for simufilam for each treatment: 
Cmax 
Maximum plasma concentration determined directly from individual 
concentration-time data 
Tmax 
Time to reach maximum plasma concentration 
AUClast 
Area under the plasma concentration versus time curve, from time 0 to the 
last quantifiable concentration (Clast), as calculated by the linear 
trapezoidal rule 


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Page 11 of 25 
Clast 
Last quantifiable concentration determined directly from individual 
concentration-time data 
Tlast 
Time of the last quantifiable concentration 
AUCinf 
AUC from the time of dosing extrapolated to infinity, calculated as: 
AUCinf = AUClast + Clast/λz 
AUCExtrap 
The percentage of AUC0-inf obtained by extrapolation, calculated as: 
AUCextrap = [(AUCinf – AUClast)/AUC0-inf]*100 
λZ 
Apparent terminal elimination rate constant calculated by linear 
regression using the terminal log-linear phase of the logarithmic (log) 
transformed concentration vs. time data 
T1/2 
The observed terminal elimination half-life, calculated as:  
T1/2 = ln(2)/λz 
λZ Criteria 
The following criteria will be used to report λZ: 
 At least three quantifiable concentrations will be used in the regression 
 Cmax or data prior to Cmax will not be included in the regression. 
 The adjusted regression coefficient (R2 adj) should be ≥ 0.80.   
If these acceptance criteria are not met, λZ and descriptive parameters (λZ time range, Adj R2, 
etc.) will be retained in a PK parameter table for informational purposes; λZ will be flagged and 
excluded from summary statistics. Parameters calculated using λZ (T1/2) will be reported as ND 
(not determinable). 
If λZ acceptance criteria are met and AUCinf is estimable, the following criteria are used to 
report AUCinf: 
• The percentage of AUCinf based on extrapolation should be <30.0%. 
If the percentage of AUCinf based on extrapolation is 30.0% or greater, AUCinf and AUCextrap will 
be excluded from summary statistics, subsequent PK calculations and statistical analysis (e.g. 
ANOVA). 
6.3 Conventions 
All clinical data listings, summaries, figures and statistical analyses will be generated using SAS 
(Version 9.4 or higher)1. 


Worldwide Clinical Trials Controlled Quality Management Document 
 
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Protocol Number: 
PTI-125-05 
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Page 12 of 25 
Summaries of the clinical data will be presented by treatment group / sequence or overall.  
PK data listings, tables, figures, and statistical analyses will be generated using Phoenix® 
WinNonlin® (Version 8.1 or higher, Certara, L.P.)2 or SAS® (Version 9.4 or higher, SAS Institute 
Inc.)1. PK concentration-time data will be summarized by the number of non-missing observations 
(n), arithmetic mean (mean), standard deviation (SD), median, minimum (min), maximum (max), 
and coefficient of variation (CV%). PK parameter data will be summarized by n, mean, SD, 
median, min, max, CV%, geometric mean, and geometric CV%. Summary statistics that are not 
calculable due to lack of quantifiable data will be presented as NC in the descriptive statistic tables. 
Treatment labels will be displayed as follows:  
Fasted Simufilam 
Low fat fed 
Simufilam 
High fat fed 
Simufilam 
Phase 2 Simufilam 
 
Sequence group labels will be displayed as follows:  
Sequence A 
Sequence B 
Sequence C 
Sequence D 
Note: Footnotes will be added in all TLFs to clarify each sequence. 
Listings will be sorted in the following order subject, period, visit / date and parameter unless 
otherwise stated. All data will be listed, subjects who were not randomized will be displayed after 
the randomized treatment / sequence groups.  
Safety parameters (continuous variables) will be summarized by the number of non-missing 
observations, mean, median, standard deviation, and minimum and maximum.  
Categorical variables will be summarized by presenting the frequency and percent. Percentages 
will be based on the number of non-missing observations or the subject population unless 
otherwise specified. For each variable, all categories will be shown. Zero frequencies (but not the 
percent) within a category will be presented.  
6.3.1 
Decimal Places 
Derived data, where it is known in advance that the result will be an integer, such as age, will be 
presented with zero decimal places.  
Mean and median will be displayed to one more decimal place than the data, standard deviation 
will have two more decimal places, and the minimum and maximum will be displayed to the same 


