Clinical trial NCT03784300
Conditions: Alzheimer Disease, Early Onset Alzheimer Disease
Sponsor: Pain Therapeutics
Start date: 2017-08-18; Completion date: 2018-03-27
Enrollment: 24 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A Phase I, Single Center, Randomized, Double-blind, Placebo-controlled, Single Ascending Dose, Pharmacokinetic and Safety Study of PTl-125 in Healthy Volunteers

Detailed description:
This was a Phase I, single center, randomized, double-blind, placebo-controlled, single ascending dose (SAD) study in healthy volunteers, 18 to 45 years of age. A total of twenty-four (24) subjects were enrolled into the study in one of three dose cohorts. Each cohort contained eight subjects; six subjects received PTI-125 and two received placebo. Three doses of PTI-125 oral solution (50, 100, and 200 mg) or placebo solution were administered to respective cohorts.

The study included a screening period (Day -28 to Day -1), an inpatient treatment period (Day 0 through Day 4), and a follow-up visit (Day 7). Subjects reported to the clinic on the day before dosing and were randomized to receive either a single dose of orally administered PTI-125 or placebo. Each dose was administered following an overnight fast of at least 10 hours.

For each dose level, dosing was staggered such that two subjects (one active and one placebo) were dosed prior to the rest of the group. After a minimum of 24 hours and review of all 24-hour safety assessments (electrocardiogram \[ECG\], a brief physical examination, vital signs, and laboratory assessments) an independent Data Safety Monitoring Board/Data Monitoring Committee (DSMB/DMC) determined whether the remaining 6 subjects were to be dosed.

Pharmacokinetic blood samples were obtained prior to dosing and at specified intervals during the study (0-72 hours post-dose). Blood draws for laboratory testing were performed prior to dosing and at 24 hours post dose. After safety assessments of ECG, vital signs, and a brief physical exam at 72 hours, subjects were discharged from the clinic and returned 7 days post-dose for a final safety assessment.

Arms: arm 1: Six (6) subjects will receive a single orally administered dose of 50 mg PTI-125 in this cohort. arm 2: Two (2) subjects will receive a single orally administered dose of 50 mg Placebo PTI-125 in this cohort. arm 3: Six (6) subjects will receive a single orally administered dose of 100 mg PTI-125 in this cohort. arm 4: Two (2) subjects will receive a single orally administered dose of 100 mg Placebo PTI-125 in this cohort. arm 5: Six (6) subjects will receive a single orally administered dose of 200 mg PTI-125 in this cohort. arm 6: Two (2) subjects will receive a single orally administered dose of 200 mg Placebo PTI-125 in this cohort.
Interventions: intervention 1: 50 mg PTI-125 intervention 2: 100 mg PTI-125 intervention 3: 200 mg PTI-125
Intervention descriptions: intervention 1: PTI-125 50 mg Oral Solution intervention 2: PTI-125 100 mg Oral Solution intervention 3: PTI-125 200 mg Oral Solution

Protocol documents:
Prot_SAP_ICF_000.pdf: 
 
Pain Therapeutics, Inc. 
Clinical Protocol PTI-125-01 
PTI-125, A novel small molecule for AD 
15 June 2017 
 
Page 1 of 24 
 
 
 
 
CONFIDENTIAL  
 
 
Pain Therapeutics, Inc. 
7801 N. Capital of Texas Hwy, Ste. 260 
Austin, TX 78731 
 
CLINICAL RESEARCH PROTOCOL 
 
 
 
 
PROTOCOL PTl-125-01 
 
 
A Phase I, Single Center, Randomized, Double-blind, Placebo-controlled, 
Single Ascending Dose, Pharmacokinetic and Safety Study  
of PTl-125 in Healthy Volunteers 
 
 
 
 
Sponsor: 
Pain Therapeutics, Inc. 
7801 N. Capital of Texas Hwy, Ste. 260 
Austin, TX 78731 
Phone: 512-501-1900 
 
 
Study Monitor: 
Nadav Friedmann, PhD, MD 
Vice President, Chief Operating & 
Medical Officer, Pain Therapeutics, 
Inc. 
Phone: 925-788-4585 
Email: 
nfriedmann@paintrials.com 
 
 
 
Protocol Date: 
15 June 2017 
 
 
Confidentiality 
The information contained in this document and all information provided to you related to PTl-125 
("Drug") are the confidential and proprietary information of Pain Therapeutics, Inc. (PTI) and except 
as may be required by federal, state, or local laws or regulations, may not be disclosed to others 
without prior written permission of PTI. The Principal Investigator may, however, disclose such 
information to supervised individuals working on the Drug, provided such individuals agree to be 
bound to maintain the confidentiality of such Drug information. 






 
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CONFIDENTIAL  
 
Table of Contents 
1. 
List of abbreviations ............................................................................................... 6 
2. 
INTRODUCTION ................................................................................................... 7 
3. 
STUDY OBJECTIVES .............................................................................................. 8 
4. 
SUMMARY OF STUDY DESIGN ........................................................................... 8 
4.1 STOPPING CRITERIA ..................................................................................................... 9 
5. 
SUBJECT SELECTION ............................................................................................ 9 
5.1. Study Population ........................................................................................................... 9 
5.2. Inclusion Criteria............................................................................................................ 9 
Each subject must comply with the following criteria: ...................................................... 9 
5.3. Exclusion Criteria ........................................................................................................ 10 
6. 
STUDY DRUG ...................................................................................................... 11 
6.1. PTI-125 Physical Description and Preparation............................................................ 11 
6.1.1. Storage ............................................................................................................... 11 
6.1.2. Drug Accountability ............................................................................................ 11 
6.2. Administration and Dosing Regimen ......................................................................... 12 
6.3. Concomitant Medications ............................................................................................. 12 
7. 
STUDY PROCEDURES ......................................................................................... 12 
7.1. Evaluations by Visit ..................................................................................................... 12 
7.1.1. Screening Period ................................................................................................ 12 
7.1.2. In-patient Period - Study Days 0-4 ..................................................................... 13 
7.2. Laboratory Assessments ............................................................................................. 15 
7.2.1. Clinical Laboratory Tests .................................................................................... 15 
7.2.2. Preparation of Plasma Samples for Pharmacokinetic Determination .................. 15 
8. 
EARLY DISCONTINUATION .................................................................................. 16 
9. 
ADVERSE EVENTS/SERIOUS ADVERSE EVENTS ............................................... 16 
9.1. Adverse Events - Definition .......................................................................................... 16 
9.2. Adverse Events - Severity Rating ................................................................................ 17 
9.3. Adverse Events - Relationship to Study Drug .............................................................. 17 
9.4. Serious Adverse Events and Unexpected Adverse Events - Definitions .................... 18 
9.5. Serious Adverse Events Reporting ............................................................................. 19 
10. 
STATISTICAL CONSIDERATIONS ......................................................................... 20 
10.1. Randomization ............................................................................................................ 20 
10.2. Analysis Populations ................................................................................................... 20 
10.3. Pharmacokinetic Parameters ...................................................................................... 20 


 
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CONFIDENTIAL  
 
10.4. Statistical Analysis ....................................................................................................... 21 
10.5. Safety Analysis ............................................................................................................ 21 
10.6. Sample Size ................................................................................................................ 21 
11. 
STUDY TERMINATION.......................................................................................... 21 
12. 
DATA COLLECTION, RETENTION AND MONITORING ...................................... 21 
12.1. Case Report Forms ..................................................................................................... 21 
12.2. Availability and Retention of Investigational Records .................................................. 21 
12.3. Subject Confidentiality ................................................................................................. 22 
12.4. Liability......................................................................................................................... 22 
12.5. Ethical and Legal Issues ............................................................................................. 22 
12.5.1. Ethics Committee/Institutional Review Board ...................................................... 23 
12.6. Informed Consent Form .............................................................................................. 23 
13. 
INVESTIGATOR RESPONSIBILITIES ................................................................. 23 
14. 
Appendix A .......................................................................................................... 25 
 


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CONFIDENTIAL  
1. LIST OF ABBREVIATIONS 
α7nAChR  
 
 
α7 nicotinic acetylcholine receptor 
Aβ42 
 
 
 
amyloid beta1-42 
AD 
 
 
 
Alzheimer’s disease 
AE 
 
 
 
adverse event 
ALT  
 
 
 
alanine transaminase 
ANOVA 
 
 
analysis of variance 
AST   
 
 
aspartate transaminase 
AUC 
 
 
 
area under the curve 
BMI 
 
 
 
body mass index 
BUN 
 
 
 
blood urea nitrogen 
CFR 
 
 
 
Code of Federal Regulations 
Cmax  
 
 
maximum plasma concentration 
CRF 
 
 
 
case report form 
CRO  
 
 
contract research organization 
DSMB/DMC                           Data Safety Monitoring Board/Data Monitoring Committee 
EC 
 
 
 
ethics committee 
ECG 
 
 
 
electrocardiogram 
EDTA  
 
 
ethylenediaminetetraacetic acid 
FDA 
 
 
 
Federal Drug Association 
FLNA  
 
 
filamin A 
GCP 
 
 
 
good clinical practics 
GGT   
 
 
gamma glutamyl transpeptidase 
GLP 
 
 
 
good laboratory practice 
HBsAg  
 
 
hepatitis B surface antigen 
HCV 
 
 
 
hepatitis C virus 
HIV 
 
 
 
human immunodeficiency virus 
hERG  
 
 
human ether-a-go-go-related gene 
ICH 
International Council on Harmonisation of Technical Require-
ments for Registration of Pharmaceuticals for Human Use 
IR 
 
 
 
insulin receptor 
IRB 
 
 
 
independent review board 
LDH   
 
 
lactose dehydrogenase 
LOQ 
 
 
 
limit of quantitation 
NMDA  
 
 
N-methyl D-aspartate 
NOAEL 
 
 
no observable adverse effect level 
OTC 
 
 
 
over-the-counter 
PHCG  
 
 
placental human chorionic gonadotropin 
PK 
 
 
 
pharmacokinetics 
PTI 
 
 
 
Pain Therapeutics, Inc. 
QS 
 
 
 
quantity sufficient 
RBC 
 
 
 
red blood cell 
SAD 
 
 
 
single ascending dose 
SAE 
 
 
 
serious adverse event 
Tmax  
 
 
time to Cmax 
WBC  
 
 
white blood cell 
 


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2. INTRODUCTION 
Pain Therapeutics Inc. (PTI) is developing PTI-125, a novel drug candidate designed to 
treat and slow the progression of Alzheimer’s disease (AD). PTI-125 binds with 
femtomolar affinity to filamin A (FLNA), a scaffolding protein we recently demonstrated 
is critical to beta amyloid’s toxicity. Beta amyloid1-42 (Aβ42) exerts its toxic effects by 
hijacking the α7-nicotinic acetylcholine receptor (α7nAChR) and signaling via this 
receptor to hyperphosphorylate tau. In addition to disrupting the normal functions of 
α7nAChR and tau protein, this toxic signaling leads to the signature tangles and plaques 
found in brains of AD patients. In two animal models and in postmortem human AD 
brain tissue, PTI-125 restored function of three receptors that are impaired in AD: the α7 
nicotinic acetylcholine receptor (α7nAChR); the NMDA receptor; and the insulin receptor 
(IR).1 PTI-125 also reduced tau hyperphosphorylation, amyloid deposits, neurofibrillary 
tangles and inflammatory cytokine release.1 We therefore expect PTI-125 to improve 
memory and slow or halt AD progression, which are clear improvements over existing 
therapeutics. Both mouse models used a single efficacious dose equivalent to 20-22 
mg/kg/day PTI-125 free base. The first mouse study administered twice daily i.p. 
injections of 10 mg/kg (equivalent to 60 mg/m2) PTI-125. The second study delivered 22 
mg/kg/day (equivalent to 66 mg/m2) via drinking water. 
A robust nonclinical ADME, safety pharmacology, and general and genetic toxicology 
program has been carried out with PTI-125.  In vitro metabolic profiling showed minimal 
metabolism across several species and in man. PTI-125 was rapidly absorbed and 
eliminated in in vivo studies in rat and dog with nearly 100% oral bioavailability, a 2.67-h 
half-life in dog, dose proportional PK and no accumulation. Safety pharmacology studies 
showed no adverse effects on gross behavioral and physiological parameters in the 
Irwin test of CNS toxicity in rats, no adverse effects on respiratory rate, tidal volume or 
minute volume in the rat respiratory test, and no adverse effects on arterial blood 
pressure, heart rate and ECG parameters in the dog cardiovascular study. The in vitro 
hERG test for cardiotoxicity also indicated no adverse effect. A full battery of 
genotoxicity studies was conducted (in vitro bacterial Ames, in vitro chromosomal 
aberration, and in vivo rat micronucleus test) and were all negative. An in vitro specificity 
screen showed no significant activation or inhibition of a panel of 67 receptors, channels 
and transporters.  
PTI-125 was tested in single dose and repeat dose oral general toxicity studies in rats 
and dogs.  In a 28-day repeat dose oral general toxicity study followed by a 28-day drug-
free recovery period in rats, with PTI-125 dose levels up to and including 1000 
mg/kg/day (equivalent to 6,000 mg/m2), toxicity was mainly characterized at 
1000 mg/kg/day by a decrease in mean body weight which continued during the 
recovery period. A diffuse cellular hypertrophy of the liver was seen at 1000 mg/kg/day 
in males and females and was interpreted as an adaptive response to the test article.   
There were no other adverse effects and all biologically significant findings noted during 
the dosing period were resolved at the end of the 28-day recovery period. A no-
observed-effect-level (NOEL) could not be determined and the no-observed-adverse-
effect-level (NOAEL) was determined to be 500 mg/kg/day (equivalent to 3,000 mg/m2).  
A 28-day repeat dose oral general toxicity study in dogs, followed by a 28-day drug-free 
recovery period, with PTI-125 dose levels up to and including 200 mg/kg/day (equivalent 


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15 June 2017 
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CONFIDENTIAL  
to 4,000 mg/m2). Findings included slight muscle fasciculations in some animals at the 
high dose only, an increase in blood pressure in high dose females, and sporadic 
alterations in clinical chemistry profiles at the high dose. All observations resolved during 
the recovery period. An NOEL could not be determined and the NOAEL was determined 
to be 100 mg/kg/day (equivalent to 2,000 mg/m2).  
It should be noted that in a 7-day non-GLP dose-range finding study in dogs, 
convulsions (rated “slight”) were observed in one of six animals administered 300 
mg/kg/day on Day 2 and Day 3. On Day 4, this dose was reduced to 150 mg/kg/day, 
and the high dose, 1000 mg/kg/day, was reduced to 200 mg/kg/day. Convulsions were 
not observed in the 1000/200 mg/kg/day animals.  
FDA Guidance1 for estimating the maximum safe starting dose in initial clinical trials was 
followed in determining the dose levels for this clinical trial. A safe human starting dose 
of 1/10th the human dose equivalent of the NOAEL in the most sensitive species (dog) 
was calculated as 330 mg. This first in human Phase I Single Ascending Dose 
(SAD) study will assess the safety and pharmacokinetics of PTI-125 solution at three 
single oral doses (50, 100 and 200 mg, equivalent to 31, 62, and 123 mg/m2, 
respectively) in healthy normal volunteers. 
3. STUDY OBJECTIVES 
The objective of this study is to determine the safety and pharmacokinetics of PTI-125 
following single-dose oral administration in healthy male and female normal volunteers, 
age 18 - 45. 
4. SUMMARY OF STUDY DESIGN 
This is a Phase I, single center, randomized, double-blind, placebo-controlled, SAD 
study of three escalating doses of PTI-125 in healthy male and female volunteers, 18-45 
years of age. A total of twenty-four (24) subjects will be enrolled into the study in one 
of three dose cohorts. Each cohort will contain 8 subjects; six (6) subjects will receive 
PTI-125 and two (2) will receive placebo in each cohort. Three single ascending doses 
of PTI-125 oral solution (50, 100, and 200 mg) or placebo solution will be administered 
to respective cohorts. 
The study includes a screening period (Day -28 to Day -1) and an inpatient treatment 
period (Day 0 through Day 4) and a follow-up visit (Day 7). Subjects will report to clinic 
the day before dosing and will be randomized to receive either a single dose of orally 
administered PTI-125 or placebo. Each dose will be administered following an 
overnight fast of 10 h.  
For each dose level, dosing will be staggered such that 2 subjects (one active and one 
placebo) will be dosed prior to the rest of the group. After a minimum of 24 h and review 
of all 24-h safety assessments (ECG, brief physical, vital signs and laboratory 
                                                     
1 Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics 
in Adult Healthy Volunteers. FDA, CDER, July 2005. 