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Page 13 of 25 
number of decimal places as reported in the raw data. Percentages will be displayed with one 
decimal place.  
For PK data, individual concentrations and PK parameters will be reported to 3 significant figures. 
Time (hour) will also be presented in 3 significant figures For summary statistics, n will be reported 
as a whole number; mean, SD, median, min, max, CV%, geometric mean, and geometric mean 
CV% will be reported to the same precision as for individual data (3 significant figures). For 
ANOVA results, geometric means, least squares means, and the difference in least squares means 
will be reported to 3 significant figures. Percent ratios of the geometric least squares means and 
associated 90% confidence intervals will be reported to 2 decimal places. CV% (intra-subject 
variability) will be presented to 2 decimal places.   
6.4 Subject Disposition 
Subject disposition will be summarized as follows:  
 
The number of subjects included in Randomized Population; number and percentage of 
subjects included in the Safety and PK Populations will be summarized. Within the Safety 
Population, the number and percentage of subjects within each period and treatment will 
be summarized.  
 
The number and percentage of subjects who completed the study and who terminated early, 
along with subject’s last period and treatment and reasons for early termination, will be 
summarized based on the Safety Population.  
The Randomized Population will be based on planned treatment, and the Safety / PK Populations 
will be based on actual treatment received. Percentages for the Safety Population will be based on 
the Randomized Population; Percentages for all other categories will be based on Safety 
Population. Percentages for sub-categories will be based on main categories. 
All subjects Disposition details, Treatment sequence and Population flags will be listed. 
In Mock Shells: Table 14.1.1.1, Listing 16.2.1.1, Listing 16.2.3.1. 
6.5 Protocol Deviations 
A listing of protocol deviations will be provided. 
In Mock Shells: Listing 16.2.2.1. 
6.6 Demographic and Baseline Characteristics 


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Page 14 of 25 
Subject demographics will be summarized by Treatment sequence. Categorical and continuous 
variables will be provided in the same table. The following variables will be presented: age 
(years), sex, ethnicity, race, height (cm), weight (kg), BMI (kg/m2). Percentages will be based on 
the respective population. 
The summaries will be repeated for all Randomized, Safety, PK Populations (as per ICH E3 
Guidelines). If the populations are the same, then demographic summary for Randomized 
Populations will be removed. 
In Mock Shells: Table 14.1.2.1 to 14.1.2.3, Listing 16.2.4.1 
6.7 Medical History 
Previous and ongoing conditions at screening will be listed for the Safety Population. Conditions 
will be coded using the Medical Dictionary of Regulated Activities (MedDRA, version 24.0 or 
higher) and primary SOC and PT will be presented in listings. 
In Mock Shells: Listing 16.2.4.2. 
6.8 Prior and Concomitant Medications 
Prior and concomitant medications will be listed for the Safety Population. Medications will be 
coded using the WHO Drug Dictionary (version Mar 2021 or later) and ATC levels will be 
presented in listings. Prior medications are defined as all medications that ended before the date of 
first dose of study drug. Concomitant medications are defined as medications ongoing on or after 
the date of first dose of study drug. 
In Mock Shells: Listing 16.2.4.3. 
6.9 Exposure to Study Drug 
All dosing and meal consumption information will be listed for the Safety Population.  
In Mock Shells: Listing 16.2.5.1.  
6.10 Statistical Analysis of PK Data 
Natural log transformed AUCinf (if data permit), AUClast, and Cmax, will be analyzed using a 
mixed effect model with sequence, period, and treatment as fixed effects and subject within 
sequence as a random effect. Estimates of the adjusted mean differences (Test-Reference) and 
corresponding 90% confidence intervals (CIs) will be obtained from the model. The adjusted 