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CONFIDENTIAL  
assessments) an independent Data Safety Monitoring Board/Data Monitoring 
Committee (DSMB/DMC) will determine whether the remaining 6 subjects will be dosed. 
If safety concerns are raised, 2 additional subjects (randomized according to the Rand 
schedule to maintain blinding) will be dosed followed by collection and review of the 24-
hour safety assessments. The DSMB/DMC will determine after review if dosing will 
proceed for the remaining 4 subjects. 
PK blood samples will be obtained prior to dosing and at specified intervals during the 
study (0-72 h post-dose). PK parameters will be calculated using non-compartmental 
analysis.  
Blood draws for laboratory testing will be performed prior to dosing and at 24 h post-
dose. After safety assessments of ECG, vital signs and a brief physical exam at 72 h, 
subjects will be discharged from the clinic and will return 7 days post-dose for a final 
safety assessment.  
4.1 STOPPING CRITERIA  
 
Dose escalation will be suspended or stopped if any of the following occur and are 
 
potentially related to administration of the study drug:  
 
• 
Clinical signs or symptoms of moderate intensity or greater in two or more 
subjects 
• 
A single clinical sign or symptom of severe intensity  
• 
AST/ALT elevation greater than 3x upper limit of normal  
• 
Bilirubin elevation greater than 2x upper limit of normal  
• 
Creatinine elevation greater than 1.5x upper limit of normal  
• 
Any significant laboratory finding, confirmed by repeat laboratory testing  
 
The DSMB/DMC may subsequently recommend a second sentinel group to proceed 
with planned protocol dosing, or termination of the study.  
 
5. SUBJECT SELECTION 
5.1. STUDY POPULATION 
A total of 24 male and female subjects will be enrolled in the study.  
5.2. INCLUSION CRITERIA 
Each subject must comply with the following criteria:  


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CONFIDENTIAL  
1. Male or female subjects between 18 and 45 years of age, inclusive. 
2. The subject has a body mass index (BMI) within 18-30 kg/m2 (inclusive). 
3. The subject is in good health as determined by medical history and physical 
examination and clinical laboratory parameters.  
4. The subject is willing and able to speak, read, and understand English and provide 
written informed consent. 
5. The subject is a non-smoker for at least 12 months. If a former smoker, the reason 
for stopping must be evaluated. 
6. Females who are physically incapable of childbearing defined as postmenopausal, 
or surgically sterile (hysterectomy, bilateral tubal ligation, bilateral oophorectomy or 
an Essure procedure).  Appropriate documentation (ex; medical record) of the 
surgical sterilization procedure to be obtained and held within the subject’s study 
file. 
7. The subject must agree to comply with the drawing of blood samples for the PK 
assessments. 
 
8. The subject is willing and able to comply with all testing and requirements defined 
in the protocol. 
9. The subject is willing and able to remain at the study site unit for the duration of 
the confinement period and return for the outpatient visit. 
5.3. EXCLUSION CRITERIA 
Subjects 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 Check-in.  
3. The subject has a history of significant neurological, hepatic, renal, endocrine, 
cardiovascular, gastrointestinal, pulmonary, or metabolic disease.  
4. The subject has used any prescription medication within 14 days of dosing or over-
the-counter (OTC) medication within 48 h of dosing or intends to use any 
prescription medication or OTC medication during the study that may interfere with 
the evaluation of study medication.  
5. The subject has used alcohol, caffeine or xanthine-containing products 48 h before 
dosing or intends to use any of these products during the study. 
6. The subject has used grapefruit, grapefruit juice, or grapefruit-containing products 
7 days before dosing or intends to use any of these products during the study.  
7. The subject has a history of substance abuse or a positive ethanol breath test, 
urine cotinine, or urine drug screen at screening or at check-in. 


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CONFIDENTIAL  
8. The subject has a positive serum hepatitis B surface antigen or positive HCV 
antibody test at the Screening Visit.  
9. The subject has a positive HIV test at the Screening Visit.  
10. Female subject is pregnant or breastfeeding. 
11. The subject has received an investigational drug within 30 days of Check-in. 
12. The subject has donated or lost a significant volume of blood (>450 mL) within 4 
weeks prior to the study. 
13. 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. 
14. The subject has an AST/ALT or total bilirubin greater than the ULN. One repeat 
test will be allowed. 
6. STUDY DRUG 
6.1. PTI-125 PHYSICAL DESCRIPTION AND PREPARATION 
Investigational PTI-125 will be supplied by PTI as the bis-HCl monohydrate salt solid 
form and buffer components. An on-site pharmacist will mix a 50 mg/ml solution (free 
base equivalent) in pH 5.2, 0.3 M citric acid / citrate buffer following the study-specific 
pharmacy manual, PTI-125 Clinical Dosing Instructions. To achieve 50 mg, 100 mg, 
and 200 mg dosing solutions, 1, 2 or 4 ml drawn into a 5-ml syringe will be mixed with 
15 ml of ORA-sweet SF drawn into a 20-ml syringe using a syringe connector as 
specified in the manual. After mixing, each dose will be contained in the 20-ml syringe 
and appropriately labeled. Further details on dose preparation and administration are 
found in PTI-125 Clinical Dosing Instructions. Placebo will be 15 ml ORA-sweet SF 
mixed with 1, 2 or 4 ml pH 5.2, 0.3 M citric acid / citrate buffer. 
All containers, syringes or bottles of PTI-125, used or unused, will be saved for final 
disposition by the sponsor or designee. 
6.1.1. Storage 
The bottles and syringes of PTI-125 prior to dissolving and as a solution must 
be stored at refrigerated conditions (2° C - 8° C). PTI-125 in solution can be 
kept at room temperature prior to dosing up to 4 h. 
 
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 


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CONFIDENTIAL  
records must be made available to the sponsor (or designee) and appropriate 
regulatory agencies upon request. 
6.2. ADMINISTRATION AND DOSING REGIMEN 
All subjects in each cohort (8 subjects) will be randomized to receive PTI-125 (6 
subjects) or placebo (2 subjects). Following an overnight fast of at least 10 h, 
subjects will receive a single oral dose of PTl-125 oral solution or placebo followed 
by approximately 240 mls of room temperature water. No food will be allowed until 4 
h post-dose. Water will be allowed as desired except for 1 h before and 1 h after 
dosing. 
6.3. CONCOMITANT MEDICATIONS 
Use of prescription medications will be prohibited for 14 days before initial drug 
administration and during the study. Non-prescription medications will be prohibited 
for 48 h before initial drug administration and during the study. 
Use of alcohol and caffeine- or xanthine-containing products is prohibited for all 
subjects 48 h before dosing and during the study. 
Use of grapefruit, grapefruit juice, and grapefruit-containing products is prohibited 
for all subjects 7 days before dosing and during the study. 
7. STUDY PROCEDURES 
Appendix A presents the Schedule of Activities. 
 
Prior to any study-related activities, the Informed Consent Form must be signed and 
dated by the subject. The format and content of the Informed Consent Form must be 
agreed upon by the Principal Investigator(s), the appropriate IRB and the Sponsor (or 
designee). Appendix B contains a sample Informed Consent for this study. The 
signed and dated Informed Consent Form must be retained by the Investigator in the 
subject's file. 
 
7.1. EVALUATIONS BY VISIT 
7.1.1. Screening Period 
The following will be completed within 29 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 


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• Medical history 
• Review of concomitant medications 
• Physical examination, including measurement of orthostatic vital 
signs (blood pressure, temperature, pulse and respiratory rate after a 3-
min sitting period followed by blood pressure and pulse after a 2-min 
stand period), height, weight and calculated BMI.  
• A 12-lead ECG (5-minute supine) 
• Laboratory assessments, including serum chemistry, hematology, 
and urinalysis; ethanol breath test, urine drug screen, urine cotinine, 
HIV test, HBsAg and HCV Antibody. 
• FSH test for female subjects claiming post-menopausal status 
7.1.2. In-patient Period - Study Days 0-4 
Note:  Study Day 1  is defined as the day of dosing for each dose cohort.  
 
Subjects will check into the clinic at the designated time on Day 0, and will remain 
confined to the clinic until Study Day 4. Upon check-in, the following assessments 
will be conducted: 
 
• Confirmation of inclusion/exclusion criteria 
• Ethanol breath test 
• Urine drug screen 
• Urine Cotinine test 
• Review of concomitant medications 
• Orthostatic vital signs (blood pressure, temperature, pulse and 
respiratory rate after a 3-min sitting period followed by blood pressure 
and pulse after a 2-min stand period). 
• Brief physical examination 
 
Following a supervised fast for at least 10 h, subjects will be administered a single 
oral dose of study drug (or placebo) on Study Day 1.  
The appropriate dosing syringe of PTI-125 or placebo (15 ml ORA-sweet SF mixed 
with 1, 2 or 4 ml pH 5.2, 0.3 M citric acid / citrate buffer) mixed with ORA-sweet SF 
for taste masking will be administered. Subjects will also consume water provided as 
a rinse of the dosing syringe, to ensure complete consumption of study drug.   
No food will be allowed for 4 h post-dose. Water will be allowed as desired except 
for 1 h before and 1 h after dosing. At 4 h post-dose, subjects will be provided a 
standard lunch.  