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Page 15 of 25 
mean differences and 90% CIs for the differences will be exponentiated to provide estimates of 
the ratio of adjusted geometric means (Test/Reference) and 90% CIs for the ratios. 
For the food effect assessment, simufilam in the fasted state will be the intended reference 
treatment. The following comparisons will be made: 
 High-fat (Test) vs. Fasted (Reference) 
 Low-fat (Test) vs. Fasted. (Reference) 
 Phase 2 tablet formulation (Test) vs. current tablet formulation (Reference; both Fasted). 
6.11 Safety Analyses 
The safety analyses will be presented by the treatment received for the Safety Analysis Set. 
6.11.1 
Adverse Events 
All AEs will be coded by system organ class (SOC) and preferred term (PT) using the latest version 
of the Medical Dictionary for Regulatory Activities (MedDRA, version 24.0 or higher) and 
summarized by treatment and total. 
The following tables/Listings will be presented for TEAEs: 
 Overall incidence and the number of TEAEs, Treatment Related TEAEs, Serious TEAEs 
and Serious Related TEAEs. TEAEs will also be presented by Severity and  Relationship  
 TEAE by system organ class and preferred term, incidence and number of events. 
 Treatment related TEAE by system organ class and preferred term, incidence and number 
of events. 
 Serious TEAE by system organ class and preferred term, incidence and number of events. 
 TEAEs leading to early withdrawal by system organ class and preferred term, incidence 
and number of events. 
 TEAE by system organ class, preferred term and maximum severity, incidence. If a subject 
had multiple occurrences of the same PT within a treatment period, it is counted once with 
maximum severity under the PT; if a subject had multiple PTs within the SOC with 
different grades of maximum severity, it is counted once within each applicable severity 
grade within the SOC and Any TEAE categories. 


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Page 16 of 25 
 TEAE by system organ class, preferred term and closest relationship, incidence. If a subject 
had multiple occurrences of the same PT within a treatment period, it is counted once with 
closest relationship under the PT; if a subject had multiple PTs within the SOC with 
different grades of closest relationship, it is counted once within each applicable 
relationship category within the SOC and Any TEAE categories.   
 Listing of Serious TEAEs (presented in the Table section of the appendices). 
 Listing of Deaths (presented in the Table section of the appendices). 
All AEs will be separately listed. 
In Mock Shells: Tables 14.3.1.1 to 14.3.1.7, Tables 14.3.2.1 to 14.3.2.2, Listing 16.2.7.1 
6.11.2 
Laboratory Data 
6.11.2.1 Descriptive Summaries 
Hematology, Serum Chemistry and Urinalysis assessment at Baseline and EOS/ET will be 
summarized. Descriptive statistics of the observed values and change from baseline will be 
presented by visit for each Hematology, Serum Chemistry and Urinalysis listed below for Safety 
Population. Only total column will be presented. For Urinalysis, categorical results will be 
presented in the same table and percentages will be based on number of subjects with non-missing 
assessments within each visit. 
All laboratory parameters will be listed in the order given below and in units in compliance with 
CDISC Controlled Terminology version 2020-11-06 or later. 
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), total bilirubin, lactose 
dehydrogenase (LDH)  
Urinalysis: color, specific gravity, pH, protein, sugar, ketones, occult blood 
In Mock Shells: Tables 14.3.4.1 and 14.3.4.3 


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Page 17 of 25 
6.11.2.2 Shift Summary 
Shift summaries of the Normal range indicator (Low/Normal/High) will be presented at EOS/ET 
visit for Safety Population.  
All laboratory data including Pregnancy tests, FSH tests, Urine Drug, Alcohol, and Cotinine 
Screens and Serology will be listed. Out of normal range laboratory results will be separately listed. 
In Mock Shells: Tables 14.3.4.4 and 14.3.4.6, 14.3.4.7, Listing 16.2.8.1 to 16.2.8.6 
6.11.3 
Vital Signs 
Vital signs will be measured once in Screening and Day 8 (discharge); on Day 1, Day 3, Day 5, 
and Day 7 at following timepoints: predose (1 hour), postdose 30 and 90 min, and 4, 8, 12 hours 
post-dose (within 15 min of nominal time); on Day 2, Day 4 and Day 6 at timepoints 4 h and 12 
h, and at any other time deemed medically necessary. Vital signs will be measured after a 3-minute 
sitting period. 
 
Vital Signs results at Baseline and all post-baseline timepoints will be summarized. Descriptive 
statistics for observed values and changes from Baseline in the following vital signs parameters 
will be presented by treatment at each visit/timepoint for Safety Population. Screening, results will 
only be listed. All parameters will be listed in the order given below and in units collected. 
 