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On the morning of Study Day 1, within 30 min prior to dosing, the following 
assessments will be conducted: 
 
• Orthostatic vital signs (blood pressure, temperature, pulse and 
respiratory rate after a 3-min sitting period followed by blood pressure 
and pulse after a 2-min stand period). 
• Review of concomitant medications 
• 
Blood sample collection for baseline PK assessment (Sample Time=0) 
• 
On Day 1, blood sample collection for laboratory testing prior to dosing 
(Time=0) 
• 
ECG (Time=0) 
 
After dose, the following assessments will be conducted: 
• Orthostatic vital signs (blood pressure, temperature, pulse and 
respiratory rate after a 3-min sitting period followed by blood pressure 
and pulse after a 2-min stand period) at approximately 10 and 30 
minutes, and 1, 2, 3, 4, 8, 12, 24, 36, 48 and 72 h post-dose. 
• Blood samples will be drawn at 20, 40, and 60 min following dosing and 
at 2, 3, 4, 6, 8, 12, 24, 36, 48 and 72 h for PK assessments 
• Adverse event monitoring 
• Clinical laboratory tests at approximately 24 h post-dose 
• Brief physical examination at approximately 24 and 72 h post-dose 
• ECG at approximately 30 min, and 1, 2, 3, 4, 8, 12, 24, 36, 48 and 72 
h post-dose. 
            Should procedures occur at the same nominal timepoint collection of the PK 
 
assessment will take priority. All other procedures will be performed within a 
 
sufficient +/- window for logistical purposes.  
 
All subjects will receive a standardized lunch 4 h post-dose. All subsequent meals 
will be served at standard meal times. 
 
Clinic personnel will monitor the subjects for the occurrence of any adverse events 
until subjects are discharged from the clinic. Subjects will be discharged from the 
clinic upon investigator judgment after results of all safety assessments following the 
last dose have been reviewed. 
 
7.1.3. Follow-up Visit – Study Day 7 
At the Day 7 follow up visit, the following assessments will be conducted: 
• Orthostatic vital signs (blood pressure, temperature, pulse and 


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CONFIDENTIAL  
respiratory rate after a 3-min sitting period followed by blood pressure 
and pulse after a 2-min stand period) 
• ECG 
• Adverse event monitoring 
• Physical examination 
• Clinical laboratory tests 
 
7.2. LABORATORY ASSESSMENTS 
7.2.1. Clinical Laboratory Tests 
The following clinical laboratory tests will be performed at screening, Day 1 pre-dose, 
at 24 h post-dose, and at the Day 7 follow-up visit: 
 
• Hematology:  white blood cell (WBC) count with differential, red blood 
cell (RBC) count, hemoglobin, hematocrit, platelet count. 
• 
Serum Chemistry:  glucose, sodium, potassium, chloride, bicarbonate, 
blood urea nitrogen (BUN), creatinine, uric acid, phosphorus, calcium, 
total 
protein, 
albumin, 
globulin, 
alkaline 
phosphatase, 
alanine 
transaminase (ALT), aspartate transaminase (AST), gamma glutamyl 
transpeptidase (GGT), total bilirubin, lactose dehydrogenase (LDH). 
• Urinalysis: color, specific gravity, pH, protein, sugar, ketones, occult 
blood, creatinine clearance calculation by Cockcroft-Gault equation. 
• At screen only: FSH will be performed on all females claiming to be of 
post-menopausal status. 
 
The following tests will be performed at screening and at check-in to the clinic: 
 
• Urine drug screen:  amphetamines, barbiturates, benzodiazepines, 
cocaine, opiates, and cannabinoids 
• Urine Cotinine 
• Ethanol breath test 
• HIV test (screening only) 
• HBsAg, HCV Antibody tests (screening only) 
7.2.2. Preparation of Plasma Samples for Pharmacokinetic Determination 
At each blood collection, blood samples (4 mL) will be drawn into a Vacutainer® 
tube containing K2EDTA.  The tubes will be placed on ice.  Within 30 minutes of 
collection, the blood will be centrifuged at approximately 1000 X G for 15 minutes 
between 4-5°C. Within 30 minutes of centrifuging, plasma (at least 1.5 mL) will be 
split evenly into two aliquots, transferred to polypropylene tubes and stored at 


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approximately -70°C or below until analysis. The time from sample collection to 
storage should not exceed 60 minutes. 
At the end of the study the samples will be shipped frozen on dry ice to: 
Worldwide Clinical Trials Bioanalytical Sciences, 8609 Cross Park Drive, Austin, 
TX 78754 for bioanalytical analysis of PTI-125 with a validated assay. Remaining 
samples following the analysis of PTI-125 are to be retained until directed for 
disposition by PTI. All samples from PTI-125 subjects will be analyzed. One sample 
around the Cmax from each placebo subject will be analyzed, such as 40 min, 1 or 2 
h. All secondary samples will be shipped to Worldwide Clinical Trials Bioanalytical 
Sciences upon confirmation of receipt of the primary samples.  
 
8. EARLY DISCONTINUATION 
Subjects may choose to discontinue study drug or study participation at any time, for 
any reason, and without prejudice. 
 
The following must be completed and documented in the source documents and 
CRFs for all subjects who discontinue the study early: 
 
• 
The reason for early study discontinuation. 
• 
Safety data should be obtained and will include the following: 
• 
Orthostatic vital signs (blood pressure, temperature, pulse and 
respiratory rate after a 3-min sitting period followed by blood pressure 
and pulse after a 2-min stand period), brief physical examination, clinical 
laboratory tests, ECG, use of concomitant medications, and adverse 
events. 
9. ADVERSE EVENTS/SERIOUS ADVERSE EVENTS  
9.1. ADVERSE EVENTS - DEFINITION 
An adverse event (AE) is any undesirable event that occurs to a subject during a 
study, whether or not that event is considered study drug-related. Monitoring for AEs 
will start at dosing. Examples include: 
• Any treatment-emergent signs and symptoms (events that are marked by a 
change from the subject's baseline/entry status [e.g., an increase in severity or 
frequency of pre-existing abnormality or disorder]) 
• All reactions from study drug, an overdose, abuse of drug, withdrawal 
phenomena, sensitivity or toxicity to study drug 
• Apparently unrelated illnesses 
• Injury or accidents (Note: if a medical condition is known to have caused the 


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injury or accident, the medical condition and the accident should be reported as 
two separate medical events [e.g., for a fall secondary to dizziness, both 
"dizziness" and "fall" should be recorded separately]) 
• Extensions or exacerbations of symptoms, subjective subject-reported events, 
new clinically significant abnormalities in clinical laboratory, physiological testing 
or physical examination 
 
All AEs, whether or not related to the study drug, must be fully and completely 
documented on the AE page of the Case Report Form (CRF) and in the subject's 
clinical chart. 
In the event that a subject is withdrawn from the study because of an AE, it must be 
recorded on the CRF as such. The subject should be followed and treated by the 
Investigator until the abnormal parameter or symptom has resolved or stabilized. 
 
The Investigator must report all directly observed AEs and all spontaneously 
reported AEs. The Investigator will ask the subject a non-specific question (e.g., 
"Have you noticed anything different since your dose of the study medication?") to 
assess whether any AEs have been experienced since the last assessment. AEs 
will be identified and documented on the AE CRF in appropriate medical 
terminology. The severity and the relationship to the study drug will be determined 
and reported on the CRF (see below). 
 
9.2. ADVERSE EVENTS - SEVERITY RATING 
The severity of each AE should be characterized and then classified into one of 
three clearly defined categories as follows: 
• Mild - the AE does not interfere in a significant manner with the subject's 
normal functioning level. It may be an annoyance. 
• Moderate - the AE produces some impairment of functioning, but is not 
hazardous to health. It is uncomfortable or an embarrassment. 
• Severe - the AE produces 
significant 
impairment 
of functioning 
or 
incapacitation and is a definite hazard to the subject's health. 
These three categories are based on the Investigator's clinical judgment, which in 
turn depends on consideration of various factors such as the subject's report, and 
the physician's observations. The severity of the AE should be recorded in the 
appropriate section of the Adverse Event CRF. 
9.3. ADVERSE EVENTS  -  RELATIONSHIP TO STUDY DRUG 
The relationship of each AE to the study drug will be classified into one of three 
defined categories as follows: 
• Unlikely - a causal relationship between the AE and the study drug is 


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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. 
9.4. SERIOUS ADVERSE EVENTS AND UNEXPECTED ADVERSE EVENTS - DEFINITIONS 
Any AE that suggests a significant hazard, contraindication, side effect or precaution 
is defined as a Serious Adverse Event (SAE).  An SAE includes (but is not limited 
to) an experience occurring at any dose that results in any of the following 
outcomes: 
• Death 
• A life-threatening event (i.e., the subject is at immediate risk of death from the 
reaction as it occurs). "Life-threatening" does not include an event that, had it 
occurred in a more serious form, might have caused death. For example, drug­ 
induced hepatitis that resolved without evidence of hepatic failure would not be 
considered life-threatening even though drug-induced hepatitis can be fatal. 
• In-patient hospitalization (hospital admission, not an emergency room visit) or 
prolongation of existing hospitalization. 
• A persistent or significant disability/incapacity (i.e., a substantial disruption of 
the subject's ability to carry out normal life functions). 
• A congenital anomaly/birth defect. 
 