Systolic blood pressure (mmHg) 
 
Diastolic blood pressure (mmHg) 
 
Heart rate (beats/min)  
 
Respiration rate (breath/min) 
 
Temperature (oC) 
All vital signs data will be listed.  
In Mock Shells: Tables 14.3.5.1, Listing 16.2.8.7 
6.11.4 
Electrocardiogram Data 
A 12 Lead ECG will be collected in Screening and at Day 8 before discharge.  


Worldwide Clinical Trials Controlled Quality Management Document 
 
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Page 18 of 25 
6.11.4.1 Descriptive Summaries 
ECG results at Baseline and EOS/ET will be summarized. Descriptive statistics for observed 
values and changes from Baseline in the following ECG variables will be tabulated at each visit, 
only total column will be presented. 
 
PR Duration(ms) 
 
QRS Duration(ms) 
 
QT interval (ms)  
 
QTc interval (ms) 
 
QTc interval (ms) [Fridericia’s formula - QTcF]  
 
QTc interval (ms) [Bazett’s formula - QTcB]  
 
Ventricular rate (bpm) 
 
RR interval (ms)  
In Mock Shells: Tables 14.3.6.1, Listing 16.2.8.8 
6.11.4.2 Interpretations 
Shift summaries of the Normal range indicator (Normal/Abnormal CS/Abnormal NCS) will be 
presented at EOS/ET visit for Safety Population.  
In Mock Shells: Tables 14.3.6.2 
6.11.5 
Physical Examination 
Physical examination collected in Screening and Day 8 before discharge. All physical and oral 
examination results will be listed including Examination results and Clinically Significant 
findings. 
In Mock Shells: Listing 16.2.8.9 
7 CHANGES TO PLANNED PROTOCOL ANALYSIS 
No changes to planned protocol analysis. 
 


Worldwide Clinical Trials Controlled Quality Management Document 
 
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Page 19 of 25 
8 REFERENCES 
1. SAS Institute Inc., Cary, NC, 27513, USA 
2. Phoenix™ WinNonlin® (Version 8.1, Certara L.P.) 
 
 


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Protocol Number: 
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STATISTICAL ANALYSIS PLAN – PHASE 1 
 
QMD Ref: Worldwide-TMP-ST-006-4.0 Effective: 12Aug2019 
 
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Confidentiality Statement 
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Page 20 of 25 
9 LIST OF TABLES, FIGURES AND LISTINGS 
The following table includes details of the tables, figures and listings to be included within each 
section of the electronic common technical document (eCTD). The eCTD section is shown in bold. 
The following validation methods maybe used:  
 
Independent programming of numbers and manual review of format (IP) 
 
Independent programming by statistician of numbers and manual review of format (Stat 
IP) 
 
Manual review (MR) 
 
Code review (CR) 
Table 
Number 
Table Title 
Validation 
Method 
Shell 
Number 
(if repeat) 
Items in bold are not table titles but references to the section headings within eCTD. 
 
14.1  
Demographics Data 
 
 
14.1.1  
Disposition 
 
 
14.1.1.1 
Subject Disposition, Analysis Populations - All Subjects  
IP 
- 
14.1.2  
Demographics 
 
 
14.1.2.1 
Subject Demographics – Safety Population 
IP 
- 
14.1.2.2 
Subject Demographics – PK Population 
IP 
14.1.2.1 
14.1.2.3 
Subject Demographics – Randomized Population 
IP 
14.1.2.1 
14.2  
Efficacy Data 
 
 
 
Not Applicable 
- 
- 
14.3  
Safety Data 
 
 
14.3.1  
Displays of Adverse Events 
 
 
14.3.1.1 
Adverse Events, Overall Summary of TEAEs - Safety 
Population 
IP 
- 
14.3.1.2 
Adverse Events, Treatment Emergent Adverse Events by 
SOC and PT - Safety Population 
IP 
- 
14.3.1.3 
Adverse Events, Related Treatment Emergent Adverse 
Events by SOC and PT - Safety Population 
IP 
14.3.1.2 


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prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
 