In addition, medical and scientific judgment should be exercised in deciding whether 
other situations should be considered an SAE (i.e., important medical events that 
may not be immediately life-threatening or result in death, but may jeopardize the 
subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the definition above). Examples of such medical events include 
(but are not limited to): allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
in-patient hospitalization, or the development of drug dependency or drug abuse. 
An unexpected AE is one for which the specificity or severity is not consistent with 
the current Investigator's Brochure. For example, hepatic necrosis would be 


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unexpected (by virtue of greater severity) if the Investigator's Brochure only listed 
elevated hepatic enzymes or hepatitis. 
Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected 
(by virtue of greater specificity) if the Investigator's Brochure only listed cerebral 
vascular accidents. 
9.5. SERIOUS ADVERSE EVENTS REPORTING 
The reporting of SAEs by the Sponsor to Regulatory Authorities (e.g., FDA) is a 
regulatory requirement.  Each Regulatory Agency has established a timetable for 
reporting SAEs based upon established criteria.  Likewise, it is the responsibility 
of the Principal Investigator to report SAEs to their EC/IRB. 
All SAEs must be reported immediately (within 24 h of learning of the event) by 
telephone to: 
 
Nadav Friedmann, PhD, MD 
Pain Therapeutics, Inc.  
Email: nfriedmann@paintrials.com 
Phone:    925-788-4585 
 
Do not delay reporting a suspected SAE to obtain additional information.  Any 
additional information, if collected, can be reported to the Sponsor as a follow-up 
to the initial report. 
 
A completed SAE report form must be faxed within five working days to the 
medical monitor. SAEs must also be reported to the responsible EC/IRB 
immediately. 
 
In the case of a death or other SAE that has occurred within 30 days after 
receiving study drug, the Principal Investigator must also report such an event 
within 24 hours of being notified. Your local EC/IRB may also require these 
reports. 
In the event of any SAE (other than death), the subject will be instructed to 
contact the study physician (Principal Investigator or designee) using the phone 
number provided in the Informed Consent Form. All subjects experiencing an 
SAE will be seen by a Principal Investigator or designee as soon as feasible 
following the report of an SAE. 


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10. STATISTICAL CONSIDERATIONS 
10.1. RANDOMIZATION 
Subjects will be assigned to PTI-125 or placebo based on a computer-generated 
randomization schedule prepared prior to the study. Pain Therapeutics, Inc. (PTI) will 
interact with the pharmacy to have study drug for each subject labeled according to 
this randomization code. Randomization Numbers will be used as subject code 
numbers and will be assigned when qualified subjects are randomized. 
The randomization code will not be revealed to study subjects, investigators, clinical 
staff or study monitors until all subjects have completed therapy and the database has 
been finalized and closed.  
Under normal circumstances, the blind should not be broken. The blind may be broken 
only if specific emergency treatment is indicated. The date, time and reason for the 
unblinding must be documented on the case report form, and the medical monitor 
must be informed as soon as possible. 
10.2. ANALYSIS POPULATIONS 
All subjects who receive study medication will be included in safety analyses. All 
subjects who have sufficient data for PK analysis will be included in the PK analysis 
population.  
10.3. PHARMACOKINETIC PARAMETERS 
PK parameters for PTI-125 will be calculated using non-compartmental methods in 
WinNonlin. The peak drug concentration (Cmax), the time to peak drug concentration 
(Tmax), Tlast and Clast, the time to and concentration of the last quantifiable drug 
concentration, will be obtained directly from the data without interpolation.  The 
following parameters will be calculated: the elimination rate constant (λz), the terminal 
elimination half-life (T1/2), the AUC from time zero to the time of the last quantifiable 
concentration (AUClast), the AUC from time zero extrapolated to infinity (AUCinf), and 
the percentage of AUCinf based on extrapolation (AUCextrap(%)), Cl/F, the apparent oral 
clearance, and Vz/F, apparent volume of distribution.  
 
In the pharmacokinetic analysis, BLQ concentrations will be treated as zero from time-
zero up to the time at which the first quantifiable concentration was observed; 
embedded and/or terminal BLQ concentrations will be treated as “missing”. Full 
precision concentration data (not rounded to three significant figures) and actual 
sample times will be used for all pharmacokinetic and statistical analyses. Nominal 
sampling times will be used to prepare concentration versus time profiles. 
 


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10.4. STATISTICAL ANALYSIS 
Comparison of the PK parameters Cmax, AUClast, and AUCinf for PTI-125 between 
treatments will be done using an analysis of variance (ANOVA) model with factors for 
period and treatment.  Tmax will be compared among groups using a non-parametric 
analysis (Wilcoxon Rank Sum or Signed Ranks tests). 
 
10.5. SAFETY ANALYSIS 
Adverse events reported on case report forms will be mapped to preferred terms 
and organ systems using the MedDRA mapping system. Vital signs and clinical 
laboratory results will be descriptively summarized in terms of change from 
screening values. 
10.6. SAMPLE SIZE 
2 4 subjects will be enrolled in this study. Sample size was determined by estimating 
the intrasubject variability for log-transformed data from previous studies of new 
chemical entities (NCEs). 
11. STUDY TERMINATION 
The study will be terminated following completion of the study or at any time at the 
discretion of the Sponsor. 
12. DATA COLLECTION, RETENTION AND MONITORING 
12.1. CASE REPORT FORMS 
Case report forms (CRFs) will be provided for each subject. The 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 Screening Number 
and Randomization Number. 
All clinical information requested in this protocol will be recorded in electronic 
CRFs. 
CRFs must be reviewed and verified for accuracy by the Principal Investigator 
and signed-off before collection by the Sponsor (or CRO designee). A copy of the 
CRF will remain at the Investigator's site at the completion of the study. 
12.2. AVAILABILITY AND RETENTION OF INVESTIGATIONAL RECORDS 
The Investigator must make study data accessible to the monitor, other 
authorized representatives of the Sponsor (or designee) and Regulatory Agency 


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(e.g., FDA) inspectors upon request. To assure accuracy of data collected in the 
CRFs, it is mandatory that Sponsor representatives have access to original 
source documents (e.g., subject records, subject charts, and laboratory reports). 
During review of these documents, the subject's anonymity will be maintained 
with adherence to professional standards of confidentiality and applicable laws. A 
file for each subject must be maintained that includes the signed Informed 
Consent Form and all source documentation related to that subject. The 
Investigator must ensure the reliability and availability of source documents from 
which the information on the CRF was derived. 
Investigators are required to maintain all study documentation until notification by 
PTI that any records may be discarded. 
The Investigator is responsible for maintaining adequate case histories in each 
subject's source records. 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. 
12.3. 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. 
12.4. LIABILITY 
In the event of a side effect or injury, appropriate medical care as determined by 
the Investigator or his/her designated alternate will be provided. 
If a bodily injury is sustained, resulting directly from the use of the study drug, 
the Sponsor will reimburse for reasonable physician fees and medical 
expenses necessary for treatment of only the bodily injury which is not covered 
by the subject's medical or hospital insurance, provided that the injury is not 
due to a negligent or wrongful act or omission by the study doctor and his/her 
staff. No other compensation of any type will be provided by the study Sponsor. 
Financial compensation for lost wages, disability or discomfort due to the study 
is not available. 
 
12.5. ETHICAL AND LEGAL ISSUES 
The Investigator and site personnel are responsible for conducting this study in 
accordance with the ICH, GCP, and all other applicable laws and regulations. 


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12.5.1. Ethics Committee/Institutional Review Board 
The protocol and Informed Consent Form must be approved by an EC/IRB 
before the study is initiated. The EC/IRB must comply with U.S. CFR 21 Part 
56 and local regulations. 
Documentation of EC/IRB approval must be provided to the Sponsor. 
Investigators are responsible for the following: 
• Obtaining EC/IRB approval of the protocol, Informed Consent Form, and 
any advertisements to recruit subjects and EC/IRB approval of any 
protocol amendments and Informed Consent Form revisions before 
implementing the changes. 
 
• Providing the EC/IRB with any required information before or during the 
study. 
 
• Submitting progress reports to the EC/IRB, as required, requesting 
additional review and approval, as needed; and providing copies of all 
relevant EC/IRB communications to the Sponsor. 
• Notifying the EC/IRB within 15 calendar days of all SAEs and unexpected 
AEs related to study medications reported by the Sponsor to the 
Investigator. 
 
12.6. INFORMED CONSENT FORM 
The Sponsor (or designee) must review the Investigator's proposed Informed 
Consent Form prior to EC/IRB submission for approval. An EC/IRB-approved 
copy of the Informed Consent Form is forwarded to the Sponsor. 
 
The Informed 
Consent 
Form documents 
study-specific 
information 
the 
Investigator provides to the subject and the subject's agreement to participate. 
The Investigator explains in plain terms the nature of the study along with the 
aims, methods, anticipated benefits, potential risks, and any discomfort that 
participation may entail. The Informed Consent Form must be signed and dated 
before the subject enters the study. The original Informed Consent Form and 
any amended Informed Consent Form, signed and dated, must be retained in 
the subject's file at the study site and a copy must be given to the subject. 
 
13. INVESTIGATOR RESPONSIBILITIES 
The Investigator agrees to: 
• Conduct the study in accordance with the protocol and only make changes 


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after notifying the Sponsor, except to protect the safety, rights, or welfare of 
subjects 
• Personally conduct or supervise the study 
• Inform any subjects or individuals used as controls that the drug is 
being used for investigational purposes 
• Ensure that requirements related to obtaining informed consent and 
EC/IRB review and approval comply with ICH, CFR 21 Parts 50 and 56, 
and local laws. 
• Report to the Sponsor any AEs that occur during the study in accordance with 
ICH, CFR 21 Part 312.64 and local laws 
• Read and understand the Investigator's Brochure including potential risks 
and side effects of the drug. 
• Ensure that all associates, colleagues, and employees assisting in the conduct 
of the study are informed about their obligations in meeting the above 
commitments. 
• Maintain adequate records in accordance with ICH, 21 CFR Part 312.62, and 
local laws and have records available for inspection by the Sponsor, FDA, or 
other authorized agency. 
• Ensure that EC/IRB complies with requirements of ICH, 21 CFR Part 56, and 
local laws and will be responsible for initial and continuing review and approval 
of the clinical study. 
• Promptly report to the EC/IRB and the Sponsor all changes in research activity 
and unanticipated problems involving risks to subjects or others (including 
amendments and expedited safety reports). 
• Comply with all other requirements regarding obligations of Clinical 
Investigators and all other pertinent requirements listed in ICH, 21 CFR Part 
312 and local laws. 


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14. APPENDIX A 
Events Schedule 
PROCEDURE 
SCREENING 
(Day -28 to 
Day -1) 
CHECK-
IN (Day 
0) 
DAY 1 
Time=0 
DAYS 
2 & 3 
DAY 4   
(72 Hours) 
 
DAY 7 
Informed consent 
X 
 
 
 
 
 
Medical and 
medication histories 
X 
X 
 
 
 
 
ECG  
X 
 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
Brief 
 
Brief b 
Brief 
X 
Biochemistry, 
hematology, 
urinalysis 
X 
 
X 
Xb 
 
X 
FSH (female 
participants claiming 
post-menopausal 
status only) 
X 
 
 
 
 
 
Urine cotinine screen 
X 
X 
 
 
 
 
Urine drug screena 
X 
X 
 
 
 
 
Ethanol breath test  
X 
X 
 
 
 
 
HIV test 
X 
 
 
 
 
 
HBsAg and HCV 
Antibody 
X 
 
 
 
 
 
Drug administration 
 
 
X 
 
 
 
Blood sample 
collection for PK 
analysis 
 
 
X 
X 
X 
 
Adverse events 
 
 
X 
X 
X 
X 
Discharge 
 
 
 
 
X 
 
 
a. amphetamines, barbituates, benzodiazepines, cocaine, opiates and cannabinoids 
b. 24 h post dose  
 
 
 
 
 


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15. APPENDIX B 
 
INFORMED CONSENT DOCUMENT 
AGREEMENT TO BE IN A RESEARCH STUDY 
 
NAME OF SPONSOR COMPANY: Pain Therapeutics, Inc. 
 
PROTOCOL NUMBER AND TITLE OF STUDY: 
PTI-125-01: “A Phase I, Single Center, 
Randomized, Double-blind, Placebo-controlled, Three-
Period Single Ascending Dose, Pharmacokinetic and 
Safety Study of PTI-125 in Healthy Volunteers” 
 
NAME OF PERSON IN CHARGE OF THE RESEARCH  
STUDY (STUDY DOCTOR/INVESTIGATOR): 
George J. Atiee, M.D. 
 
TELEPHONE NUMBER(S), DAYTIME: 
(210) 635-1500 (Monday-Friday, 8:00 a.m.-5:00 
p.m.) 
AFTER HOURS: 
(210) 426-5342 
 
INTRODUCTION 
 
You are being invited to volunteer for a medical research study. You must read and sign this form 
before you agree to take part in this study. This form will give you more information about this study. 
Please ask as many questions as you need to before you decide if you want to be in the study. You 
should not sign this form if you have any questions that have not been answered. 
 
The investigator is being paid by the sponsor (the company paying for this study) to conduct this 
research study. 
 
You must be honest with the investigator about your health history or you may harm yourself by 
participating in this study. 
 
THIS IS THE FIRST STUDY IN WHICH THE STUDY DRUG IS BEING GIVEN TO 
HUMANS. 
 
PURPOSE OF THE STUDY 
In this document, you may see the terms “medication”, “treatment”, and “treatment period”; these are 
terms used in research studies as mentioned above.  This does not mean that you will be receiving 


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medical treatment for any condition. These terms apply to the investigational study drug and parts of 
the study where you will be receiving this investigational product. 
 
The purpose of this study is to measure the blood levels of Pain Therapeutics, Inc.’s new 
investigational drug PTI-125, and to determine if there are any side effects associated with the drug. 
PTI-125 is intended to slow the progression of Alzheimer’s disease as well as provide some cognitive 
recovery.  
 
 
"Investigational" means the study drug being tested is not approved by the United States Food and 
Drug Administration (FDA). 
 
If you qualify for the study, you will receive three doses of PTI-125 (investigational product), listed 
below, or three doses of placebo. Each dose (active or placebo) will be separated by a 3-day drug-
free (washout) period. The first two subjects (sentinel group) in the group will receive the first dose 
of study drug or placebo and the rest of the group will receive their assigned dose at least 24 hours 
later unless it is determined that an additional sentinel group is necessary.  
• 
A single 50 mg dose of oral solution of PTI-125 or placebo oral solution  
• 
A single 100 mg dose of oral solution of PTI-125 or placebo oral solution  
• 
A single 200 mg dose of oral solution of PTI-125 or placebo oral solution  
 
Placebo contains no active ingredient. 
 
This is a double-blind study, which means that neither you nor the investigator will know whether 
you are taking PTI-125 or placebo.  The study staff can get this information if needed. 
 
Whether you receive PTI-125 or placebo will be assigned by chance, like the flip of a coin.   
 
 
HOW LONG THE STUDY WILL LAST AND HOW MANY PEOPLE WILL BE IN THE 
STUDY 
The study will last about 11 days, excluding the screening period, and involve up to 10 
nights at the facility. About 16 healthy men and women, ages 18 through 45, are expected 
to be in this study.  
TO BE IN THIS STUDY 
You cannot be in this study if you: 
 
• 
Are in another research study or if you have been in any other research study in which you 
received study drug within 30 days before the first dose of study formulation 
• 
Are taking any drugs of abuse (illegal and/or prescription).  A urine test will be performed to 
check for the use of these drugs. You may be observed during any urine sample collection 
process. 
• 
Have donated blood within 4 weeks before the first dose of study formulation 
Subject Responsibilities: 


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While participating in this research study, you will need to: 
 
• 
Be willing and able to follow the study directions and procedures 
• 
Tell the study staff about any side effects or problems 
• 
Ask questions as you think of them 
• 
Tell the investigator or the study staff if you change your mind about staying in the study. 
 
This study involves testing an investigational drug developed by the sponsor. We ask subjects to keep 
information as confidential as possible. This would include not sharing details of the study, including 
requirements for participation, information received on the risks and benefits of dosing with this 
study drug, and symptoms or reactions to study drug dosing while enrolled in the study, with persons 
other than the clinic staff, your family and your healthcare provider. This would also include not 
disclosing such information on social media sites or webpages. 
 
WHAT WILL HAPPEN DURING THE STUDY 
Screening 
 
Before the study starts, you will be asked to sign this consent form, give your health and social 
history, and tell study staff if you take any over-the-counter or prescription medicines, vitamins, or 
herbs.  
 