Page 21 of 25 
Table 
Number 
Table Title 
Validation 
Method 
Shell 
Number 
(if repeat) 
14.3.1.4 
Adverse Events, Serious Treatment Emergent Adverse 
Events by SOC and PT - Safety Population 
IP 
14.3.1.2 
14.3.1.5 
Adverse Events, Treatment Emergent Adverse Events 
leading to Early Withdrawal by SOC and PT - Safety 
Population 
IP 
14.3.1.2 
14.3.1.6 
Adverse Events, Treatment Emergent Adverse Events by 
SOC, PT and Maximum Severity - Safety Population 
IP 
- 
14.3.1.7 
Adverse Events, Treatment Emergent Adverse Events by 
SOC, PT and Closest Relationship - Safety Population 
IP 
- 
14.3.2  
Listings of Deaths, Other Serious and Significant 
Adverse Events 
 
 
14.3.2.1 
Adverse Event Leading to Death – Safety Population 
IP 
16.2.7.1 
14.3.2.2 
Serious Adverse Event Data – Safety Population 
IP 
16.2.7.1 
14.3.3  
Narratives of Deaths, Other Serious and Certain Other 
Significant Adverse Events  
 
 
14.3.4  
Abnormal Laboratory Values 
 
 
14.3.4.1 
Hematology Data, Descriptive Statistics - Safety 
Population 
IP 
- 
14.3.4.2 
Clinical Chemistry Data, Descriptive Statistics - Safety 
Population 
IP 
14.3.4.1 
14.3.4.3 
Urinalysis Data, Descriptive Statistics - Safety Population IP 
- 
14.3.4.4 
Hematology Data, Shift Summary - Safety Population 
IP 
- 
14.3.4.5 
Clinical Chemistry Data, Shift Summary - Safety 
Population 
IP 
14.3.4.4 
14.3.4.6 
Urinalysis Data, Shift Summary - Safety Population 
IP 
14.3.4.4 
14.3.4.7 
Out of Range Laboratory Data – Safety Population 
IP 
16.2.8.1 
14.3.5  
Vital Signs  
 
 
14.3.5.1 
Vital Signs Data, Descriptive Statistics - Safety 
Population 
IP 
- 
14.3.6  
Other Safety 
 
 
14.3.6.1 
12 Lead ECG, Descriptive Statistics - Safety Population 
IP 
- 


Worldwide Clinical Trials Controlled Quality Management Document 
 
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Page 22 of 25 
Table 
Number 
Table Title 
Validation 
Method 
Shell 
Number 
(if repeat) 
14.3.6.2 
12 Lead ECG, Shift Summary - Safety Population 
IP 
- 
14.4  
PK Tables 
 
 
14.4.1 
Descriptive 
Statistics 
of 
Simufilam 
Plasma 
Concentration-Time Data after Administration of Phase 3 
Simufilam 100 mg Tablet under Fasted Conditions, with a 
Low-fat Breakfast, with a High-fat Breakfast, and after 
Administration of Phase 2 Simufilam 100 mg Tablet under 
Fasted Conditions– PK Population 
IP 
- 
14.4.2 
Pharmacokinetic Parameters of Simufilam in Plasma after 
Administration of Phase 3 Simufilam 100 mg Tablet under 
Fasted Conditions, with a Low-fat Breakfast, with a High-
fat Breakfast, and after Administration of Phase 2 
Simufilam 100 mg Tablet under Fasted Conditions– PK 
Population 
IP 
- 
14.4.3 
Statistical Analysis of the Natural Log-Transformed 
Systemic Exposure Parameters of Simufilam Comparing 
Phase 3 Simufilam 100 mg Tablet Administered with a 
Low-fat Breakfast (Test) or a High-fat Breakfast (Test) to  
Phase 3 Simufilam 100 mg Tablet Administered under 
Fasted Conditions (Reference)– PK Population 
IP 
- 
14.4.4 
Statistical Analysis of the Natural Log-Transformed 
Systemic Exposure Parameters of Simufilam Comparing 
Phase 2 Simufilam 100 mg Tablet (Test) and Phase 3  
Simufilam 100 mg Tablet (Reference)– PK Population 
IP 
- 
14.6  
Other Data 
 
 
 
Not Applicable 
- 
- 
 
 
 