The investigator will do some tests to find out if you can be in the study. These tests include: 
 
• 
Physical exam, including vital signs (blood pressure, temperature, heart and breathing rates), 
height and weight   
• 
An electrocardiogram (ECG) will be taken - this is a recording of the electrical activity of your 
heart 
• 
Lab tests (blood and urine) 
• 
Blood test for HIV and hepatitis B and C  
• 
Urine test for drugs of abuse (illegal and/or prescription) and cotinine (tobacco)  
• 
Alcohol breath test will be done 
• 
Urine pregnancy tests for female participants of childbearing potential 
 
The Screening Visit may take up to 2 hours and 30 minutes of your time. 
 
If you qualify for the study, you will return to the clinic for the three Treatment Periods.  If you are 
more than 1 hour late to your study check in, you may be placed in alternate/backup status. 
 
 
Study Procedures 
 
Prior to Treatment Period 1 
 
The following will be done prior to the first of three Treatment Periods (each of three doses will be 
separated by 3 days):  


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• 
You will be asked questions to be sure that you still qualify for this study 
• 
You will be asked about any changes in your health or drugs you have taken since your last visit 
• 
Vital signs (blood pressure, heart rate, breathing rate and temperature) will be taken prior to 
receiving each dose of study drug  
• 
If you are female of childbearing potential, a urine pregnancy test will be performed at check in  
• 
A urine sample will be taken at check in – the urine tests will include finding out if you have 
used any cotinine or drugs of abuse (illegal and prescription). You may be observed during any 
urine sample collection process. 
• 
An alcohol breath test will be done at check-in to ensure you have not recently consumed alcohol  
• 
An optional snack will be given the evening of check-in at the clinic 
 
Treatment Periods 1, 2 and 3 
 
• 
Standard meals will be given at scheduled times during each stay in the clinic 
• 
You will have to fast (nothing to eat or drink except water) for at least 10 hours before taking 
study drug and for 4 hours after dosing 
• 
You will be randomly assigned, like the flip of a coin, to take PTI-125 or placebo. 
• 
You will take an oral solution of the assigned study drug or placebo. The study staff will perform 
a mouth check to ensure that the solution is swallowed completely. 
• 
Aside from the oral solution and two rinses of the dosing syringe with water, you may not drink 
any other water from 1 hour before dosing through 1 hour after dosing. At other times during the 
study, you can drink water. 
• 
After taking the study drug you will not be allowed to lie down for the first 1-2 hours and must 
stay seated during that time 
• 
The level of study drug in your blood will be measured.  About 3/4 teaspoon (4 mL) of blood 
will be taken at multiple time-points during your stay in the study clinic  
• 
Vital Signs (temperature, blood pressure, heart rate and breathing rate) will be performed at 
multiple time points during the study 
• 
A physical exam will be conducted at 48 hours after each dose of study drug or placebo  
• 
An electrocardiogram (ECG; a recording of the electrical activity of your heart) will be 
conducted at 48 hours after each dose of study drug or placebo.  
• 
Lab tests (blood and urine)  
• 
You will be monitored for any side effects  
 
If you leave the study early or are withdrawn the following procedures will be performed:  
• 
Vital Signs (temperature, blood pressure, heart and breathing rates)  
• 
Physical examination  
• 
Lab tests (blood and urine)  
• 
Electrocardiogram (ECG)  
 
Blood Samples: 
 
Blood samples will be taken by single needle-sticks or by a tube that is left in your arm.  You cannot 
choose how the blood is taken. 
There will be about 41 blood draws. The total amount of blood drawn will be about 227 mL, or about 
1 cup. For comparison, the standard blood donation is about 480 mL (two cups). Additional blood 
may be drawn and additional tests performed for your safety.   


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CONFIDENTIAL  
HIV AND HEPATITIS TESTING 
As required by the study and if any person is exposed to your blood, you must have your blood tested 
for the hepatitis viruses and for HIV.  HIV is the virus that causes AIDS.  If you have a positive HIV 
or hepatitis test you cannot be in the study. 
 
It may take weeks or months after being infected with HIV for the test to be positive.  The HIV test is 
not always right. 
 
We are required to report positive HIV test results to the San Antonio Metro Health District.  We 
may also be required to report positive hepatitis test results to the San Antonio Metro Health District.  
Positive test results may be required to be reported to the State Department of Health.  If you have 
any questions about what information is required to be reported please ask the investigator or study 
staff. 
 
Although this testing is supposed to be private, this cannot be guaranteed.  For example, it is possible 
for a court of law to get health or study records without your permission. 
 
Additionally, in the unlikely event that a study employee has been exposed to your blood or other 
body fluid either through a needle stick injury, splash incident or contact with broken skin (i.e., cut, 
bite), additional samples may be collected to determine and confirm whether or not you have a 
certain infection.  Your de-identified results will be released to the injured employee, and to the 
health care provider evaluating and treating that employee, to aid the injured employee and the 
medical provider make decisions regarding his/her medical treatment and follow-up care as a result 
of this on-the-job exposure. 
 
POSSIBLE SIDE EFFECTS AND RISKS  
If you do not understand what any of these side effects mean, please ask the investigator or study 
staff to explain these terms to you.  
 
Because this drug is investigational, all its side effects may not be known. There may be rare and 
unknown side effects. Some of these may be life threatening.  
  
In pre-clinical (animal studies) the following side effects were seen:  
• 
Vomiting  
• 
Increased salvation  
• 
Increased blood pressure  
• 
Weight loss 
• 
Changes to the size of the liver cells 
 
You must tell the investigator or study staff about all side effects that you have. If you are not honest 
about your side effects, you may harm yourself by staying in this study. 
 
All drugs may cause allergic reactions in some people. Below is a list of symptoms of an allergic 
reaction: 
 


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CONFIDENTIAL  
• 
Swelling of the face, lips, throat, and other areas of the skin 
• 
Difficulty swallowing or breathing 
• 
Raised, red areas on your skin 
• 
Skin rash, itching, flaking, or peeling 
 
If you have a side effect of the drug, such as a skin rash or other visible injury, it might be useful to 
take a digital picture of the affected area to send to the sponsor. By signing this consent, you 
authorize the study doctor or study staff to take such a picture and provide it to the sponsor.  Every 
effort will be made to protect your identity if a photograph is necessary. 
 
ADDITIONAL RISKS OR DISCOMFORTS 
Blood Samples (taken by single needle-sticks or by a tube that is left in your arm): 
 
There may be side effects of having blood drawn such as: 
 
• 
Fainting 
• 
Redness 
• 
Pain 
• 
Bruising 
• 
Bleeding 
• 
Infection 
• 
Blood clots, which may cause inflammation, swelling and pain 
• 
Nerve damage 
 
If you feel faint tell the study staff right away. 
 
Risks of Using an Intravenous (IV) Catheter for blood draws: 
 
•         Infection 
•         Pain 
•         Redness 
•         Bruising 
•         Vein irritation from the fluids or medication being given 
•         Local swelling due to IV fluid (saline) accidentally entering the tissue rather than the vein 
•         Blood clots, which may cause inflammation, swelling and pain 
 
Electrocardiogram (ECG): 
 
The ECG test is a recording of the electrical activity of your heart.  The sticky pads used may be cold 
when applied and sometimes cause some discomfort such as redness or itching.  If the hair under the 
patches needs to be shaved, irritation from shaving also could occur. 
 
Fasting 
 
Fasting could cause dizziness, headaches, stomach discomfort or fainting 
 


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15 June 2017 
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CONFIDENTIAL  
Pregnancy/Birth Control 
 
Participation in this study may involve unforeseen risks to you or your baby if you become pregnant 
during the study.  Females must not be able to physically have children or must use an appropriate 
method of birth control, as described below. 
 
If you are a man, it is suggested that you use birth control if you choose to have sex with women 
while in this study.  
 
Methods of birth control for this study include: 
 
• 
Postmenopausal (at least 1 years 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 
• 
Double barrier (diaphragm with spermicide; condoms with spermicide) 
• 
Intrauterine device (IUD) 
• 
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 
 
If you are a woman and have discontinued the use of implanted, intrauterine, or injected hormonal 
contraceptives, you must not have used any within 6 months before the first dose of study drug. 
 
If you are a woman and have discontinued the use of oral, patch, or vaginal hormonal contraceptives, 
you must not have used any within 3 months before the first dose of study drug. 
 
Even if you use birth control during the study, there is a chance you could become pregnant. You 
cannot be in the study if you are pregnant. If you are pregnant or become pregnant during the study, 
the study drug may involve unforeseeable risks to the unborn baby. 
 
A pregnancy test can be wrong, especially if it is early in the pregnancy. If you become pregnant 
during the study, inform the investigator at once. 
 
You cannot be in the study if you are breastfeeding. It is not known whether the study drug is safe for 
breast fed babies.  
 
POSSIBLE BENEFITS OF THE STUDY 
You will get no medical benefit from this study.  You may receive a chance to be in a research study 
that may help others.   
 