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Page 23 of 25 
Figure 
Number 
Figure Title 
Validation 
Method 
14.4.1  
Mean Plasma Simufilam Concentration-Time Data after 
Administrations of Phase 3 Simufilam 100 mg Tablet under 
Fasted Conditions, with a Low-fat Breakfast, and with a High-
fat Breakfast on Linear and Semi-logarithmic Scales– PK 
Population 
IP 
14.4.2 
Mean Plasma Simufilam Concentration-Time Data after 
Administrations of Phase 2 Simufilam 100 mg Tablet and 
Phase 3 Simufilam 100 mg Tablet on Linear and Semi-
logarithmic Scales– PK Population 
IP 
14.4.3 
Plasma Simufilam Concentration-time Profiles for All Subjects 
after Administrations of Phase 3 Simufilam 100 mg Tablet 
under Fasted Conditions, with a Low-fat Breakfast, with a 
High-fat Breakfast, and after Administration of Phase 2 
Simufilam 100 mg Tablet under Fasted Conditions on Linear 
and Semi-logarithmic Scales – PK Population 
IP 
14.4.4 
Plasma Simufilam Concentration-time Profiles for Individual 
Subjects after Administrations of Phase 3 Simufilam 100 mg 
Tablet under Fasted Conditions, with a Low-fat Breakfast, and 
with a High-fat Breakfast on Linear and Semi-logarithmic 
Scales – PK Population 
IP 
14.4.5 
Plasma Simufilam Concentration-time Profiles for Individual 
Subjects after Administrations of Phase 2 Simufilam 100 mg 
Tablet and Phase 3 Simufilam 100 mg Tablet on Linear and 
Semi-logarithmic Scales – PK Population 
IP 
14.4.6 
Plasma Simufilam Concentration-time Profiles with Linear 
Regression for Estimating the Terminal Elimination Rate – PK 
Population 
IP 
 
 
 


Worldwide Clinical Trials Controlled Quality Management Document 
 
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Page 24 of 25 
 
Listing 
Number 
Listing Title 
Validation 
Method 
Shell 
Number 
(if repeat) 
16.2  
Subject Data Listings 
 
 
16.2.1  
Discontinued Subjects 
 
 
16.2.1.1  
Subject Disposition – Randomized Population 
IP 
- 
16.2.2 
Protocol Deviations 
 
 
16.2.2.1 
Protocol Deviations – Safety Population 
IP 
- 
16.2.3 
Subjects 
Excluded 
from 
the 
Pharmacokinetic 
Analyses 
 
 
16.2.3.1  
Analysis Populations – Randomized Population 
IP 
- 
16.2.4  
Demographic Data 
 
 
16.2.4.1  
Demographic Data – Safety Population 
IP 
- 
16.2.4.2 
Medical History – Safety Population   
IP 
- 
16.2.4.3 
Prior and Concomitant Medications – Safety Population  
IP 
- 
16.2.5  
Compliance and / or Drug Concentration Data 
 
 
16.2.5.1  
Exposure and Meal Data – Safety Population 
IP 
- 
16.2.6  
Individual Efficacy Response Data   
 
 
16.2.6.1 
Plasma Simufilam Concentration-Time Data Listing by 
Subject - Safety Population 
 
 
16.2.6.2 
Plasma Terminal Elimination Rate of Simufilam for 
Individual Subjects - PK Population 
 
 
16.2.6.3 
PK Output Text (WinNonlin Text File) 
 
 
16.2.6.4 
SAS Output Text 
 
 
16.2.7  
Adverse Event Listings 
 
 
16.2.7.1 
Adverse Event Data – Safety Population 
IP 
- 
16.2.8  
Individual Laboratory Measurements and Other 
Safety 
 
 
16.2.8.1 
Hematology Data – Safety Population 
 
 
16.2.8.2 
Serum Chemistry Data – Safety Population 
IP 
16.2.8.1 
16.2.8.3 
Urinalysis Data – Safety Population 
IP 
16.2.8.1 
16.2.8.4 
Drug, Alcohol and Cotinine Screen – Safety Population 
IP 
- 
16.2.8.5 
Serology Data – Safety Population 
IP 
16.2.8.1 


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Page 25 of 25 
Listing 
Number 
Listing Title 
Validation 
Method 
Shell 
Number 
(if repeat) 
16.2.8.6 
Pregnancy Test Data – Safety Population 
IP 
- 
16.2.8.7 
Vital Signs Data – Safety Population 
IP 
- 
16.2.8.8 
ECG Data – Safety Population 
IP 
- 
16.2.8.9 
Physical Examination Data – Safety Population 
IP 
-