 
16. ALTERNATIVES TO PARTICIPATING IN THE STUDY   
Since this study is for research only, the only other choice would be not to be in the study.   
 


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CONFIDENTIAL  
CONFIDENTIALITY  
Your records of being in this study will be kept private except when ordered by law. The following 
people will have access to your study records: 
 
• 
The investigator 
• 
Sponsor company or research institution [including monitor(s) and auditor(s)] 
• 
The United States Food and Drug Administration (FDA) 
• 
Other state or federal regulatory agencies 
• 
IntegReview IRB 
 
The Institutional Review Board (IRB), IntegReview, and accrediting agencies may inspect and copy 
your records, which may have your name on them. Therefore, total confidentiality cannot be 
guaranteed. If the study results are presented at meetings or printed in publications, your name will 
not be used. 
 
IN CASE OF STUDY RELATED INJURY 
If you are injured while in this study, you should contact the study investigator as soon as possible in 
person or at the telephone number listed on page one of this consent form. Medical care may be 
obtained in the same way you would ordinarily obtain other medical treatment. If you suffer a study-
related injury, the reasonable costs of necessary medical treatment of the injury will be reimbursed 
by the study sponsor to the extent these costs are not covered by your insurance or other third party 
coverage.  No other form of compensation is offered.  A study-related injury is a physical injury 
that is directly caused by the study drug given as described in the study protocol or by medical 
procedures that are required by the study and that are not standard of care. 
 
Please be aware that some insurance plans may not pay for research-related injuries.  You should 
contact your insurance company for more information. 
 
LEGAL RIGHTS 
You will not lose any of your legal rights by signing this consent form. 
 
CONTACT INFORMATION 
If you have questions, concerns, or complaints about this study or to report a study related injury, 
contact: 
 
George J. Atiee, M.D., or a member of the study staff at 
(210) 635-1500, Monday-Friday between 8:00 am-5:00 pm  
(210) 426-5342 after hours 
 
If you feel this emergency may be life-threatening, call 911. 
 


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CONFIDENTIAL  
If you are unable to reach anyone at the number(s) listed above and you require immediate 
(life threatening) medical attention, please go to the nearest emergency room. 
 
If you do not want to talk to the investigator or study staff, if you have concerns or complaints about 
the research, or to ask questions about your rights as a study subject you may contact IntegReview.  
IntegReview’s policy indicates that all concerns/complaints are to be submitted in writing for review at 
a convened IRB meeting to: 
 
                    Mailing Address:            OR            Email Address: 
Chairperson 
IntegReview IRB 
3815 S. Capital of Texas Highway 
Suite 320 
Austin, Texas 78704 
integreview@integreview.com 
 
If you are unable to provide your concerns/complaints in writing or if this is an emergency situation 
regarding subject safety, contact IntegReview at: 
 
512-326-3001 or  
toll free at 1-877-562-1589 
between 8 a.m. and 5 p.m. Central Time  
IntegReview has approved the information in this consent form and has given approval for the 
investigator to do the study. This does not mean IntegReview has approved your being in the study.  
You must consider the information in this consent form for yourself and decide if you want to be in 
this study. 
PAYMENT FOR BEING IN THE STUDY 
You may receive up to $2000.00 for being in this study.  This money covers the costs for time spent 
at the clinic and is to help cover travel expenses to and from Worldwide Clinical Trials.  If you 
choose to leave or are withdrawn by the study staff before finishing all study procedures, you will be 
paid a lesser amount that is based on the completed visits made to Worldwide Clinical Trials. If you 
take study drug, you will be paid as listed below, for each completed visit: 
 
• 
$150.00 for each overnight stay (10 total) 
 
If you successfully complete the entire study, you will receive up to an additional $500.00: 
 
• 
$500.00 for completion of entire study (all visits) 
 
You will not be paid for the screening visit.   
 
Should you be required to stay additional time in the research unit for safety follow up you will be 
compensated for your time based on the overnight compensation of $150.00 per overnight.  


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CONFIDENTIAL  
No other payment will be offered to you.  You will receive your payment within two weeks of your 
final study visit. 
 
If you are a backup subject who has to stay the night in the clinic, you will be paid $75.00.  If you do 
not have to stay the night, you will be paid $25.00.  
 
You must follow the Worldwide Clinical Trials inpatient clinic rules of conduct while you are taking 
part in this study. If you do not follow the rules, part of your payment (not to exceed the amount of 
the additional payment) may be taken away. You may not be able to take part in other studies at 
Worldwide Clinical Trials. These rules will be reviewed with you at the screening visit and are 
available on the Worldwide Clinical Trials website. 
 
You may be required to report the payment received for this study to the Internal Revenue Service as 
taxable income. 
 
VOLUNTEERING TO BE IN THE STUDY 
It is your choice if you want to be in the study.  No one can force you to be in the study. You may not 
want to be in this study or you may leave the study at any time without penalty or loss of benefits to 
which you are otherwise entitled. If you break the study rules you may be discontinued from this 
study. If you break the study rules leaving the impression you may not be a compliant participant you 
may not be allowed to participate in Worldwide Clinical Trials studies for a period of time or in 
some cases you may not be allowed to participate in any future Worldwide Clinical Trials studies. 
All participants are considered a back-up until told otherwise. No one can be sure they will be in a 
study.   
 
The investigator, the sponsor company, IntegReview, or the FDA may take you out of the study 
without your permission, at any time, for the following reasons: 
 
• 
If you do not follow the investigator’s instructions  
• 
If we find out you should not be in the study 
• 
If the study is stopped 
• 
If it becomes harmful to your health 
 
If you leave the study or if you are taken out of the study, you may be asked to return for a final visit 
to have some end of study evaluations or tests. If information generated from this study is published 
or presented, your identity will not be revealed. If you leave the study, no more information about 
you will be collected for this study. However, all of the information you gave us before you left the 
study will still be used.  
 
ADDITIONAL COSTS 
There is no cost to you during the study for any of the following: 
 
• 
Any study test or procedure, including physical exam and blood tests 
• 
Study drug 


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CONFIDENTIAL  
 
NEW FINDINGS 
If there is new information or any significant new findings that could relate to your willingness to 
continue participation we will tell you.  You can then decide if you still want to be in the study.   
 
THE REASON FOR INSTITUTIONAL REVIEW BOARDS AND INFORMED CONSENT 
What is a consent form? 
The informed consent document contains information required by federal regulations.  The informed 
consent document must be approved by an Institutional Review Board (IRB). 
 
What is an Institutional Review Board (IRB)? 
An Institutional Review Board (IRB) is a group of people that reviews research studies.  The main 
goal of this review is to protect the rights and well-being of the human subjects participating in 
research studies. 
 
IntegReview, the IRB for this study 
IntegReview is an IRB whose board members provide IRB services across the United States, Canada, 
Latin America, and Japan. 
 
To meet requirements of the law, the IntegReview Boards currently include:  
 
• 
Doctors  
• 
Pharmacists  
• 
Nurses  
• 
Toxicologists (people who study the harmful effects of chemicals)  
• 
Other specialists 
• 
Others who do not have a background in science/medicine 
 
AGREEMENT TO BE IN THE STUDY 
 
This consent form contains important information to help you decide if you want to be in the study.  
If you have any questions that are not answered in this consent form, ask one of the study staff.  
 
Please answer YES or NO to the following questions: 
 
A. 
Is this document in a language you understand?  
 
 
 
 
 
 
B. 
Do you understand the information in this consent form? 
 
 
 
 
 
C. 
Have you been given enough time to ask questions and talk about the study? 
 
 
 


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CONFIDENTIAL  
D. 
Have all of your questions been answered to your satisfaction?  
 
 
 
 
E. 
Do you think you received enough information about the study?  
 
 
 
 
F. 
Do you volunteer to be in this study of your own free will and without being  
pressured by the investigator or study staff? 
 
 
 
 
 
 
 
G. 
Do you know that you can leave the study at any time without giving 
a reason and without affecting your health care?  
 
 
 
 
 
 
H. 
Do you know that your health records from this study may be reviewed 
by the sponsor company and by government authorities?  
 
 
 
 
 
I. 
Do you know that you cannot be in another study while you are in this study? 
 
 
 
 
 
 
IF YOU ANSWERED “NO” TO ANY OF THE ABOVE QUESTIONS, 
OR YOU ARE UNABLE TO ANSWER ANY OF THE ABOVE QUESTIONS, 
YOU SHOULD NOT SIGN THIS CONSENT FORM. 
 
You will be given a signed and dated copy of this consent form to keep. 
 
 
 
Printed Name of Adult Study Subject 
 
 
Signature of Adult Study Subject 
Date 
Time (24-hour clock) 
  
 
 
Printed Name of Person Explaining Consent Form 
 
 
 
Signature of Person Explaining Consent Form 
Date  
Time (24-hour clock)